( 12 ) United States Patent ( 10 ) Patent No .: US 10,786,501 B2 Rajasekhar Et Al

US010786501B2

( 12 ) United States Patent ( 10 ) Patent No .: US 10,786,501 B2 Rajasekhar et al . ( 45 ) Date of Patent : * Sep . 29 , 2020

( 54 ) TREATMENT OF PROSTATE CANCER 7,056,927 B2 6/2006 Guo et al . 7,176,211 B2 2/2007 Guo et al . 7,300,935 B2 11/2007 Cho et al. ( 71 ) Applicants: Myovant Sciences GmbH , Basel ( CH ) ; 7,419,983 B2 9/2008 Guo et al . Takeda Pharmaceutical Company 7,569,570 B2 8/2009 Furuya et al . Limited , Osaka ( JP ) 8,058,280 B2 11/2011 Cho et al. 8,735,401 B2 5/2014 Cho et al. ( 72 ) Inventors : Vijaykumar Reddy Rajasekhar, Apple 8,765,948 B2 7/2014 Gallagher et al . 9,346,822 B2 5/2016 Cho et al. Valley, CA (US ); Brendan Mark 9,382,214 B2 7/2016 Gallagher et al . Johnson , Chapel Hill , NC ( US ) ; David 9,422,310 B2 8/2016 Beaton et al . B. MacLean , Cambridge , MA (US ); 9,758,528 B2 9/2017 Fukuoka et al . Lynn Seely , San Mateo , CA ( US ) ; Paul 10,150,778 B2 12 /2018Mwa N. Mudd , Jr., Cary, NC ( US ) 10,449,191 B2 10/2019 Rajasekhar et al . 2009/0048273 Al 2/2009 Furuya et al . 2011/0172249 Al 7/2011 Kamikawa et al . ( 73 ) Assignees : Myovant Sciences GmbH , Basil ( CH ) ; 2017/0210753 A1 7/2017 Fukuoka et al . Takeda Pharmaceutical Company 2018/0036250 A1 2/2018 Yamane et al. Limited , Osaka ( JP ) 2018/0319816 A1 11/2018 Miwa et al. 2019/0055261 A1 2/2019 Miwa ( * ) Notice : Subject to any disclaimer , the term of this 2019/0262346 Al 8/2019 Johnson et al . patent is extended or adjusted under 35 U.S.C. 154 ( b ) by 0 days. FRENPATENT DOCUMENTS This patent is subject to a terminal dis CA 27822341 9/2016 claimer. WO W -2126931 3/2010 WO W -2145116442 4/2014 WO W - 201511483 4/2014 ( 21 ) Appl . No .: 16 /563,161 WO W - 2016 / 1368441 9/2016 WO W - 2018 6050A2 4/2018 ( 22 ) Filed : Sep. 6 , 2019 WO W - 2018 / 65013 4/2018 ( 65 ) Prior Publication Data THERPUBLICATIONS US 2020/0129507 A1 Apr. 30 , 2020 Albertsen , P.C. et al . ( 2014 ) . “ Cardiovascular Morbidity Associated with Gonadotropin Releasing Hormone Agonists and an Antago Related U.S. Application Data nist, ” Europ. Urology 65 : 565-73 . ( 63 ) Continuation of application No. 16 / 369,729 , filed on Amory, J.K. et al. ( 2002 ) . “ Preoperative Supraphysiological Tes tosterone in Older Men Undergoing Knee Replacement Surgery ,” J Mar. 29 , 2019 , now Pat. No. 10,449,191 , which is a Am Geriatr Soc . 50 ( 10 ) : 1698-1701. continuation of application No. PCT / EP2017 / cancer.org ( 2018 ) . “ Hormone Therapy for Prostate Cancer , ” located 074849 , filed on Sep. 29 , 2017 . at https://www.cancer.org/cancer/prostate cancer treating/ hormone ( 60 ) Provisional application No. 62 / 402,004 , filed on Sep. therapy.html, 8 total pages . 30 , 2016 , provisional application No. 62 / 402,150 , ( Continued ) filed on Sep. 30 , 2016 . Primary Examiner — Raymond J Henley, III ( 51 ) Int . Ci . ( 74 ) Attorney , Agent , or Firm — Cooley LLP A61K 31/517 ( 2006.01 ) A61K 31/4164 ( 2006.01 ) ( 57 ) ABSTRACT A61K 31/501 ( 2006.01 ) Methods for treating prostate cancer , including advanced prostate cancer, in a subject in need thereof, include admin A61P 35/00 ( 2006.01 ) istering once - daily to the subject, at least 80 mg of N-( 4 A61K 31/513 ( 2006.01 ) ( 1- (2,6 - difluorobenzyl) -5- (dimethylamino )methyl ) -3- ( 6 A61K 9/00 ( 2006.01 ) methoxy - 3 -pyridazinyl ) -2,4 - dioxo - 1,2,3,4 - tetrahydrothieno A61K 31/4166 ( 2006.01 ) [ 2,3 - d ] pyrimidin - 6 - yl ) phenyl ) -N '- methoxyurea , or a ( 52 ) U.S. Cl . corresponding amount of a pharmaceutically acceptable salt CPC A61K 31/501 ( 2013.01 ) ; A61K 9/0053 thereof. Another method includes: administering once - daily ( 2013.01 ) ; A61K 31/4166 ( 2013.01 ) ; A61K to the subject in need thereof, an oral load dose formulation having from 240 mg to 480 mg of N-( 4- (1- ( 2,6 -difluoroben 31/513 ( 2013.01 ) ; A61P 35/00 ( 2018.01 ) zyl) -5 - ( ( dimethylamino )methyl ) -3- (6 -methoxy - 3 -pyridazi ( 58 ) Field of Classification Search nyl ) -2,4 -dioxo - 1,2,3,4 - tetrahydrothieno [2,3 - d ]pyrimidin - 6 CPC A61K 31/517 ; A61K 31/4164 yl ) phenyl )-N '- methoxyurea , or a corresponding amount of a USPC 514 / 260.1 , 389 pharmaceutically acceptable salt thereof; and thereafter See application file for complete search history. administering once - daily to the subject, an oral maintenance dose formulation having 80 mg to 160 mg of N-( 4- ( 1-( 2,6 ( 56 ) References Cited difluorobenzyl) -5- (dimethylamino )methyl ) -3- ( 6 -methoxy 3 -pyridazinyl ) -2,4 - dioxo - 1,2,3,4 -tetrahydrothieno [ 2,3 -d ] U.S. PATENT DOCUMENTS pyrimidin - 6 -yl ) phenyl ) -N ' -methoxyurea , or a corresponding 6,297,379 B1 10/2001 Furuya et al . amount of a pharmaceutically acceptable salt thereof. 6,340,686 B1 1/2002 Furuya et al . 6,849,738 B2 2/2005 Fukuoka et al. 1 , 55Drawing Sheets US 10,786,501 B2 Page 2

( 56 ) References Cited Nakata , D. et al. ( 2014 ) . “ Suppression of the Hypothalamic -Pituitary Gonadal Axis by TAK - 385 ( Relugolix ) , a Novel, Investigational, Orally Active , Small Molecule Gonadotropin - Releasing Hormone OTHER PUBLICATIONS (GnRH ) Antagonist: Studies in Human Gnrh Receptor Knock - In Mice, ” Eurp . J. Pharmacol. 723 : 167-74 . clinicaltrials.gov ( 2016 ) . Bioavailability and Effect of Food on Notice of Allowance dated Jun . 18 , 2019 , for U.S. Appl. No. TAK - 385 Tablet Formulations in Healthy ParticipantsStudy Results 16 / 369,729 , filed Mar. 29 , 2019 , 7 pages . Clinical Trials.gov, located at https://www.clinicaltrials.gov/ct2/show/ Paller, C.J. et al . ( 2013 ) . “ Management of Biochemically Recurrent results /NCT02396147 ? term = relugolix & rank = 9 , 8 total pages. Prostate Cancer after Local Therapy: Evolving Standards of Care clinicaltrials.gov ( 2016 ) . NCT02135445 , located at https : //clinicaltrials . and New Directions, ” Clin . Adv . Hematol. Oncol . 11 : 14-23 . gov /archive /NCT02135445 / 2016_06_02, 6 total pages . clinicaltrialss.gov . ( 2016 ) . NCT02083185 , located at https: // clinicaltrials. Prostate Cancer UK ( 2018 ) . Locally Advanced Prostate Cancer, gov /archive /NCT02083185 / 2016_06_02, 4 total pages . located at https://prostatecanceruk.org/media/2491080/locally Crawford ( 2011 ) . " A Phase III Extension Trial With a 1 - Arm advanced_prostate_cancer -ifm.pdf , 12 total pages. Crossover From Leuprolide to Degarelix: Comparison of Gonadotropin Shore , N. et al . ( 2016 ) . “ PD28-01 Testosterone Lowering , PSA Releasing Hormone Agonist and Antagonist Effect on Prostate Response and Quality of Life in Patients with Advanced Hormone Cancer, " J Urol. 186 ( 3 ) : 889-97 . Sensitive Prostate Cancer Receiving TAK - 385 , an Oral GnRH Crawford et al . ( 2014 ) . “ The Role of the FSH System in the Antagonist: Phase 2 Interim Analysis , ” Journal of Urology 195 ( 4S Development and Progression of Prostate Cancer ,” The American Suppl ) : e654 , 1 total page . Journal of Hematology /Oncology 10 : 5-13 . Shore , N. et al . ( 2015 ) . “ S474 Abstracts 2502 : TAK - 385, an Oral Crawford et al . ( 2017 ) . “ The Potential Role of Follicle - Stimulating GnRH Antagonist: Efficacy and Safety Results from a Randomized Hormone in the Cardiovascular, Metabolic , Skeletal, and Cognitive Phase 2 Trial in Prostate Cancer Patients (pts ), " 8049 : 31324-7 . Effects Associated with Androgen Deprivation Therapy, ” Urologic Takeda Press Release. ( 2016 ) . Roivant Sciences and Takeda Launch Oncology : Seminars and Original Investigations 35 : 183-91 . Myovant Sciences to Develop Innovative Therapeutics for Wom Dandona, P. et al . ( 2010 ) . “ A Practical Guide to Male Hypogonad en's Health and Prostate Cancer, located at https://www.takeda.com/ ism in the Primary Care Setting , ” Int . J. Clin . Pract . 64 : 682-96 . newsroom /newsreleases / 2016 / roivant -sciences -and -takeda -launch Hoare D. et al . ( 2015 ) . “ Serum Follicle - Stimulating Hormone myovant- sciences - to -develop -innovative -therapeutics - for -womens Levels Predict Time to Development of Castration - Resistant Pros health - and - prostate - cancer /, 2 total pages . tate Cancer , ” Can Urol Assoc J. 9 : 122-71 . Tanaka, A. et al . ( 2009 ) . “ Pharmacological Profile of TAK - 385 , an International Search Report dated Mar. 28 , 2018 , for PCT Appli Orally Active Gonadotropin Releasing Hormone (GnRH ) Antago cation No. PCT / EP2017 / 074849 , filed on Sep. 29 , 2017 , 5 pages . nist, ” Fertility & Sterility P - 86 , p . S113 . Maclean , D.B. et al . ( 2015 ) . “ Medical Castration Using the Inves Texas Oncology ( 2019 ) . Recurrent Prostate Cancer , located at tigational Oral GnRH Antagonist TAK - 385 ( Relugolix ): Phase 1 https://www.texasoncology.com/types-of-cancer/prostate-cancer/ Study in Healthy Males ,” Journal of Clinical Endocrinology and recurrent -prostate - cancer, 5 total pages . Metabolism 100 : 4579-87 . Tombal, B. et al . ( 2010 ) . “ Additional Analysis of the Secondary End Maggio , M. et al . ( 2012 ) . “ Effects of Testosterone Supplementation Point of Biochemical Recurrence Rate in a Phase 3 Trial ( CS21 ) on Clinical and Rehabilitative Outcomes in Older Men Undergoing Comparing Degarelix 80 mg Versus Leuprolide in Prostate Cancer On - Pump CABG ,” Conte . Clin . Trials 33 : 730-38 . Patients Segmented by Baseline Characteristics, ” Eur Urol 57 (5 ) :836 Magnan , S. et al . ( 2015 ) . “ Intermittent vs Continuous Androgen 42 . Deprivation Therapy for Prostate Cancer: A Systematic Review and Travison , T.G. et al . ( 2017 ) . " Harmonized Reference Ranges for Meta - analysis ," JAMA Oncol . 1 : 1261-69 . Circulating Testosterone Levels in Men of Four Cohort Studies in Matrana , M.R. ( 2017 ) . “ LATITUDE and STAMPEDE Trials Pre the United States and Europe, " J. Clin . Endocrinol . Metab . 102 : 1161 sented at ASCO 2017 Offer Refreshing , Practicing - Changing Alter 73 . natives to Upfront Docetaxel for Men with High - Risk Metastatic Tsumura , H. et al . ( 2015 ) . “ Recovery of Serum Testosterone Fol Prostate Cancer, but Questions Remain , ” Med . & Surg . Urol. lowing Neoadjuvant and Adjuvant Androgen Deprivation Therapy 6 : 1000e120 . in Men Treated with Prostate Brachytherapy , ” World J. Radiol . Miranda , E.P. et al . ( 2017 ) . “ MP91-10 Testosterone Recovery 7 : 494-500 . Profiles after Cessation of Androgen Deprivation Therapy, ” J. Urol. Urology Care Foundation ( 2018 ) . “ What Is Advanced Prostate 197 ( 45 ) : e1221 - e1222 , 2 total pages . Cancer, ” located at https://www.urologyhealth.org/urologic-conditions/ Miwa , K. et al . ( 2011 ) . “ Discovery of 1- { 4- [ 1-( 2,6 - difluorobenzyl ) advanced - prostate - cancer, 15 total pages . 5 - [ ( dimethylamino )methyl ] -3-( 6 -methoxypyridazin - 3 - yl) -2,4 -dioxo WebMD ( 2019 ) . “ Advanced Prostate Cancer : Frequently Asked 1,2,3,4 - tetrahydrothieno [ 2,3 - d ] pyrimidin - 6 - yl ] phenyl ) -3 Questions, ” 3 total pages . methoxyurea ( TAK - 385 ) as a Potent , Orally Active , Non -Peptide Wessler, J.D. et al . ( 2013 ) . “ The P -Glycoprotein Transport System Antagonist of the Human Gonadotropin -Releasing Hormone Recep and Cardiovascular Drugs, " JACC 61 : 2495-02 . tor, " J. Med . Chem . 54 : 4998-12 . Written Opinion of the International Searching Authority dated Mar. Moul , J.W. ( 2015 ) . “ Hormone Naïve Prostate Cancer : Predicting 28 , 2018 , for PCT Application No. PCT / EP2017 / 074849 , filed on and Maximizing Response Intervals ,” Asian J Androl. 17 : 929-35 . Sep. 29 , 2017 , 8 pages . U.S. Patent Sep. 29 , 2020 Sheet 1 of 55 US 10,786,501 B2

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want part US 10,786,501 B2 1 2 TREATMENT OF PROSTATE CANCER initial increase in hormones caused by GnRH agonists leads to a temporary worsening of symptoms known as a clinical CROSS - REFERENCE TO RELATED flare, such as an increase in bone pain and , more seriously, APPLICATIONS spinal cord compression . The effectiveness of GnRH agonist 5 therapy does not begin to appear until about 3 to 4 weeks This application is a continuation application of U.S. after the initial dose . In addition , known GnRH agonists are patent application Ser. No. 16 / 369,729 , filed Mar. 29 , 2019 , peptides that are unable to be administered orally and must now issued as U.S. Pat. No. 10,449,191 , which is a con be administered subcutaneously ( SC ) , intravenously ( IV ) , tinuation application of International Application No. PCT / intramuscularly , or intranasally. Often these GnRH agonists EP2017 / 074849 , filed Sep. 29 , 2017 , which claims priority 10 are administered as depot formulation once every 1-3 to U.S. Provisional Application No. 62 / 402,150 , filed Sep. months. Consequently, development is needed for a new 30 , 2016 , and U.S. Provisional Application No. 62 / 402,004 , filed Sep. 30 , 6 , the disclosures of which are incorpo treatment that is easy and convenient to administer, does not rated herein by reference in their entireties . cause clinical flare , and which allows for suspension of 15 treatment for a variety of time periods, and an increase in serum testosterone levels over a short period of time once FIELD treatment is suspended . The present disclosure relates to methods for treating prostate cancer , including advanced prostate cancer and BRIEF SUMMARY OF THE DISCLOSURE hormone dependent or sensitive prostate cancer , in a subject 20 by an oral formulation . It also includes the treatment of men One aspect of the disclosure relates to a method for with castration - resistant prostate cancer . In particular, the treating prostate cancer in a subject in need of an increase in present disclosure relates to methods for suppressing one or serum testosterone levels to a level above 50 ng / dL , the more sex hormones in a subject, by once - daily oral admin method comprising administering to the subject once - daily istration of a dosage form . The present disclosure also 25 an oral formulation comprising about 80 mg to about 480 mg relates to a dosage pack having a separate oral load dose of Compound 1 : N-( 4- ( 1-( 2,6 -difluorobenzyl ) -5- (dimethyl formulation and oral maintenance dose formulation . amino )methyl ) -3-( 6 -methoxy - 3 -pyridazinyl )-2,4 - dioxo - 1,2 , 3,4 - tetrahydrothieno [ 2,3 - d ]pyrimidin -6 - yl ) phenyl ) -N' BACKGROUND methoxyurea , or a corresponding amount of a 30 pharmaceutically acceptable salt thereof, wherein when the Prostate cancer is the second most prevalent form of once - daily administration is suspended for a suspension cancer in men and the second leading cause of death due to period , the subject experiences an increase of serum testos cancer in men in the United States . According the terone levels . National Cancer Institute , approximately 2.9 million men Another aspect of the disclosure relates to a method for are currently living with prostate cancer in the United States, 35 treating prostate cancer in a subject in need thereof, the and approximately 180,000 men are newly diagnosed in the method comprising administering to the subject once -daily United States each year. an oral formulation comprising about 80 mg to about 480 mg After diagnosis of prostate cancer , treatments generally of Compound 1 , or a corresponding amount of a pharma androgeninclude combinations deprivation oftherapies surgery, andor ADTradiation, are therapyalso used , but. 40 ceutically acceptable salt thereof; suspending administration Prostate cancer is responsive to surgical castration and the of the oral formulation for a suspension period to allow for effectiveness of this therapy results from the elimination of an increase of serum testosterone levels , and resuming androgens . An androgen may refer to any natural or syn administering to the subject once -daily the oral formulation thetic compound, usually a steroid hormone, which stimu at the end of the suspension period . lates or controls the development and maintenance of male 45 One aspect of the disclosure relates to an oral formulation characteristics in vertebrates by binding to androgen recep comprising about 80 mg to about 480 mg of Compound 1 , tors . Androgens include testosterone , dihydrotestosterone or a corresponding amount of a pharmaceutically acceptable ( DHT ) , dehydroepiandrosterone, and androstenedione . Most salt thereof, for use in a method of treating prostate cancer prostate cancers are androgen dependent and androgens, in a subject in need thereof. such as testosterone , promote the growth of cancerous 50 Another aspect of the disclosure relates to an oral formu prostate cells . ADT drastically reduces serum testosterone lation comprising about 80 mg to about 480 mg of Com levels , blocks androgen receptor signaling, and delays pros pound 1 , or a corresponding amount of a pharmaceutically tate cancer progression. ADT serves as alternative to surgi acceptable salt thereof, for use in a method for treating cal castration and is valuable in the treatment of prostate prostate cancer in a subject in need thereof, the method cancer . 55 comprising: administering the oral formulation to the subject Castration by orchiectomy or a gonadotropin -releasing once daily; suspending administration of the oral formula hormone ( GnRH ) agonist ( GnRH receptor agonist ) is the tion for a suspension period to allow for an increase of serum main mode of therapy for localized progressive and meta testosterone levels ; and resuming administering to the sub static cancers , and GnRH agonists , such as leuprolide ject once daily the oral formulation at the end of the acetate , are widely used . When multiple doses of a GnRH 60 suspension period. agonist are administered , a temporary increase in gonado In certain embodiments of any of the foregoing or fol tropin secretion occurs . That is followed by a decrease in lowing , after the suspension period, once -daily administra responsiveness ( desensitization ) in the pituitary gland and a tion of the oral formulation of the disclosure is not resumed . decrease in secretion of the pituitary sex hormones , such as In certain embodiments of any of the foregoing or fol luteinizing hormone ( LH ) and follicle - stimulating hormone 65 lowing , the serum testosterone level increases to above ( FSH ) , which results in the decrease of sex hormones medical castration level . In some embodiments, the serum produced by the testes , such as testosterone and DHT . The testosterone level increases to greater than about 55 ng / dL or US 10,786,501 B2 3 4 to greater than about 350 ng / dL . In certain embodiments, the suspension period may be discontinued when the subject's serum testosterone level increases to about 300 ng / dL to PSA level is 3 ng /mL , 210 ng /mL , 220 ng /mL , or 230 about 600 ng/ dL . ng /mL . In some embodiments of any of the foregoing or follow In certain embodiments of any of the foregoing or fol ing , the serum testosterone level increases to the subject's 5 lowing , the oral formulation is administered once - daily for serum testosterone level prior to once - daily administration 12 consecutive weeks or greater, for 24 consecutive weeks of the oral formulation of the disclosure . In certain embodi or greater, for 48 consecutive weeks or greater, for 52 ments of any of the foregoing or following, the serum consecutive weeks or greater, for 72 consecutive weeks or testosterone level increases to the subject's serum testoster greater, or for 96 consecutive weeks or greater. one level prior to once -daily administration of the oral 10 In certain embodiments of any of the foregoing or fol formulation of the disclosure within 7 days of the beginning lowing , once -daily administration of an oral formulation of of the suspension period . In certain embodiments of any of the disclosure is suspended after at least 24 consecutive the foregoing or following, the serum testosterone level weeks of treatment, at least 36 consecutive weeks of treat increases to the subject's serum testosterone level prior to ment, or at least 52 consecutive weeks of treatment . once - daily administration of the oral formulation of the 15 In certain embodiments of any of the foregoing or fol disclosure within 45 days of the beginning of the suspension lowing , the subject is in need of an increase in serum period. testosterone levels due to an intercurrent illness , receiving In some embodiments of any of the foregoing or follow radiation therapy, while bedridden , having suffered an ing , the prostate cancer is hormone dependent prostate 20 injury, having a surgical procedure or other invasive proce cancer. In certain embodiments , the prostate cancer is dure , or a desire for a period of restored sexual function . In advanced prostate cancer . In some embodiments , the pros some embodiments, the subject is in need of an increase in tate cancer is metastatic, non -metastatic , locally advanced , serum testosterone levels due to an intercurrent illness or advanced hormone sensitive , advanced castration resistant, surgical or other invasive procedure with projected full or recurrent . In certain embodiments, the prostate cancer is 25 recovery time of at least two weeks . In certain embodiments, castration - resistant metastatic prostate cancer . In some once - daily administration of the oral formulation of the embodiments, the prostate cancer is castration - resistant non disclosure is suspended prior to a surgical or other invasive procedure or radiation therapy . In some embodiments, once metastatic prostate cancer . In certain embodiments, the daily administration of the oral formulation of the disclosure prostatecancer. Incancer some isembodiments hormone - sensitive, the prostate metastatic cancer prostate is hor- 30 is suspended after or during the surgical or other invasive mone - sensitive non -metastatic prostate cancer . procedure , injury, or radiation therapy. In certain embodi In certain embodiments of any of the foregoing or fol ments of any of the foregoing or following, once - daily lowing, said administering comprises administration once administration of the oral formulation of the disclosure daily of an oral load dose formulation of from about 240 mg 35 procedureoccurs prior or toradiation and during therapy the andsurgical once -ordaily other administra invasive to about 480 mg of Compound 1 , or a corresponding amount tion of the oral formulation of the disclosure is suspended of a pharmaceutically acceptable salt thereof, for 1-3 days at after the surgery or other invasive procedure or radiation the beginning of treatment. In some embodiments, said therapy. In some embodiments, the surgical procedure is administering comprises administration once - daily of an heart surgery , knee replacement, hip replacement, abdomi oral load dose formulation of from about 240 mg to about 40 nal surgery , pelvic surgery, vascular surgery, spine surgery, 480 mg of Compound 1 , or a corresponding amount of a or an emergency procedure due to injury. In certain embodi pharmaceutically acceptable salt thereof, for 1-3 days at the ments of any of the foregoing or following, the subject is beginning of treatment after the suspension period . In cer identified as at risk for acute postoperative frailty . In some tain embodiments, said administering comprises administra embodiments, once -daily administration of the oral formu tion once - daily of an oral maintenance dose formulation of 45 lation of the disclosure is suspended during the intercurrent from about 80 mg to about 160 mg of Compound 1 , or a illness or while the subject is bedridden . In some embodi corresponding amount of a pharmaceutically acceptable salt ments , once - daily administration of the oral formulation of thereof. In certain embodiments of any of the foregoing or the disclosure is suspended following an accident or injury following, the once - daily oral maintenance dose formulation requiring prolonged recovery . In some embodiments , once administration begins on the day after administering the last 50 daily once - daily administration of the oral formulation of the dose of the once -daily oral load dose formulation . disclosure is suspended following a stroke, cerebral hemor In certain embodiments of any of the foregoing or fol rhage , myocardial infarction , congestive heart failure , hip lowing, the suspension period is up to 52 weeks , up to 36 fracture or other event resulting in limited mobility and weeks, up to 24 weeks , up to 12 weeks , up to 8 weeks , or up requiring prolonged recovery . In certain embodiments , to 4 weeks . 55 once -daily administration of the oral formulation of the In certain embodiments of any of the foregoing or fol disclosure resumes after the subject is recovered from the lowing, the suspension period is discontinued when the intercurrent illness, is no longer bedridden , has resumed subject's prostate - specific antigen ( PSA ) level is 220 % of normal activities of daily living , or has regained a normal the subject's PSA level of the nadir during treatment. In level of function . In some embodiments, the invasive pro some embodiments, the suspension period is discontinued 60 cedure is a colonoscopy, angioplasty, stent placement, endo when the subject's PSA level is 250 % of the subject's PSA vascular coil placement, endovascular aneurysm repair, level prior to treatment. In certain embodiments, the sus endoscopy , laparoscopy, arthroscopy, coronary catheteriza pension period is discontinued when the subject’s PSA level tion , or another cathether -based procedure . is greater than the subjects PSA level at the beginning of the In certain embodiments of any of the foregoing or fol suspension period. In certain embodiments, the suspension 65 lowing , the serum testosterone level is above medical cas period is discontinued when the subject experiences return tration levels within 7 days of the suspension of once - daily of symptoms of prostate cancer . In some embodiments , the administration of the oral formulation of the disclosure . US 10,786,501 B2 5 6 In certain embodiments of any of the foregoing or fol In certain embodiments of any of the foregoing or fol lowing, the oral load dose formulation comprises about 240 lowing , the method or use further comprises suspending mg , about 360 mg , or about 480 mg of Compound 1 , or a once - daily administration of the oral formulation of the corresponding amount of a pharmaceutically acceptable salt disclosure for a subsequent suspension period after comple thereof. In certain such embodiments , the ralad dosetion of the suspension period and resumption of once -daily formulation comprises about 360 mg of Compound 1 , or a administration of the oral formulation of the disclosure . In corresponding amount of a pharmaceutically acceptable salt some embodiments, the subsequent suspension period thereof. occurs at least 12 weeks after resuming once - daily admin istration of the oral formulation comprising about 80 mg to In certain embodiments of any of the foregoing or fol 10 about 480 mg of Compound 1 , or a corresponding amount lowing, the oral maintenance dose formulation comprises of a pharmaceutically acceptable salt thereof. about 80 mg , about 120 mg , or about 160 mg of Compound In certain embodiments of any of the foregoing or fol 1 , or a corresponding amount of a pharmaceutically accept lowing , within about 4 to about 8 days of first administering able salt thereof. In certain such embodiments , the oral once -daily the oral formulation, or oral load dose formula maintenance dose formulation comprises about 120 mg of 15 tion and oral maintenance dose formulation , the serum Compound 1 , or a corresponding amount of a pharmaceu testosterone levels in the subject are at or below medical tically acceptable salt thereof. castration level . In some embodiments , within 4 days of first In certain embodiments of any of the foregoing or fol administering once - daily the oral formulation , or oral load lowing, the oral load dose formulation comprises about 360 dose formulation and oral maintenance dose formulation , mg of Compound 1 , or a corresponding amount of a phar- 20 the serum testosterone levels in the subject are at or below maceutically acceptable at thereof, and administered medical castration level . once on day 1 of treatment, and the oral maintenance One aspect of the disclosure relates to use of Compound formulation comprises about 120mg of compound 1,0 1 , or a pharmaceutically acceptable salt thereof, for the corresponding amount of a pharmaceutically acceptable salt manufacture of a medicament for the treatment of prostate thereof, and is administered once - daily. 25 cancer . In certain such embodiments, the prostate cancer is In certain embodiments of any of the foregoing or fol hormone dependent prostate cancer, advanced prostate can lowing, the oral formulation comprises about 80 mg to about cer, metastatic, non -metastatic , locally advanced , advanced 160 mg of Compound 1 , or a corresponding amount of a hormone sensitive , advanced castration resistant, recurrent, pharmaceutically acceptable salt thereof. castration - resistant metastatic prostate cancer, castration In certain embodiments of any of the foregoing or fol- 30 resistant non -metastatic prostate cancer, hormone - sensitive lowing, the administering is pre - prandial. In some embodi metastatic prostate cancer , or hormone - sensitive non - meta ments , the administering is at least hour before eating or static prostate cancer . In some embodiments, the medica at least 2 hours after eating . In certain embodi ents, the ment comprises 80 mg to about 480 mg of Compound 1 , or administering is at least 30 minutes before eating or while a corresponding amount of the pharmaceutically acceptable subject is fasting 35 salt thereof. In certain embodiments of any of the foregoing or fol Other objects and advantages of the present disclosure lowing, the oral formulation , oral load dose formulation and will become apparent from the detailed description that oral maintenance dose formulation are immediate release follows. formulations. In certain embodiments of any of the foregoing or fol- 40 BRIEF DESCRIPTION OF THE DRAWINGS lowing, the oral maintenance dose formulation comprises 102 mg to 204 mg of mannitol, 6 mg to 12 mg of hydroxy FIG . 1 graphically depicts mean serum testosterone con propyl cellulose , 10 mg to 20 mg of sodium starch glycolate , centrations for a treatment period of 28 days in accordance 2mg4mgfmagnesium stearate . with Example 6 . One aspect of the disclosure relates to any of the forego- 45 FIG . 2 is a table of individual changes in serum testos ing or following methods or uses further comprising admin terone concentration of each Compound 1 dose level in istering an anti - androgen . In certain such embodiments , the accordance with Example 6 in which the serum testosterone anti- androgen is selected from the group consisting of concentrations are graphically depicted in FIGS . 1 and 7 . flutamide, nilutamide , bicalutamide , enzalutamide , apaluta FIG . 3 graphically depicts mean serum LH concentrations mide, cyproterone acetate , megestrol acetate, chlormadi- 50 for a treatment period (Part A ) in accordance with Example none acetate , spironolactone, canrenone, drospirenone, keto 6 . naze, toplumdeurdi ), and cimetidine. FIG . 4 graphically depicts mean serum FSH concentra In certain embodiments of any of the foregoing or fol tions for a treatment period ( Part A ) in accordance with lowing methods or uses , the methods or uses further com Example 6 . prise administering a CYP17 lyase inhibitor. In certain such 55 FIG . 5 graphically depicts mean serum dihydrotestoster embodiments, the CYP17 lyase inhibitor is abiraterone. one ( DHT ) concentrations for a treatment period ( Part A ) in In certain embodiments of any of the foregoing or fol accordance with Example 6 . lowing, the subject's serum testosterone level is suppressed FIG . 6 graphically depicts mean serum sex hormone prior to and after the suspension of once -daily administra binding globulin ( SHBG ) concentrations for a treatment inftheralformulation the disclosure . 60 period ( Part A ) in accordance with Example 6 . In certain embodiments of any of the foregoing or fol FIG . 7 graphically depicts mean serum testosterone con lowing, the method or use does not comprise administration centrations for a treatment period ( Part B ) in accordance of an anti -androgen . with Example 6 . In certain embodiments of any of the foregoing or fol FIGS . 8A and 8B graphically depict mean serum testos lowing, the method or use does not comprise administration 65 terone concentrations for a treatment period ( Part B ) for 80 of prednisone. In some embodiments , the method or use mg Compound 1 and 120 mg Compound 1 in accordance further comprises administration of prednisone. with Example 6 . US 10,786,501 B2 7 8 FIG.9 graphically depicts mean serum LH concentrations FIG . 29 is a table of mean serum LH concentration - time for a treatment period (Part A ) in accordance with Example data ( IU / L ) for the treatment period ( Part 2 ) in accordance 6 . with Example 7 . FIG . 10 graphically depicts mean serum FSH concentra FIG . 30 graphically depicts mean time - course of serum tions for a treatment period (Part A ) in accordance with 5 testosterone lowering following a multiple dose administra Example 6 . tion of Compound 1 ( Part 2 ) in accordance with Example 7 . FIG . 11 graphically depicts mean serum DHT concentra FIGS . 31A and 31B are a table of mean serum testoster tions for a treatment period ( Part A ) in accordance with one concentration - time data ( nmol /L ) for the treatment Example 6 . period ( Part 2 ) in accordance with Example 7 . FIG . 12 graphically depicts mean serum sex hormone- 10 FIG . 32 is a table of mean serum FSH concentration - time binding globulin ( SHGB ) concentrations at maintenance data ( IU / L ) for the treatment period ( Part 2 ) in accordance doses of 80 mg or 120 mg or a treatment period ( Part A ) in with Example 7 . accordance with Example 6 . FIG . 33 is a table of mean serum dihydrotestosterone FIG . 13 is a table of serum prostate - specific antigen ( PSA ) ( DHT ) concentration - time data ( nmol/ L ) for the treatment and change from the subject's serum PSA level prior to 15 period (Part 2 ) in accordance with Example 7 . treatment commencing with each Compound 1 dose level FIG . 34 is a table of mean serum LH concentration - time ( Part A ) in accordance with Example 6 . data ( IU / L ) for the treatment period ( Part 3 ) in accordance FIG . 14 is a table of serum PSA and change from the with Example 7 . subject's serum PSA level prior to treatment commencing FIG . 35 graphically depicts mean time - course of serum with each Compound 1 dose level ( Part B ) in accordance 20 testosterone lowering following a multiple dose administra with Example 6 . tion of Compound 1 ( Part 3 ) in accordance with Example 7 . FIGS . 15A , 15B , and 15C graphically depict mean plasma FIG . 36 is a table of mean serum testosterone concentra concentrations of unchanged Compound 1 for a treatment tion - time data ( nmol/ L ) for the treatment period ( Part 3 ) in period ( Part A ) in accordance with Example 6 . accordance with Example 7 . FIG . 16 is a table of plasma pharmacokinetic ( PK ) param- 25 FIG . 37 is a table of mean serum FSH concentration - time eters of Compound 1 for a treatment period ( Part A ) in data ( IU /L ) for the treatment period ( Part 3 ) in accordance accordance with Example 6 . with Example 7 . FIGS . 17A and 17B graphically depict mean plasma FIG . 38 is a table of mean serum dihydrotestosterone trough concentrations of unchanged Compound 1 for a ( DHT ) concentration - time data (nmol / L ) for the treatment treatment period ( Part B ) in accordance with Example 6 . 30 period ( Part 3 ) in accordance with Example 7 . FIGS . 18A and 18B graphically depict mean plasma FIG . 39 is a table of mean serum LH concentration - time concentration - time profiles of Compound 1 after single oral data ( IU / L ) for the treatment period ( Part 4 ) in accordance dose administration ( Part 1 ) in accordance with Example 7 . with Example 7 . FIG . 19 graphically depicts mean plasma concentration FIG . 40 graphically depicts mean time - course of serum time profiles of Compound 1 after single oral dose admin- 35 testosterone lowering following a multiple dose administra istration ( Part 1 ) under fasted and fed conditions in accor tion of Compound 1 ( Part 4 ) in accordance with Example 7 . dance with Example 7 . FIG . 41 is a table of mean serum testosterone concentra FIG . 20 is a table of mean plasma and urine pharmacoki tion - time data (nmol / L ) for the treatment period ( Part 4 ) in netic ( PK ) parameters following a single oral Compound 1 accordance with Example 7 . dose administration (Part 1 ) in accordance with Example 7. 40 FIG . 42 is a table of mean serum FSH concentration - time FIGS . 21A and 21B graphically depict mean plasma data ( IU / L ) for the treatment period ( Part 4 ) in accordance concentration - time profiles of Compound 1 after single and with Example 7 . multiple oral dose administration ( Part 2 ) in accordance with FIG . 43 is a table of mean serum dihydrotestosterone Example 7 . ( DHT ) concentration - time data ( nmol/ L ) for the treatment FIG . 22 is a table of mean plasma and urine Compound 45 period ( Part 4 ) in accordance with Example 7 . 1 pharmacokinetic ( PK ) parameters obtained after day 1 FIGS . 44A , 44B , 44C , and 44D graphically depict time after oral Compound 1 administration ( Part 2 ) in accordance course of serum testosterone suppression following treat with Example 7 . ment ( Part 2 ) with Compound 1 in healthy men for 14 days FIG . 23 is a table of mean plasma and urine Compound in accordance with Example 7 . 1 pharmacokinetic ( PK ) parameters obtained after day 14 50 FIG . 45 graphically depicts the correlation between serum after multiple oral Compound 1 administration ( Part 2 ) in testosterone suppression and Compound 1 steady state expo accordance with Example 7 . sure in healthy men ( Part 2 ) in accordance with Example 7 . FIG . 24 is a table of mean serum LH concentration - time FIGS . 46A , 46B , 46C , and 46D graphically depict the data ( IU / L ) for the treatment period ( Part 1 ) in accordance time - course of serum testosterone suppression following with Example 7 . 55 treatment ( Parts 3 and 4 ) with Compound 1 in healthy men FIG . 25 graphically depicts mean time - course of serum for 28 days in accordance with Example 7 . testosterone lowering following a single dose administration FIGS . 47A and 47B graphically depict the percent of of Compound 1 ( Part 1 ) in accordance with Example 7 . subjects reaching serum testosterone below castration levels FIG . 26 is a table of mean serum testosterone concentra after 28 days of treatment ( Parts 3 and 4 ) with Compound 1 tion - time data ( nmol/ L ) for the treatment period ( Part 1 ) in 60 in accordance with Example 7 . accordance with Example 7 . FIG . 48 graphically depicts the correlation between serum FIG . 27 is a table of mean serum FSH concentration - time testosterone suppression and Compound 1 steady state expo data ( IU / L ) for the treatment period ( Part 1 ) in accordance sure in healthy men (Parts 3 and 4 ) in accordance with with Example 7 . Example 7 . FIG . 28 is a table of mean serum dihydrotestosterone 65 FIG . 49 is a table of castration and profound castration ( DHT ) concentration - time data ( nmol / L ) for the treatment rate data for Compound 1 compared to degarelix in accor period ( Part 1 ) in accordance with Example 7 . dance with Example 9. CI = confidence interval, Q4W Fonce= US 10,786,501 B2 9 10 every 4 weeks, QD = daily . ( a ) Castration rate was defined as static prostate cancer, or hormone - sensitive non -metastatic the estimated proportion of patients who have serum testos prostate cancer . After administration to a subject, formula terone concentrations < 50 ng / dL at all scheduled visits Week tions comprising Compound 1 , or a pharmaceutically 5 , Day 1 to specific timepoint (Week 25 , Day 1 ) . ( b ) The acceptable salt thereof, rapidly inhibit production of sex 2 - sided 95 % CI was calculated using the normal approxi- 5 hormones, such as testosterone, LH , and FSH , and are not mation method , if the number of non - castration patients associated with an initial aggravation of symptoms, also was = 5 in any treatment arm , the exact CI was presented . ( c ) known as clinical or hormonal flares . Profound castration rate was defined as the estimated pro Unlike GnRH agonists such as leuprolide acetate , Com portion of patients who had serum testosterone concentra pound 1 , or a pharmaceutically acceptable salt thereof, is tions < 20 ng / dL at all scheduled visits Week 13 , Day 1 10 present in an oral formulation and is not a depot, or a through specific timepoint (Week 25 , Day 1 ) . slow - release formulation and , once treatment is suspended , FIG . 50 graphically depicts a Kaplan -Meier survival hormone levels increase and may return to the subject's curve for time to serum testosterone recovery ( i.e. , the serum hormone levels prior to treatment commencing ( i.e. , subject's serum testosterone level prior to treatment com baseline levels ) after once - daily administration of Com mencing or > 280 ng /dL ) in accordance with Example 9. 15 pound 1 , or a pharmaceutically acceptable salt thereof, is ADT = androgen deprivation therapy , QD = daily, discontinued , thereby providing more control for patients SC = subcutaneous. ( a ) Time to serum testosterone recovery and their physicians. Thus, in contrast to a treatment that was defined as the time from day after the last dose of uses depot injections, the treatment methods and uses of this Compound 1 or 4 weeks plus 1 day after the last dose of disclosure allow for suspension periods in which subjects degrelitorum testosterone recovery.Serum testosteronastoptreatment for a period of time and later restart recovery was defined as back to the subject's serum testos treatment with no adverse effects . Suspension of treatment terone level prior to treatment commencing or > 280 ng/ dL can be planned ( e.g. , in advance of, during or after a whichever occurs first . It was censored for patients starting scheduled surgical or invasive procedure ( e.g. , knee replace alternative ADT without recovery at the last serum testos ment surgery or colonoscopy )) or can be implemented after terone lab assessment before the start of ADT . 25 the subject experiences, for example, intercurrent illness or FIG . 51 is a table of time to serum testosterone recovery injury. In either scenario ( planned or unplanned ), increasing .., the subject's serum testosterone levelprior to treatment the serum testosterone levels aids in recovery or helps to commencing or > 280 ng /dL ) in accordance with Example 9 . maintain the subject's physical health . CI = confidence interval, Max = maximum , Min = minimum , Additionally, in some patients receiving GnRH antago NE = not estimable , Q4W = once every 4 weeks , QD = daily . * 30 nists or GnRH agonists , even after treatment is discontinued indicates a censored observation . ( a ) Time to serum testos for significant time periods, pre - treatment levels of serum terone recovery was defined as the time from 1 day after the testosterone are not achieved . Miranda et al . , The Journal of last dose of Compound 1 or 4 weeks plus 1 day after the last Urology , May 16 , 2017 , Volume 197 , Issue e1221 - e1222 dose of degarelix to serum testosterone recovery . Serum (noting 23 % of patients receiving ADT with a GnRH agonist testosterone recovery was defined as back to the subjects 35 maintained medical castration testosterone levels at 24 serum testosterone level prior to treatment commencingor months after ADT cessation ); Tsumura et al . , World J. > 280 ng /dL whichever occurs first. It was censored for Radiol. , Dec. 28 , 2015 ; 7 ( 12 ) : 494-500 ( noting five years patients starting alternative ADT without recovery at the last after the cessation of GnRH agonist therapy , approximately erum testosterone bassessment before the start of one - fifth of patients still had medical castration testosterone ( b ) Probability of event ( n = number of subjects at risk ). ( c ) 40 levels ) . One of the advantages of Compound 1 , or a phar 4,8 or 12 weeks from 1 day after the last dose of Compound maceutically acceptable salt thereof, is that , as shown in 1 or 4 , 8 or 12 weeks plus 1 day after the last dose of Example 9 and FIGS . 50 and 53 , 43 % of subjects achieve degarelix . ( d ) The 2 - sided 95 % CI for proportion was pre - treatment serum testosterone levels or a serum testos calculated using the normal approximation method . terone level at or above 280 ng / dL by 12 weeks versus only FIG . 52 graphically depicts the PSA reduction provided in 45 5.3 % with degarelix . Example 8 . The disclosure provides methods and uses for treating FIG . 53 graphically depicts the recovery of serum testos prostate cancer in a subject in need thereof comprising terone levels provided in Example 9 . administering, once - daily, formulations comprising Com FIG . 54 graphically depicts the clinical trial detailed in pound 1 , or a pharmaceutically acceptable salt thereof. Example 11. Compound i will be dosed daily ( Day 1 to 50 Subjects treated once -daily with oral formulations compris Week 48 , Day 7 ) . Leuprolide acetate will be dosed every 12 ing Compound 1 , or a pharmaceutically acceptable salt weeks ( Day 1 ; Week 13 , Day 1 ; Week 25 , Day 1 ; and Week thereof, experience an increase in serum testosterone levels 37 , Day 1 ) . * The +60 days and +90 days testosterone after the last dose of the formulation comprising Compound recovery visits will happen with a subset of patients. 1 , or a pharmaceutically acceptable salt thereof. Accord 55 ingly, the disclosure provides methods of using oral formu DETAILED DESCRIPTION lations comprising Compound 1 , or a pharmaceutically acceptable salt thereof, for treating prostate cancer in a Disclosed herein are methods of using an orally active subject in need of an increase in serum testosterone levels to GnRH antagonist (GnRH receptor antagonist ), Compound a level above 50 ng / dL . Once - daily administration of for 1 , or a pharmaceutically acceptable salt thereof, once - daily 60 mulations comprising Compound 1 , or a pharmaceutically for the treatment of prostate cancer . The prostate cancer can acceptable salt thereof, can be suspended for a suspension be hormone dependent prostate cancer , advanced prostate period , leading to an increase in the subject's serum testos cancer, advanced hormone sensitive prostate cancer , meta terone levels shortly after the beginning of the suspension static , non -metastatic , locally advanced, advanced hormone period . For example, for most subjects , serum testosterone dependent, advanced castration resistant, recurrent, castra- 65 levels will increase within 1 week of beginning a suspension tion - resistant metastatic prostate cancer , castration - resistant period. An increase in a subject's serum testosterone level non - metastatic prostate cancer , hormone - sensitive meta can be very beneficial for subjects experiencing an intercur US 10,786,501 B2 11 12 rent illness , receiving radiation therapy, while bedridden , methods and uses allow for suspension of treatment by having suffered an injury, having a surgical procedure or stopping the once -daily administration of the oral formula other invasive procedure , or a desire for a period of restored tions , leading to an immediate rise in serum testosterone sexual function ( e.g. , 25th wedding anniversary ). Higher levels , without adverse effects in response to unexpected serum testosterone levels can be beneficial in such subjects 5 events. Additionally, where upcoming surgeries may be planned , for example a hip or knee replacement, the treat because testosterone has an anabolic effect, helping to ment can be suspended either shortly prior to or at the time rebuild tissues , increase weight and muscle mass , and pro of surgery to ensure optimal recovery of the patient after mote growth and mineralization of bone . Treatment can also surgery and potentially better outcomes due to higher levels be suspended to improve the subject's quality of life and 10 of the anabolic hormone testosterone . The methods and uses energy levels; to help with healing after injury , illness, disclosed herein may allow for resumption of once - daily surgery , or radiation therapy ; to aid subjects in remaining in administration of Compound 1 , or a pharmaceutically control of their lifestyles; and to assist in regaining strength acceptable salt thereof, during the postoperative recovery and mobility after intercurrent illness . Even before serum stage if a subject's prostate cancer begins to worsen or testosterone levels reach the subject's serum testosterone 15 spread . Upon resumption of administration of Compound 1 , level prior to treatment commencing , the benefit of or a pharmaceutically acceptable salt thereof, after Sus increased serum testosterone compared to a medical castra pension period for a surgery, serum testosterone levels tion level may be important in a subject's recovery from , for typically fall to at or below medical castration levels within example , surgery, such as knee replacement or hip surgery about 4 to about 8 days of first administering once - daily an ( whether planned or unplanned ). The contribution of testos 20 oral formulation of the disclosure. As it may take up to one terone to rebuilding tissue and increasing muscle mass can month to observe a decrease in a subject's serum testoster be a factor for successful post - surgery physical therapy and one levels after administering depot formulations of GnRH regaining range of movement, mobility and strength . Once agonists , treatments involving these agonists may not have daily administration of oral formulations comprising Com as much flexibility as treatments involving once - daily pound 1 , or a pharmaceutically acceptable salt thereof, can 25 administrationacceptable salt thereofof Compound. The maximum 1 , or adecline pharmaceutically in PSA , or resume at the end of the suspension period. Alternatively, PSA nadir, may also occur more rapidly with once - daily once -daily administration of oral formulations comprising administration of Compound 1 , or a pharmaceutically Compound 1 , or a pharmaceutically acceptable salt thereof, acceptable salt thereof, after a suspension period than with does not necessarily resume after suspension of once - daily GnRH agonists. Once - daily administration of Compound 1 , administration , for example , if prostate -specific antigen 30 or a pharmaceutically acceptable salt thereof, after sus ( PSA ) levels remain at an acceptable level during the pension period, may result in rapid ( within days ) and com suspension period . plete suppression of FSH unlike the GnRH agonists . Upon initial treatment or resumption of administration of The intermittent therapy allowed by the methods , uses , Compound 1 , or a pharmaceutically acceptable salt thereof, and formulations of this disclosure may prevent the change after a suspension period, serum testosterone levels typically 35 from hormone dependent to androgen independent prostate fall to at or below medical castration levels within about 4 cancer. Androgen independence may be an intrinsic , but to about 8 days of first administering once -daily an oral dormant, property of some prostate cancer cells that is formulation of the disclosure . This is in contrast with activated in response to androgen deprivation . The Com leuprolide and other GnRH agonists . If a subject stops and pound 1 , or a pharmaceutically acceptable salt thereof, restarts treatment with leuprolide , or other GnRH agonists , intermittent therapy disclosed herein could be dosed so that it may take up to one month to observe a decrease in the 40 a complete and continuous androgen deprivation does not subject's serum testosterone levels . Furthermore , the maxi happen, possibly preventing androgen independence. Rather mum decline in PSA , or PSA nadir, occurs more rapidly with than having a steady low level of serum testosterone, Com once - daily administration of Compound 1 , or a pharmaceu pound 1 , or a pharmaceutically acceptable salt thereof, can tically acceptable salt thereof, than with GnRH agonists . allow fluctuations back and forth (many peaks and valleys) Once -daily administration of Compound 1 , or a pharmaceu- 45 with testosterone. “ Intermittent treatment ,” intermittent tically acceptable salt thereof, after a suspension period, also therapy , ” or “ intermittent dosing " may refer to on - again , results in rapid (within days ) and complete suppression of off- again treatment or a " drug holiday . ” An example of FSH unlike the GnRH agonists . There is a correlation intermittent treatment is stopping once - daily administration between higher FSH levels and the progression of prostate of oral formulations of the disclosure once the PSA drops to cancer , as FSH stimulates FSH receptors expressed on the 50 a very low level and if the PSA level begins to rise, restarting endothelial cells of tumor blood vessels in prostate cancer once - daily administration . Another form of intermittent specimens. Further, patients with low FSH levels have a therapy using the claimed methods and uses may employ significantly longer time to castration resistance . therapy for fixed periods of time , for example , 6 months on These advantages of the present methods and uses are followed by 6 months off . important both in the treatment setting , for example , where Compound 1 , or a pharmaceutically acceptable salt a subject may be receiving radiation treatment or where 55 thereof, has a faster onset of action than currently available there is the occurrence of a condition or procedure unrelated GnRH agonists, and unlike available peptide GnRH agonists to the prostate cancer treatment. For example , as noted that are given either subcutaneously or intranasally , Com previously consider a subject undergoing prostate cancer pound 1 is a non - peptide preparation that may be adminis treatmenta surgical whoprocedure is involved is required in a car to accidentaid in recovery . Whether from or notthe 60 agoniststered orally, such and as onceleuprolide - daily . Whenacetate ,compared which is totypically GnRH car accident, higher serum testosterone levels will aid in the administered as depot formulation , Compound 1 , or a subject's recovery , such as in rebuilding damaged tissues or pharmaceutically acceptable salt thereof, offers several promoting the mineralization of bone in the case of frac advantages. Such advantages may include, but are not tures. Unlike in a treatment regimen involving a depot limited to , oral administration , rapid onset of serum testos formulation, which is injected and requires a long period of 65 terone suppression within four days, rapid onset of serum time for a subject's serum testosterone levels to rise even FSH suppression, rapid PSA depression , absence of clinical after the nominal treatment period is complete, the present flare, no need for anti - androgen therapy to protect the patient US 10,786,501 B2 13 14 from clinical flare symptoms. The ability to suspend treat Pat . Nos . 7,300,935 , 8,058,280 , 9,346,822 , 9,758,528 , ment for periods of time can lead to an increase in serum 8,735,401 , and WO 2016136849 , the disclosures of which testosterone levels shortly after treatment is suspended and are herein incorporated by reference . may also return serum testosterone to the subject's serum In some embodiments, Compound 1 is a pharmaceutically testosterone level prior to treatment commencing after treat- 5 acceptable salt . “ Physiologically acceptable , ” “ pharmaceu ment is suspended, depending on the suspension period , and tically acceptable , ” or “ pharmacologically acceptable ” com each of these outcomes may quickly result in improvements pounds and compositions may include materials which are in quality of life, healing , and energy levels . not biologically, or otherwise, undesirable . For example , the Compound 1 , or a pharmaceutically acceptable salt material may be administered to an individual without thereof, also offers advantages over other GnRH antagonists . 10 causing any substantially undesirable biological effects or Once - daily oral administration of formulations comprising interacting in a deleterious manner with any of the compo Compound 1 , or a pharmaceutically acceptable salt thereof, nents of the composition in which it is contained . In certain allows hormone levels , such as serum testosterone levels, to such embodiments , the pharmaceutically acceptable salt of return to the subject's serum hormone levels prior to treat Compound 1 is a pharmaceutically acceptable acid addition ment commencing more rapidly than a GnRH antagonist 15 salt . Such salts include , but are not limited to , salts with depot formulation , such as degarelix , after discontinuation . inorganic acids ( e.g. , hydrochloric acid , hydrobromic acid , The option of increased serum testosterone levels, including nitric acid , sulfuric acid , phosphoric acid , and the like ) , and a return to the subject's serum testosterone level prior to salts with organic acids ( e.g. , formic acid , acetic acid , treatment commencing, is desirable for patients wanting to trifluoroacetic acid , fumaric acid , oxalic acid , tartaric acid , eliminate any unwanted effects of hormone suppression . The 20 maleic acid , citric acid, succinic acid , malic acid, methane more rapid return of hormonal levels to the subject's serum sulfonic acid , benzenesulfonic acid , p - toluenesulfonic acid , and the like ). hormone levels prior to treatment commencing is also Throughout the present disclosure , amounts of Compound advantageous in the restoration of energy levels and strength 1 disclosed refer to the amount of Compound 1 free form abovein men . However , for example, when, thefor symptomsthe reasons or markerssuch as ( describede.g. , PSA 25 present in the formulation. The term “ corresponding levels ) of the prostate cancer indicate a resumption of amount ” as used herein refers to the amount of a pharma treatment is advisable , once - daily administration of Com ceutically acceptable salt of Compound 1 required to obtain pound 1 , or a pharmaceutically acceptable salt thereof, can the amount of Compound 1 free form recited in the formu resume at short notice , with a rapid onset of action , and lation . It would be clear to one of skill in the art how to without a clinical flare . 30 calculate the corresponding amount of the salt of a com Provided herein is the use of oral formulations comprising pound , such as the corresponding amount of the pharma Compound 1 , or a pharmaceutically acceptable salt thereof, ceutically acceptable salt of Compound 1 , taking into account the difference in molecular weight between the free for the manufacture of a medicament for treatment accord form of a compound and a salt form . For example , 80.0 mg oraling toformulations any of methods comprising described Compound herein . 1Provided , or a pharmaceu- also are 35 of compound free base , would correspond to 84.7 mg of the tically acceptable salt thereof, for use in any of the methods HC1 salt . described herein . Compound 1 has been characterized as an orally active , Further embodiments of the present disclosure are nonpeptide, GnRH antagonist. Compound 1 has been shown described hereinafter, in which some , but not all , embodi to antagonize GnRH through the GnRH receptors, which are ments of the disclosure are illustrated . 40 present in the pituitary anterior lobe basophiles ( secretory cells ) , and inhibits the GnRH - stimulated secretion of LH Each embodiment disclosed herein may be used individu and FSH from these cells . As a result, the drug decreases ally or in combination with any other embodiment disclosed blood concentrations of hormones , including testosterone . herein . Compound 1 , or a pharmaceutically acceptable salt thereof, referredPublications to in this, patents application , and published are specifically patent incorporatedapplications 45 improves clinical symptoms observed in patients with pros by reference herein . tate cancer . Administration of oral formulations comprising Compounds Compound 1 , or a pharmaceutically acceptable salt thereof, As used herein, Compound 1 , namely N- ( 4- ( 1- ( 2,6 - dif also causes a rapid decline in serum PSA levels . As Com luorobenzyl) -5 - (( dimethylamino )methyl )-3- ( 6 -methoxy -3 pound 1 is a GnRH antagonist, it does not cause clinical flare pyridazinyl) -2,4 - dioxo - 1,2,3,4 - tetrahydrothieno [ 2,3 - d ]py 50 and has a faster onset of action than GnRH agonists. Unlike rimidin - 6 -yl ) phenyl ) -N ' -methoxyurea , is represented by the GnRH agonists , Compound 1 is not a peptide preparation . Therapeutic Uses and Methods of Treatment formula : Disclosed herein are methods of using an orally active , once - daily administered , GnRH antagonist, Compound 1 , or ??3 55 a pharmaceutically acceptable salt thereof, for the treatment | of prostate cancer . H3C CH3 . The present disclosure provides oral formulations com prising at least 80 mg of Compound 1 , or a corresponding amount of a pharmaceutically acceptable salt thereof, that 60 can be employed in methods and uses for treating prostate cancer in a subject in need thereof. “ Prostate cancer ” may H3C - 06 capture any cancer of the prostate , such as those described herein . Most prostate cancer is adenocarcinoma, but rarely -F can also include transitional cell ( urothelial) cancer , 65 squamous cell , small cell , carcinoid , or sarcomas . Prostate Compound 1 and pharmaceutical compositions including cancer can spread beyond the prostate ( e.g. , advanced pros Compoundroben 1 can be produced by methods described in U.S. tate cancer ) or it can be non -metastatic . “ Non - metastatic US 10,786,501 B2 15 16 prostate cancer ” may refer to prostate cancer that has not In some embodiments of the methods and uses described spread from the primary site of the prostate and may be herein , the prostate cancer is locally advanced , advanced hormone - sensitive . Hormonal therapy is used to reduce the castration resistant, or recurrent. “ Locally advanced prostate serum testosterone levels in prostate cancer. Hormonal cancer” may refer to cancer that has started to break out of therapy can also be used to reduce the serum PSA and FSH 5 the prostate , or has spread to the area just outside , or nearby, levels in prostate cancer. A “ patient ” or a “ subject " may refer the prostate . It may also be characterized as stage T3 or T4 to a mammal or a non -mammal . Examples of mammals prostate cancer . It may have spread to one or more of e.g. , include , but are not limited to , any member of the class the prostate capsule , the seminal vesicles , the pelvic lymph Mammalia : humans, non - human primates such as chimpan nodes , the bladder, and the back passage ( rectum ). zees , and other apes and monkey species ; farm animals such 10 “ Advanced castration - resistant prostate cancer ” or as cattle , horses , sheep , goats , swine ; domestic animals such “ advanced hormone - resistant prostate cancer ” may refer to as rabbits , dogs , and cats ; laboratory animals including castration - resistant prostate cancer that has spread beyond rodents, such as rats, mice and guinea pigs , and the like . the prostate gandandthere around the prostate.This type Examples of non -mammals include , but are not limited to , of cancer continues to grow and progress even when andro birds , fish and the like . In some embodiments of the present 15 gen levels in the body are extremely low or undetectable. disclosure , the mammal is a human . In some embodiments “ Recurrent prostate cancer ” may refer to prostate cancer that of the present disclosure , the patient or subject is a human has been detected or has returned following initial treatment, man . such as after surgery , radiation therapy, and / or hormone In some embodiments of the methods and uses described therapy. Recurrent prostate cancer may have a biochemical herein , the prostate cancer is hormone dependent prostate 20 and / or clinical recurrence . Some patients may only have a cancer . “ Hormone dependent prostate cancer, ” “ hormone sein PAlevevidence ofthe recurrent prostate cancer sensitive prostate cancer, " " androgen dependent prostate (biochemical recurrence ) and others will have evidence of cancer, ” or “ androgen sensitive prostate cancer ” may refer to recurrent prostate cancer X - ray and clinical recur prostate cancer needing relatively high levels of androgens rence ). “ Biochemical recurrence ” may refer to the return of to grow early in its development. Such prostate cancer may 25 the prostate cancer after initial treatment, but the return be referred to as androgen / hormone dependent or androgen / cannot be measured by standard imaging methods. There hormone sensitive because treatments that decrease andro fore, prostate cancer may be present with or without evi gen levels or block androgen activity can effectively inhibit dence on diagnostic imaging tests and with or without its growth . clinical symptoms. The return of the prostate cancer In some embodiments of the methods and uses described 30 identified by a rise in PSA as determined by a blood test . The herein , the prostate cancer is advanced prostate cancer . criteria for is biochemical recurrence may include a rise in Prostate cancer is typically considered " advanced ” if it has PSA of “ nadir + 2 ng / mL ” for relapse after radiation therapy, spread beyond the prostate gland and the area around the > 0.2 ng /mL if recurrent after prostatectomy, and > 2 ng /mL prostate . It may spread to nearby tissues , lymph nodes, if recurrent after all other treatments . “ Clinical recurrence " bones, or other parts of the body. When it spreads to tissues 35 may refer to the return of clinical symptoms associated with directly adjacent to the prostate gland , it is often referred to growth or spread of prostate cancer after initial treatment of as “ locally advanced prostate cancer . ” When it spreads prostate cancer . beyond the tissues directly adjacent to the prostate gland , it In some embodiments of the methods and uses described is typically referred to as “ metastatic prostate cancer .” herein , the prostate cancer is castration - resistant prostate Metastatic prostate cancer typically may have spread to the 40 cancer . In some embodiments of the methods and uses bone , lung, liver, brain , lymph nodes outside the pelvis , or described herein , the prostate cancer is castration - resistant other organs, and may be hormone - sensitive. The following metastatic prostate cancer. In some embodiments of the types of prostate cancer are also generally considered methods and uses described herein , the prostate cancer is “ advanced ” : PSA biochemical relapse following primary castration - resistant non -metastatic prostate cancer. " Castra surgical or radiation therapy of curative intent; newly diag- 45 tion - resistant prostate cancer ” or “ hormone - resistant pros nosed metastatic prostate cancer ; advanced localized disease tate cancer ” may refer to prostate cancer that continues to for which immediate radiation or surgical therapy is not grow even when androgen levels in the body are extremely indicated , or men whose disease progresses after prostate wor undetectable . For example, with astration - resistant ctomy or radiation . The clinical recurrence of advanced prostate cancer, PSA may increase or the cancer may show prostate cancer occurs when it is associated with symptoms. 50 other signs of growing even after using hormone therapy to Therefore , “ advanced ” prostate cancer may be present with bring serum testosterone to castration levels ( < 50 ng /dL ). or without evidence on diagnostic imaging tests and with or For castration - resistant prostate cancer, hormonal therapy without clinical symptoms. The treatment methods and uses ( e.g. , suppression of serum testosterone levels ) is continued , of this disclosure include palliative treatment of advanced and additional therapies are added to the treatment protocol prostate cancer . 55 in addition to the continued administration of drugs used to In some embodiments of the methods and uses described lower serum testosterone . Castration - resistant prostate can herein , the prostate cancer is advanced hormone sensitive cer may be either metastatic ( castration - resistant metastatic prostate cancer . “ Advanced hormone dependent prostate prostate cancer) or non -metastatic ( castration - resistant non cancer, " " advanced hormone sensitive prostate cancer ," metastatic prostate cancer ) prostate cancer . “ Metastatic cas “ advanced androgen dependent prostate cancer , " or 60 tration resistant prostate cancer ” or “ castration - resistant " advanced androgen sensitive prostate cancer ” as used metastatic prostate cancer ” may refer to prostate cancer that herein may refer to prostate cancer that has spread beyond has spread beyond the prostate and continues to grow and the prostate gland and the area around the prostate. The progress ( including but not limited to a rise in PSA ) in the growth of prostate cancer is suppressed or the cancer may setting of suppressed androgen levels ( i.e. , hormonal therapy even shrink when androgen levels are suppressed ( e.g. , 65 that lowers serum testosterone below castration levels < 50 hormonal therapy that lowers serum testosterone below ng ) .In membodiments, once - daily administration of castration levels < 50 ng /dL ). an oral formulation comprising Compound 1 , or a pharma US 10,786,501 B2 17 18 ceutically acceptable at thereof, reduces serFSHevels of Compound 1 , or a corresponding amount of a pharma and, therefore , may reduce the rate of subjects who develop ceutically acceptable salt thereof. castration - resistant prostate cancer. In some embodiments, The methods and uses described herein also include ce - daily administration of an oral formulation comprising treating prostate cancer in a subject in need thereof by Compound 1 , or a pharmaceutically acceptable salt thereof, 5 administering to the subject once - daily for at least 12 reduces serum FSH levels and , therefore, may slow the consecutive weeks , an oral formulation comprising at least development of castration - resistant prostate cancer . In some 80 mg of Compound 1 , or a corresponding amount of a embodiments of the methods and uses described herein , the pharmaceutically acceptable salt thereof. In certain such prostate cancer is hormone - sensitive metastatic prostate embodiments, the oral formulation comprises about 120 mg , cancer. In some embodiments of the methods and uses 10 about 180 mg , about 240 mg , or about 360 mg of Compound described herein , the prostate cancer hormon - sensitive 1 , or a corresponding amount of a pharmaceutically accept non -metastatic prostate cancer . able salt thereof. In certain such embodiments , the oral In some embodiments of the methods and uses described formulation comprises about 120 mg or about 360 mg of herein , the prostate cancer is hormone naïve advanced Compound 1 , or a corresponding amount of a pharmaceu prostate cancer. “ Hormone naïve advanced prostate cancer ” 15 tically acceptable salt thereof. The methods and uses may be subdivided into two disease states : biochemical described herein also include treating prostate cancer in a recurrence or traditional metastatic prostate cancer and may subject in need thereof by administering to the subject be characterized by no prior hormonal therapy or androgen once - daily for at least 4 consecutive weeks , at least 8 deprivation therapy ( ADT ). consecutive weeks , at least 12 consecutive weeks, at least 16 In some embodiments, the oral formulations of the meth- 20 consecutive weeks , at least 20 consecutive weeks, or at least ods and uses described herein comprise about 80 mg to 24 consecutive weeks an oral formulation comprising at about 480 mg of Compound 1 , or a corresponding amount least 80 mg of Compound 1 , or a corresponding amount of of a pharmaceutically acceptable salt thereof. As used a pharmaceutically acceptable salt thereof. herein , “ oral formulation ” encompasses the terms " oral load Several benefits may result from treating prostate cancer dose formulation , ” “ oral load dosage , ” “ oral load dose .” 25 by administering Compound 1 , or a pharmaceutically “ oral maintenance dose formulation , " " oral maintenance acceptable salt thereof, thereby suppressing one or more sex dosage , ” and the like , unless clearly dictated otherwise by hormones, to a subject in need of treatment as described context. An “ oral load dose formulation ,” “ oral load dos herein . “ Suppression ” as used herein may occur by inhibit age , ” or “ oral load dose ” is an initial dose of a Compound ing the production of luteinizing hormone ( LH ) and follicle 1 , or a pharmaceutically acceptable salt thereof, that may be 30 stimulating hormone ( FSH ) by the pituitary gland , a hor given at the beginning of a course of treatment before mone required by the testes to make testosterone and other changing to a different maintenance dose . As described androgens or sex hormones . Follicle - stimulating hormone herein , it is typically a larger initial dose of Compound 1 , or ( FSH ) stimulates FSH receptors expressed on the endothe a pharmaceutically acceptable salt thereof, or series of such lial cells of tumor blood vessels in prostate cancer speci doses given to rapidly achieve a therapeutically effective 35 mens . FSH signaling in prostate cancer may contribute to the amount of drug in the body therapeutically effective progression of castration resistant prostate cancer. Suppres amount” may refer to an amount of a compound sufficient to sion of serum testosterone levels may mean that the testes treat a specified disorder or disease or one or more of its are not producing testosterone at the levels normally symptoms and / or to prevent the occurrence of the disease or observed in the absence of treatment for an oral formulation disorder. For example, a therapeutically effective dose for 40 comprising Compound 1 , or a pharmaceutically acceptable prostate cancer treatment includes where the treatment salt thereof. The degree of suppression is measured by serum brings about an amelioration of one or more symptoms of testosterone , or other sex hormone, levels in the blood . Sex the prostate cancer , slows the progression of the prostate hormones may refer to any glandular secretions that are cancer, results in remission , etc. An " oral maintenance dose responsible for controlling sexual development and repro formulation , " " oral maintenance dosage , " or " oral mainte- 45 ductive function in males . Such sex hormones include, for nance dose ” is the dose of Compound 1 , or a pharmaceuti example , testosterone , dihydrotestosterone, follicle - stimu cally acceptable salt thereof, given after a certain period of lating hormone ( FSH ) , LH , GnRH , androsterone, and taking the addosage and is typically a lower amount of inhibin . In accordance with this disclosure , one or more sex Compound 1 , or a pharmaceutically acceptable salt thereof, hormones, including testosterone , FSH , and LH , may be than the load dosage yet maintains the desired therapeutic 50 suppressed by the once - daily administration of Compound effect . 1 , or a pharmaceutically acceptable salt thereof, to a subject In some embodiments , the oral formulations of the meth having prostate cancer. In particular, medical castration ods and uses described herein comprise about 80 mg to levels of less than or equal to 50 ng / dL ( 1.73 nmol / L ) serum about 160mg of Compound1rresponding amount testosterone may be achieved and maintained from day 14 to of a pharmaceutically acceptable salt thereof. In some 55 day 28 after beginning once - daily administration. Also , embodiments , the oral formulations of the methods and uses following once - daily administration of an oral formulation described herein comprise about 120 mg of Compound 1 , or of 180 mg on day 1 of Compound 1 , or a corresponding a corresponding amount of a pharmaceutically acceptable amount of a pharmaceutically acceptable salt thereof, medi salt thereof. In some embodiments, the oral formulations of cal castration levels of less than or equal to 50 ng/ dL ( 1.73 the methods and uses described herein comprise about 360 60 nmol/ L ) serum testosterone may be achieved within 24 to 48 mg of Compound 1 , or a corresponding amount of a phar hours . Further, following once - daily administration of a maceutically acceptable salt thereof. In some embodiments, single oral load dose formulation of 360 mg and once - daily the oral formulations of the methods and uses described administration of oral maintenance dose formulations of 120 herein comprise about 240 mg of Compound 1 , or a corre mg of Compound 1 , or a corresponding amount of a phar sponding amount of a pharmaceutically acceptable salt 65 maceutically acceptable salt thereof, for 48 consecutive thereof. In some embodiments, the oral formulations of the weeks, medical castration levels of less than or equal to 50 methods and uses described herein comprise about 180 mg ng / dL ( 1.73 nmol / L ) serum testosterone are achieved by the US 10,786,501 B2 19 20 beginning of week 5 and maintained through the end of is neither a depot or a slow - release formulation , and hor week 48. Further, following once - daily administration of a mone levels , particularly serum testosterone levels , increase single oral load dose formulation of 240 mg and once - daily and may return to the subject's serum hormone levels prior administration of oral maintenance dose formulations of 120 to treatment commencing more rapidly after once - daily mg of Compound 1 , or a corresponding amount of a phar- 5 administration is discontinued , providing more control and maceutically acceptable salt thereof, for 48 consecutive treatment options for patients and their physicians. For weeks, medical castration levels of less than or equal to 50 example, a more rapid increase of hormone levels , including ng / dL ( 1.73 nmol/ L ) serum testosterone are achieved by the beginning of week 5 and maintained through the end of increases in serum testosterone levels, in some cases to the week 48. As used herein , “ medical castration ” generally 10 subject's serum hormone levels prior to treatment commenc refers to serum testosterone levels of about 550 ng / dL and ing ( pre -treatment levels ), may be advantageous in the " profound castration ” generally refers to serum testosterone management of an intercurrent illness , among other condi levels of about 520 ng / dL . tions and procedures, and for the restoration of sexual In accordance with this disclosure , methods and uses are function and energy levels in men . Methods and uses provided for suppressing one or more sex hormones, includ- 15 described herein may permit more rapid recovery from ing testosterone , LH , and FSH , in a subject having prostate short -term medical castration , when used for neoadjuvant/ cancer. Additionally, in accordance with this disclosure , adjuvant therapy or intermittent ADT . As noted previously , methods and uses are provided for suppressing serum PSA this flexibility is important in both the treatment setting, for levels . In some embodiments, the methods and uses include : example, where a subject may be receiving radiation treat administering to the subject once -daily for at least one day , 20 ment or where there is the occurrence of a condition or an oral dosage form that includes at least one oral load dose procedure unrelated to the prostate cancer treatment. For formulation , wherein the oral load dose formulation com example, as noted previously consider a subject undergoing prises about 240 mg to about 480 mg of Compound 1 , or a prostate cancer treatment who is involved in car accident. corresponding amount of a pharmaceutically acceptable salt Whether or not a surgical procedure is required to aid in thereof; and administering once - daily to the subject for at 25 recovery from the car accident, higher serum testosterone least 4 consecutive weeks, at least 8 consecutive weeks, at levels will aid in the subject's recovery because testosterone least 12 consecutive weeks, at least 16 consecutive weeks , at has an anabolic effect, helping to rebuild tissues and increase least 20 consecutive weeks , or at least 24 consecutive weeks , weight and muscle mass . Unlike in a treatment regimen an oral maintenance dose formulation , in which the oral maintenance dose formulation comprise about 80 mg to 30 allowinvolving for suspensiona depot formulation of treatment , the withoutpresent methodsadverse effectsand uses in about 160 mg of Compound 1 , or a corresponding amount response to unexpected events ( e.g. , illness , injury, etc. ) . of a pharmaceutically acceptable salt thereof. In some Additionally, where upcoming surgeries may be planned , for embodiments, the methods and uses include administering example a hip or knee replacement, the treatment may be toin anthe oralsubject maintenance once - daily dose for formulationat least 24 consecutive , at least 80 weeks mg of , 35 suspended either shortly prior to or at the time of surgery to Compound 1 , or a corresponding amount of a pharmaceu ensure optimal recovery of the patient after surgery and tically acceptable salt thereof. potentially better outcomes due to higher serum testosterone In the methods and uses of this disclosure , serum testos levels . terone may be suppressed in the subject to a level less than Subjects undergoing treatment in accordance with this or equal to 50 ng / dL ( 1.73 nmol / L ) or less than or equal to 40 disclosure may be able to remain in control of their lifestyle 20 ng / dL ( 0.69 nmol / L ). In some embodiments, following and quality of life . In contrast to conventional treatments once - daily administration of an oral formulation of 180 mg which use depot injections, treatment with formulations of on day 1 of Compound 1 , or a corresponding amount of a this disclosure allows for suspension periods, or intermittent pharmaceutically acceptable salt thereof, medical castration treatment, in which subjects can stop treatment for a period levels of less than or equal to 50 ng / dL ( 1.73 nmol / L ) serum 45 of time and later restart treatment with no adverse effects, testosterone may be achieved within 24 to 48 hours after including no incidence of clinical flare . “ Clinical ” or “ hor commencing administration . In some embodiments, follow monal flare ” may refer to a temporary increase in serum ing once - daily administration of a single oral load dose testosterone levels from complete serum testosterone sup formulation of 360 mg and oral maintenance dose formu pression levels in the body caused by certain types of lations of 120 mg of Compound 1 , or a corresponding 50 hormone therapy ( e.g. , androgen deprivation therapy) used amount of a pharmaceutically acceptable salt thereof, for 48 to treat prostate cancer. Clinical flare can be serious in consecutive weeks , medical castration levels of less than or nature, for example , causing exacerbation of bone pain and equal to 50 ng / dL ( 1.73 nmol /L ) serum testosterone may be urinary problems. The treatment methods and uses of this achieved by the beginning of week 5 and maintained disclosure may provide a desirable quick on / off option for through the end of week 48. In some embodiments, follow- 55 subjects. The treatment methods and uses of this disclosure ing once - daily administration of a single oral load dose allow maintenance of sexual activity by subjects at certain formulation of 240 mg and oral maintenance dose formu times during the treatment period. Increases in serum tes lations of 120 mg of Compound 1 , or a corresponding tosterone levels can also promote an increase in energy amount of a pharmaceutically acceptable salt thereof, for 48 levels , which may have a positive impact on the subject's consecutive weeks , medical castration levels of less than or 60 ( and the subject's family's) quality of life. For example , for equal to 50 ng / dL ( 1.73 nmol / L ) serum testosterone may be important life events ( e.g. , attending one's daughter's wed achieved by the beginning of week 5 and maintained ding , walking her down the aisle , and dancing with the through the end of week 48 . mother of the bride or celebrating an important wedding The treatment methods and uses of this disclosure may anniversary ), the present methods and uses can incorporate provide fast onset and fast offset for subjects. With respect 65 suspension period allowing for increased energy levels or to offset, unlike GnRH agonists , such as leuprolide acetate , improvement in sexual function and therefore greater enjoy Compound 1 , or a pharmaceutically acceptable salt thereof, ment of such events , without the potential adverse impact on US 10,786,501 B2 21 22 the control of the prostate cancer related to the clinical flare the oral formulation of the disclosure within 4 weeks , or associated with restarting treatment after the suspension within 8 weeks , or within 12 weeks , or within 16 weeks , or period . within 24 weeks , after the last dose administered prior to the The disclosure provides methods of using oral formula suspension period . In some embodiments, the serum testos tions comprising Compound 1 , or a pharmaceutically 5 terone level may increase to the subject's serum testosterone acceptable salt thereof, for treating prostate cancer in a level prior to once - daily administration of the oral formu subject in need of an increase in serum testosterone levels to lation of the disclosure within 4 weeks to 12 weeks after the a level above 50 ng / dL . The disclosure also provides meth last dose . In some embodiments after stopping once - daily ods and uses for treating prostate cancer in a subject in need administration of oral formulations of the disclosure for a thereof comprising administering once - daily formulations 10 suspension period , the serum testosterone level may increase comprising Compound 1 , or a pharmaceutically acceptable to the subject's serum testosterone level prior to adminis salt thereof. Once - daily administration of formulations com tration of the oral formulations comprising Compound 1 , or prising Compound 1 , or a pharmaceutically acceptable salt a pharmaceutically acceptable salt thereof, within 1 day of thereof, can be suspended for a suspension period , leading to the suspension of administration . In some embodiments an increase in the subject's serum testosterone levels . In 15 after stopping once - daily administration of oral formulations certain embodiments, once - daily administration of oral for of the disclosure for a suspension period, the serum testos mulations comprising Compound 1 , or a pharmaceutically terone level may increase to the subject's serum testosterone acceptable salt thereof, resumes at the end of the suspension level prior to administration of the oral formulations within period . In some embodiments, once - daily administration of 2 days of the suspension of administration . In some embodi oral formulations comprising Compound 1 , or a pharmaceu- 20 ments after stopping once - daily administration of oral for tically acceptable salt thereof, does not resume after it is mulations of the disclosure for a suspension period , the suspended. serum testosterone level may increase to the subject's serum The present disclosure further provides that, after sus testosterone level prior to administration of the oral formu pending once - daily administration of oral formulations of lations of the disclosure within 3 days of the suspension of the disclosure for a suspension period, the subject may 25 administration . In some embodiments after stopping once experience an increase in serum testosterone levels . In some daily administration of oral formulations of the disclosure embodiments after stopping once - daily administration of for a suspension period, the serum testosterone level may oral formulations comprising Compound 1 , or a pharmaceu increase to the subject's serum testosterone level prior to tically acceptable salt thereof, for a suspension period , a administration of the oral formulations of the disclosure subject's serum testosterone level may increase within 1 day 30 within 4 days of the suspension of administration . In some of the beginning of the suspension period . In some embodi embodiments after stopping once - daily administration of ments after stopping once - daily administration of oral for oral formulations of the disclosure for a suspension period , mulations of the disclosure for a suspension period , a the serum testosterone level may increase to the subject's subject's serum testosterone level may increase within 2 serum testosterone level prior to administration of the oral days of the beginning of the suspension period . In some 35 formulations of the disclosure within 5 days of the suspen embodiments after stopping once -daily administration of sion of administration . In some embodiments after stopping oral formulations of the disclosure for a suspension period , once -daily administration of oral formulations of the disclo a subject's serum testosterone level may increase within 3 sure for a suspension period , the serum testosterone level days of the beginning of the suspension period . In some may increase to the subject's serum testosterone level prior embodiments after stopping once - daily administration of 40 to administration of the oral formulations of the disclosure oral formulations of the disclosure for a suspension period, within 6 days of the suspension of administration . In some a subject's serum testosterone level may increase within 4 embodiments after stopping once - daily administration of days of the beginning of the suspension period . In some oral formulations of the disclosure for a suspension period, embodiments after stopping once -daily administration of the serum testosterone level may increase to the subject's oral formulations of the disclosure for a suspension period , 45 serum testosterone level prior to administration of the oral a subject's serum testosterone level may increase within 5 formulations of the disclosure within 7 days of the suspen days of the beginning of the suspension period . In some sion of administration . In some embodiments after stopping embodiments after stopping once - daily administration of once -daily administration of oral formulations of the disclo oral formulations of the disclosure for a suspension period, sure for a suspension period , the serum testosterone level a subject's serum testosterone level may increase within 6 50 may increase to the subject's serum testosterone level prior days of the beginning of the suspension period. In some to administration of the oral formulations of the disclosure embodiments after stopping once -daily administration of within 8 days of the suspension of administration . In some oral formulations of the disclosure for a suspension period, embodiments after stopping once - daily administration of a subject's serum testosterone level may increase within 7 oral formulations of the disclosure for a suspension period , days of the beginning of the suspension period. In some 55 the serum testosterone level may increase to the subject's embodiments after stopping once - daily administration of serum testosterone level prior to administration of the oral oral formulations of the disclosure for a suspension period , formulations of the disclosure within 9 days of the suspen a subject's serum testosterone level may increase within 10 sion of administration . In some embodiments after stopping days of the beginning of the suspension period . once - daily administration of oral formulations of the disclo During a suspension period , a subject's serum testoster- 60 sure for a suspension period , the serum testosterone level one level may increase to the subject's serum testosterone may increase to the subject's serum testosterone level prior level prior to once -daily administration of an oral formula to administration of the oral formulations of the disclosure tion of the disclosure comprising Compound 1 , or a phar within 10 days of the suspension of administration . In some maceutically acceptable salt thereof. With respect to offset, embodiments after stopping once - daily administration of after stopping once - daily administration for a suspension 65 oral formulations of the disclosure for a suspension period , period , the serum testosterone level may increase to the the serum testosterone level may increase to the subject's subject's serum testosterone level prior to administration of serum testosterone level prior to administration of the oral US 10,786,501 B2 23 24 formulations of the disclosure within 15 days of the suspen sion of administration . In some embodiments after stopping sion of administration . In some embodiments after stopping once -daily administration of oral formulations of the disclo once - daily administration of oral formulations of the disclo sure for a suspension period, the serum testosterone level sure for a suspension period, the serum testosterone level may increase to the subject's serum testosterone level prior may increase to the subject's serum testosterone level prior 5 to administration of the oral formulations of the disclosure to administration of the oral formulations of the disclosure within 85 days of the suspension of administration . In some within 20 days of the suspension of administration . In some embodiments after stopping once - daily administration of embodiments after stopping once - daily administration of oral formulations of the disclosure for a suspension period, oral formulations of the disclosure for a suspension period, the serum testosterone level may increase to the subject's the serum testosterone level may increase to the subject's 10 serum testosterone level prior to administration of the oral serum testosterone level prior to administration of the oral formulations of the disclosure within 90 days of the suspen formulations of the disclosure within 30 days of the suspen sion of administration . In some embodiments after stopping sion of administration . In some embodiments after stopping once - daily administration of oral formulations of the disclo once - daily administration of oral formulations of the disclo sure for a suspension period , the serum testosterone level sure for a suspension period, the serum testosterone level 15 may increase to the subject's serum testosterone level prior may increase to the subject's serum testosterone level prior to administration of the oral formulations of the disclosure to administration of the oral formulations of the disclosure within 95 days of the suspension of administration . In some within 35 days of the suspension of administration . In some embodiments after stopping once - daily administration of embodiments after stopping once -daily administration of oral formulations of the disclosure for a suspension period , oral formulations of the disclosure for a suspension period, 20 the serum testosterone level may increase to the subject's the serum testosterone level may increase to the subject's serum testosterone level prior to administration of the oral serum testosterone level prior to administration of the oral formulations of the disclosure within 100 days of the sus formulations of the disclosure within 40 days of the suspen pension of administration . sion of administration . In some embodiments after stopping The disclosure provides for increases in a subject's serum once - daily administration of oral formulations of the disclo- 25 testosterone level to greater than medical castration levels . sure for a suspension period , the serum testosterone level In some embodiments after stopping once - daily administra may increase to the subject's serum testosterone level prior tion of oral formulations of the disclosure comprising Com to administration of the oral formulations of the disclosure pound 1 , or a pharmaceutically acceptable salt thereof, for a within 45 days of the suspension of administration . In some suspension period , a subject's serum testosterone level may embodiments after stopping once - daily administration of 30 increase to greater than medical castration levels within 1 oral formulations of the disclosure for a suspension period, day of the beginning of the suspension period . In some the serum testosterone level may increase to the subject's embodiments after stopping once - daily administration of serum testosterone level prior to administration of the oral oral formulations of the disclosure for a suspension period , formulations of the disclosure within 50 days of the suspen a subject's serum testosterone level may increase to greater sion of administration . In some embodiments after stopping 35 than medical castration levels within 2 days of the beginning once - daily administration of oral formulations of the disclo of the suspension period. In some embodiments after stop sure for a suspension period , the serum testosterone level ping once - daily administration of oral formulations of the may increase to the subject's serum testosterone level prior disclosure for a suspension period , a subject's serum tes to administration of the oral formulations of the disclosure tosterone level may increase to greater than medical castra within 55 days of the suspension of administration . In some 40 tion levels within 3 days of the beginning of the suspension embodiments after stopping once - daily administration of period. In some embodiments after stopping once - daily oral formulations of the disclosure for a suspension period , administration of oral formulations of the disclosure for a the serum testosterone level may increase to the subject's suspension period , a subject's serum testosterone level may serum testosterone level prior to administration of the oral increase to greater than medical castration levels within 4 formulations of the disclosure within 60 days of the suspen- 45 days of the beginning of the suspension period . In some sion of administration . In some embodiments after stopping embodiments after stopping once - daily administration of once - daily administration of oral formulations of the disclo oral formulations of the disclosure for a suspension period, sure for a suspension period , the serum testosterone level a subject's serum testosterone level may increase to greater may increase to the subject's serum testosterone level prior than medical castration levels within 5 days of the beginning to administration of the oral formulations of the disclosure 50 of the suspension period . In some embodiments after stop within 65 days of the suspension of administration . In some ping once - daily administration of oral formulations of the embodiments after stopping once -daily administration of disclosure for a suspension period, a subject's serum tes oral formulations of the disclosure for a suspension period , tosterone level may increase to greater than medical castra the serum testosterone level may increase to the subject's tion levels within 6 days of the beginning of the suspension serum testosterone level prior to administration of the oral 55 period. In some embodiments after stopping once - daily formulations of the disclosure within 70 days of the suspen administration of oral formulations of the disclosure for a sion of administration . In some embodiments after stopping suspension period , a subject's serum testosterone level may once - daily administration of oral formulations of the disclo increase to greater than medical castration levels within 7 sure for a suspension period , the serum testosterone level days of the beginning of the suspension period. In some may increase to the subject's serum testosterone level prior 60 embodiments after stopping once - daily administration of to administration of the oral formulations of the disclosure oral formulations of the disclosure for a suspension period, within 75 days of the suspension of administration . In some a subject's serum testosterone level may increase to greater embodiments after stopping once - daily administration of than medical castration levels within 10 days of the begin oral formulations of the disclosure for a suspension period, ning of the suspension period. In some embodiments after the serum testosterone level may increase to the subject's 65 stopping once - daily administration of oral formulations of serum testosterone level prior to administration of the oral the disclosure for a suspension period , a subject's serum formulations of the disclosure within 80 days of the suspen testosterone level may increase to greater than medical US 10,786,501 B2 25 26 castration levels within 15 days of the beginning of the embodiments after stopping once - daily administration of suspension period. In some embodiments after stopping oral formulations of the disclosure for a suspension period, once - daily administration of oral formulations of the disclo a subject's serum testosterone level may increase to greater sure for a suspension period , a subject's serum testosterone than about 55 ng / dL within 30 days of the beginning of the level may increase to greater than medical castration levels 5 suspension period. within 20 days of the beginning of the suspension period. In Normal serum testosterone levels for European and some embodiments after stopping once - daily administration American men , 19 to 39 years , are variable and are reported of oral formulations of the disclosure for a suspension to be between about 250 ng / dL to about 920 ng / dL ( see , The period , a subject's serum testosterone level may increase to Journal of Clinical Endocrinology & Metabolism , Volume greater than medical castration levels within 25 days of the 10 102 , Issue 4 , 1 Apr. 2017 , Pages 1161-1173 ) . Suspension of beginning of the suspension period. In some embodiments once -daily administration of the oral formulations of the after stopping once -daily administration of oral formulations disclosure may allow for increases in a subject's serum of the disclosure for a suspension period, a subject's serum testosterone levels to a range between about 250 ng / dL to testosterone level may increase to greater than medical about 920 ng /dL , or to “ normal” serum testosterone levels . castration levels within 30 days of the beginning of the 15 The Endocrine Society recommends about 300 ng /dL as the suspension period. lower limit of “ normal” serum testosterone levels . Other In some embodiments after stopping once -daily adminis medical societies recommend 150 ng /dL , 200 ng / dL , or 230 tration of oral formulations of the disclosure comprising ng / dL as the lower limit of “ normal ” serum testosterone Compound 1 , or a pharmaceutically acceptable salt thereof, levels . The methods and uses of the disclosure may allow for for a suspension period , a subject's serum testosterone level 20 a return to “ normal ” serum testosterone levels . In some may increase to greater than about 55 ng / dL within 1 day of embodiments after stopping once - daily administration of the beginning of the suspension period . In some embodi oral formulations of the disclosure comprising Compound 1 , ments after stopping once -daily administration of oral for or a pharmaceutically acceptable salt thereof, for a suspen mulations of the disclosure for a suspension period , a sion period, a subject's serum testosterone level may subject's serum testosterone level may increase to greater 25 increase to greater than or about 60 ng /dL , about 65 ng / dL , than about 55 ng / dL within 2 days of the beginning of the about 70 ng / dL , about 75 ng /dL , about 80 ng/ dL , about 85 suspension period . In some embodiments after stopping ng / dL , about 90 ng / dL , about 95 ng / dL , about 100 ng / dL , once - daily administration of oral formulations of the disclo about 150 ng / dL , about 200 ng / dL , about 250 ng/ dL , about sure for a suspension period , a subject's serum testosterone 280 ng / dL , about 300 ng /dL , about 350 ng /dL , about 400 level may increase to greater than about 55 ng / dL within 3 30 ng / dL , about 450 ng / dL , about 500 ng /dL , about 550 ng / dL , days of the beginning of the suspension period . In some or about 600 ng / dL within 1 day of the beginning of the embodiments after stopping once - daily administration of suspension period. In some embodiments after stopping oral formulations of the disclosure for a suspension period, once -daily administration of oral formulations of the disclo a subject's serum testosterone level may increase to greater sure for a suspension period, a subject's serum testosterone than about 55 ng / dL within 4 days of the beginning of the 35 level may increase to greater than or about 60 ng / dL , about suspension period . In some embodiments after stopping 65 ng / dL , about 70 ng / dL , about 75 ng / dL , about 80 ng / dL , once - daily administration of oral formulations of the disclo about 85 ng /dL , about 90 ng / dL , about 95 ng /dL , about 100 sure for a suspension period, a subject's serum testosterone ng / dL , about 150 ng / dL , about 200 ng /dL , about 250 ng / dL , level may increase to greater than about 55 ng / dL within 5 about 280 ng /dL , about 300 ng / dL , about 350 ng /dL , about days of the beginning of the suspension period . In some 40 400 ng / dL , about 450 ng / dL , about 500 ng / dL , about 550 embodiments after stopping once - daily administration of ng / dL , or about 600 ng / dL within 2 days of the beginning of oral formulations of the disclosure for a suspension period, the suspension period . In some embodiments after stopping a subject's serum testosterone level may increase to greater once - daily administration of oral formulations of the disclo than about 55 ng / dL within 6 days of the beginning of the sure for a suspension period , a subject's serum testosterone suspension period. In some embodiments after stopping 45 level may increase to greater than or about 60 ng / dL , about once - daily administration of oral formulations of the disclo 65 ng / dL , about 70 ng / dL , about 75 ng / dL , about 80 ng / dL , sure for a suspension period, a subject's serum testosterone about 85 ng /dL , about 90 ng / dL , about 95 ng /dL , about 100 level may increase to greater than about 55 ng / dL within 7 ng/ dL , about 150 ng / dL , about 200 ng / dL , about 250 ng / dL , days of the beginning of the suspension period . In some about 280 ng /dL , about 300 ng / dL , about 350 ng / dL , about embodiments after stopping once - daily administration of 50 400 ng / dL , about 450 ng / dL , about 500 ng / dL , about 550 oral formulations of the disclosure for a suspension period, ng / dL , or about 600 ng / dL within 3 days of the beginning of a subject's serum testosterone level may increase to greater the suspension period. In some embodiments after stopping than about 55 ng / dL within 10 days of the beginning of the once - daily administration of oral formulations of the disclo suspension period. In some embodiments after stopping sure for a suspension period, a subject's serum testosterone once - daily administration of oral formulations of the disclo- 55 level may increase to greater than or about 60 ng / dL , about sure for a suspension period , a subject's serum testosterone 65 ng / dL , about 70 ng / dL , about 75 ng / dL , about 80 ng / dL , level may increase to greater than about 55 ng / dL within 15 about 85 ng /dL , about 90 ng / dL , about 95 ng /dL , about 100 days of the beginning of the suspension period . In some ng / dL , about 150 ng / dL , about 200 ng / dL , about 250 ng / dL , embodiments after stopping once - daily administration of about 280 ng /dL , about 300 ng / dL , about 350 ng / dL , about oral formulations of the disclosure for a suspension period , 60 400 ng / dL , about 450 ng / dL , about 500 ng / dL , about 550 a subject's serum testosterone level may increase to greater ng / dL , or about 600 ng / dL within 4 days of the beginning of than about 55 ng / dL within 20 days of the beginning of the the suspension period . In some embodiments after stopping suspension period . In some embodiments after stopping once - daily administration of oral formulations of the disclo once - daily administration of oral formulations of the disclo sure for a suspension period, a subject's serum testosterone sure for a suspension period, a subject's serum testosterone 65 level may increase to greater than or about 60 ng / dL , about level may increase to greater than about 55 ng / dL within 25 65 ng /dL , about 70 ng / dL , about 75 ng /dL , about 80 ng / dL , days of the beginning of the suspension period . In some about 85 ng /dL , about 90 ng / dL , about 95 ng / dL , about 100 US 10,786,501 B2 27 28 ng / dL , about 150 ng /dL , about 200 ng / dL , about 250 ng / dL , sure for a suspension period, a subject's serum testosterone about 280 ng / dL , about 300 ng / dL , about 350 ng /dL , about level may increase to greater than or about 60 ng / dL , about 400 ng / dL , about 450 ng /dL , about 500 ng /dL , about 550 65 ng /dL , about 70 ng / dL , about 75 ng /dL , about 80 ng / dL , ng / dL , or about 600 ng / dL within 5 days of the beginning of about 85 ng /dL , about 90 ng / dL , about 95 ng/ dL , about 100 the suspension period. In some embodiments after stopping 5 ng / dL , about 150 ng / dL , about 200 ng / dL , about 250 ng / dL , once - daily administration of oral formulations of the disclo about 280 ng /dL , about 300 ng / dL , about 350 ng / dL , about sure for a suspension period, a subject's serum testosterone 400 ng / dL , about 450 ng /dL , about 500 ng /dL , about 550 level may increase to greater than or about 60 ng / dL , about ng / dL , or about 600 ng / dL within 30 days of the beginning 65 ng / dL , about 70 ng / dL , about 75 ng / dL , about 80 ng / dL , of the suspension period. In some embodiments after stop about 85 ng /dL , about 90 ng / dL , about 95 ng / dL , about 100 10 ping once - daily administration of oral formulations of the ng / dL , about 150 ng / dL , about 200 ng / dL , about 250 ng / dL , disclosure for a suspension period, a subject's serum tes about 280 ng /dL , about 300 ng / dL , about 350 ng /dL , about tosterone level may increase to greater than or about 60 400 ng / dL , about 450 ng / dL , about 500 ng / dL , about 550 ng / dL , about 65 ng / dL , about 70 ng / dL , about 75 ng / dL , ng / dL , or about 600 ng /dL within 6 days of the beginning of about 80 ng / dL , about 85 ng /dL , about 90 ng / dL , about 95 the suspension period . In some embodiments after stopping 15 ng / dL , about 100 ng / dL , about 150 ng /dL , about 200 ng / dL , once - daily administration of oral formulations of the disclo about 250 ng /dL , about 280 ng / dL , about 300 ng / dL , about sure for a suspension period, a subjects serum testosterone 350 ng / dL , about 400 ng /dL , about 450 ng /dL , about 500 level may increase to greater than or about 60 ng /dL , about ng/ dL , about 550 ng / dL , or about 600 ng /dL within 35 days 65 ng/ dL , about 70 ng / dL , about 75 ng /dL , about 80 ng / dL , of the beginning of the suspension period . In some embodi about 85 ng / dL , about 90 ng / dL , about 95 ng / dL , about 100 20 ments after stopping once - daily administration of oral for ng / dL , about 150 ng /dL , about 200 ng / dL , about 250 ng / dL , mulations of the disclosure for a suspension period , a about 280 ng / dL , about 300 ng / dL , about 350 ng /dL , about subject's serum testosterone level may increase to greater 400 ng / dL , about 450 ng /dL , about 500 ng / dL , about 550 than or about 60 ng / dL , about 65 ng /dL , about 70 ng / dL , ng / dL , or about 600 ng / dL within 7 days of the beginning of about 75 ng / dL , about 80 ng /dL , about 85 ng / dL , about 90 the suspension period . In some embodiments after stopping 25 ng / dL , about 95 ng / dL , about 100 ng / dL , about 150 ng / dL , once - daily administration of oral formulations of the disclo about 200 ng /dL , about 250 ng / dL , about 280 ng / dL , about sure for a suspension period, a subject's serum testosterone 300 ng / dL , about 350 ng / dL , about 400 ng /dL , about 450 level may increase to greater than or about 60 ng /dL , about ng /dL , about 500 ng / dL , about 550 ng /dL , or about 600 65 ng /dL , about 70 ng / dL , about 75 ng /dL , about 80 ng / dL , ng /dL within 40 days of the beginning of the suspension about 85 ng / dL , about 90 ng / dL , about 95 ng / dL , about 100 30 period. In some embodiments after stopping once - daily ng / dL , about 150 ng /dL , about 200 ng / dL , about 250 ng / dL , administration of oral formulations of the disclosure for a about 280 ng / dL , about 300 ng / dL , about 350 ng /dL , about suspension period , a subject's serum testosterone level may 400 ng / dL , about 450 ng /dL , about 500 ng / dL , about 550 increase to greater than or about 60 ng /dL , about 65 ng / dL , ng / dL , or about 600 ng / dL within 10 days of the beginning about 70 ng / dL , about 75 ng /dL , about 80 ng /dL , about 85 of the suspension period . In some embodiments after stop- 35 ng / dL , about 90 ng / dL , about 95 ng / dL , about 100 ng / dL , ping once -daily administration of oral formulations of the about 150 ng / dL , about 200 ng / dL , about 250 ng / dL , about disclosure for a suspension period, a subject's serum tes 280 ng / dL , about 300 ng / dL , about 350 ng / dL , about 400 tosterone level may increase to greater than or about 60 ng /dL , about 450 ng / dL , about 500 ng /dL , about 550 ng / dL , ng / dL , about 65 ng /dL , about 70 ng / dL , about 75 ng / dL , or about 600 ng / dL within 45 days of the beginning of the about 80 ng / dL , about 85 ng / dL , about 90 ng / dL , about 95 40 suspension period . In some embodiments after stopping ng / dL , about 100 ng /dL , about 150 ng/ dL , about 200 ng / dL , once - daily administration of oral formulations of the disclo about 250 ng / dL , about 280 ng / dL , about 300 ng / dL , about sure for a suspension period, a subject's serum testosterone 350 ng / dL , about 400 ng /dL , about 450 ng /dL , about 500 level may increase to greater than or about 60 ng / dL , about ng / dL , about 550 ng / dL , or about 600 ng / dL within 15 days 65 ng / dL , about 70 ng / dL , about 75 ng / dL , about 80 ng / dL , of the beginning of the suspension period . In some embodi- 45 about 85 ng / dL , about 90 ng / dL , about 95 ng / dL , about 100 ments after stopping once - daily administration of oral for ng / dL , about 150 ng / dL , about 200 ng/ dL , about 250 ng / dL , mulations of the disclosure for a suspension period , a about 280 ng / dL , about 300 ng / dL , about 350 ng / dL , about subject's serum testosterone level may increase to greater 400 ng / dL , about 450 ng /dL , about 500 ng /dL , about 550 than or about 60 ng /dL , about 65 ng / dL , about 70 ng / dL , ng /dL , or about 600 ng / dL within 50 days of the beginning about 75 ng / dL , about 80 ng / dL , about 85 ng /dL , about 90 50 of the suspension period. In some embodiments after stop ng / dL , about 95 ng / dL , about 100 ng /dL , about 150 ng / dL , ping once - daily administration of oral formulations of the about 200 ng /dL , about 250 ng / dL , about 280 ng /dL , about disclosure for a suspension period, a subject's serum tes 300 ng / dL , about 350 ng /dL , about 400 ng / dL , about 450 tosterone level may increase to greater than or about 60 ng / dL , about 500 ng /dL , about 550 ng / dL , or about 600 ng /dL , about 65 ng / dL , about 70 ng / dL , about 75 ng / dL , ng / dL within 20 days of the beginning of the suspension 55 about 80 ng / dL , about 85 ng / dL , about 90 ng / dL , about 95 period . In some embodiments after stopping once - daily ng /dL , about 100 ng / dL , about 150 ng / dL , about 200 ng / dL , administration of oral formulations of the disclosure for a about 250 ng / dL , about 280 ng / dL , about 300 ng / dL , about suspension period, a subject's serum testosterone level may 350 ng / dL , about 400 ng / dL , about 450 ng /dL , about 500 increase to greater than or about 60 ng / dL , about 65 ng /dL , ng / dL , about 550 ng / dL , or about 600 ng /dL within 55 days about 70 ng /dL , about 75 ng / dL , about 80 ng / dL , about 85 60 of the beginning of the suspension period. In some embodi ng / dL , about 90 ng / dL , about 95 ng / dL , about 100 ng / dL , ments after stopping once - daily administration of oral for about 150 ng / dL , about 200 ng / dL , about 250 ng / dL , about mulations of the disclosure for a suspension period , a 280 ng / dL , about 300 ng /dL , about 350 ng /dL , about 400 subject's serum testosterone level may increase to greater ng / dL , about 450 ng /dL , about 500 ng / dL , about 550 ng / dL , than or about 60 ng / dL , about 65 ng /dL , about 70 ng / dL , or about 600 ng / dL within 25 days of the beginning of the 65 about 75 ng / dL , about 80 ng /dL , about 85 ng / dL , about 90 suspension period . In some embodiments after stopping ng / dL , about 95 ng /dL , about 100 ng /dL , about 150 ng / dL , once - daily administration of oral formulations of the disclo about 200 ng /dL , about 250 ng / dL , about 280 ng / dL , about US 10,786,501 B2 29 30 300 ng / dL , about 350 ng /dL , about 400 ng /dL , about 450 tosterone level may increase to greater than or about 60 ng / dL , about 500 ng / dL , about 550 ng /dL , or about 600 ng / dL , about 65 ng / dL , about 70 ng / dL , about 75 ng / dL , ng / dL within 60 days of the beginning of the suspension about 80 ng / dL , about 85 ng / dL , about 90 ng/ dL , about 95 period. In some embodiments after stopping once - daily ng / dL , about 100 ng / dL , about 150 ng / dL , about 200 ng / dL , administration of oral formulations of the disclosure for a 5 about 250 ng /dL , about 280 ng / dL , about 300 ng /dL , about suspension period, a subject's serum testosterone level may 350 ng / dL , about 400 ng / dL , about 450 ng /dL , about 500 increase to greater than or about 60 ng /dL , about 65 ng /dL , ng /dL , about 550 ng / dL , or about 600 ng /dL within 95 days about 70 ng /dL , about 75 ng / dL , about 80 ng /dL , about 85 of the beginning of the suspension period . In some embodi ng / dL , about 90 ng / dL , about 95 ng / dL , about 100 ng / dL , ments after stopping once - daily administration of oral for about 150 ng / dL , about 200 ng / dL , about 250 ng / dL , about 10 mulations of the disclosure for a suspension period, a 280 ng / dL , about 300 ng /dL , about 350 ng / dL , about 400 subject's serum testosterone level may increase to greater ng / dL , about 450 ng /dL , about 500 ng /dL , about 550 ng / dL , than or about 60 ng /dL , about 65 ng /dL , about 70 ng / dL , or about 600 ng / dL within 65 days of the beginning of the about 75 ng / dL , about 80 ng / dL , about 85 ng /dL , about 90 suspension period. In some embodiments after stopping ng /dL , about 95 ng /dL , about 100 ng / dL , about 150 ng / dL , once - daily administration of oral formulations of the disclo- 15 about 200 ng / dL , about 250 ng / dL , about 280 ng / dL , about sure for a suspension period , a subject's serum testosterone 300 ng / dL , about 350 ng /dL , about 400 ng /dL , about 450 level may increase to greater than or about 60 ng / dL , about ng / dL , about 500 ng / dL , about 550 ng / dL , or about 600 65 ng /dL , about 70 ng / dL , about 75 ng /dL , about 80 ng / dL , ng / dL within 100 days of the beginning of the suspension about 85 ng /dL , about 90 ng / dL , about 95 ng / dL , about 100 period. In some embodiments after stopping once - daily ng / dL , about 150 ng /dL , about 200 ng / dL , about 250 ng / dL , 20 administration of oral formulations of the disclosure for a about 280 ng / dL ??, about 300 ng / dL , about 350 ng / dL , about suspension period , a subject's serum testosterone level may 400 ng / dL , about 450 ng / dL , about 500 ng /dL , about 550 increase to greater than or about 350 ng / dL after the begin ng / dL , or about 600 ng / dL within 70 days of the beginning ning of the suspension period. of the suspension period . In some embodiments after stop In some embodiments after stopping once - daily adminis ping once - daily administration of oral formulations of the 25 tration of oral formulations comprising Compound 1 , or a disclosure for a suspension period , a subject's serum tes pharmaceutically acceptable salt thereof, for a suspension tosterone level may increase to greater than or about 60 period , a subject's serum testosterone level may increase to ng / dL , about 65 ng /dL , about 70 ng / dL , about 75 ng / dL , about 50 ng /dL to about 100 ng / dL , about 100 ng / dL to about about 80 ng /dL , about 85 ng / dL , about 90 ng /dL , about 95 150 ng / dL , about 150 ng / dL to about 200 ng /dL , about 200 ng / dL , about 100 ng /dL , about 150 ng / dL , about 200 ng / dL , 30 ng / dL to about 250 ng / dL , about 250 ng / dL to about 300 about 250 ng /dL , about 280 ng / dL , about 300 ng /dL , about ng /dL , about 300 ng /dL to about 350 ng /dL , about 350 ng /dL 350 ng / dL , about 400 ng / dL , about 450 ng / dL , about 500 to about 400 ng / dL , about 400 ng / dL to about 450 ng / dL , ng / dL , about 550 ng / dL , or about 600 ng / dL within 75 days about 450 ng /dL to about 500 ng /dL , about 500 ng / dL of the beginning of the suspension period . In some embodi about 550 ng / dL , about 550 ng / dL to about 600 ng / dL , or ments after stopping once - daily administration of oral for- 35 about 300 ng / dL to about 600 ng / dL within 1 day of the mulations of the disclosure for a suspension period , a beginning of the suspension period . In some embodiments subject's serum testosterone level may increase to greater after stopping once - daily administration of oral formulations than or about 60 ng /dL , about 65 ng / dL , about 70 ng / dL , of the disclosure for a suspension period , a subject's serum about 75 ng / dL , about 80 ng / dL , about 85 ng /dL , about 90 testosterone level may increase to about 50 ng /dL to about ng / dL , about 95 ng / dL , about 100 ng / dL , about 150 ng / dL , 40 100 ng / dL , about 100 ng / dL to about 150 ng /dL , about 150 about 200 ng / dL , about 250 ng / dL , about 280 ng /dL , about ng /dL to about 200 ng / dL , about 200 ng / dL to about 250 300 ng / dL , about 350 ng /dL , about 400 ng /dL , about 450 ng /dL , about 250 ng /dL to about 300 ng /dL , about 300 ng /dL ng / dL , about 500 ng / dL , about 550 ng / dL , or about 600 to about 350 ng / dL , about 350 ng / dL to about 400 ng / dL , ng / dL within 80 days of the beginning of the suspension about 400 ng / dL to about 450 ng /dL , about 450 ng / dL to period. In some embodiments after stopping once - daily 45 about 500 ng / dL , about 500 ng /dL to about 550 ng / dL , about administration of oral formulations of the disclosure for a 550 ng / dL to about 600 ng / dL , or about 300 ng /dL to about suspension period, a subject's serum testosterone level may 600 ng / dL within 2 days of the beginning of the suspension increase to greater than or about 60 ng / dL , about 65 ng / dL , period. In some embodiments after stopping once - daily about 70 ng /dL , about 75 ng / dL , about 80 ng / dL , about 85 administration of oral formulations of the disclosure for a ng / dL , about 90 ng / dL , about 95 ng / dL , about 100 ng / dL , 50 suspension period , a subject’s serum testosterone level may about 150 ng / dL , about 200 ng / dL , about 250 ng /dL , about increase to about 50 ng / dL to about 100 ng / dL , about 100 280 ng / dL , about 300 ng / dL , about 350 ng / dL , about 400 ng / dL to about 150 ng / dL , about 150 ng / dL to about 200 ng / dL , about 450 ng /dL , about 500 ng /dL , about 550 ng / dL , ng /dL , about 200 ng /dL to about 250 ng /dL , about 250 ng /dL or about 600 ng / dL within 85 days of the beginning of the to about 300 ng / dL , about 300 ng / dL to about 350 ng / dL , suspension period. In some embodiments after stopping 55 about 350 ng / dL to about 400 ng / dL , about 400 ng / dL to once - daily administration of oral formulations of the disclo about 450 ng / dL , about 450 ng /dL to about 500 ng / dL , about sure for a suspension period, a subjects serum testosterone 500 ng / dL to about 550 ng / dL , about 550 ng / dL to about 600 level may increase to greater than or about 60 ng /dL , about ng/ dL , or about 300 ng /dL to about 600 ng / dL within 3 days 65 ng/ dL , about 70 ng / dL , about 75 ng /dL , about 80 ng / dL , of the beginning of the suspension period . In some embodi about 85 ng / dL , about 90 ng / dL , about 95 ng / dL , about 100 60 ments after stopping once - daily administration of oral for ng / dL , about 150 ng /dL , about 200 ng / dL , about 250 ng / dL , mulations of the disclosure for a suspension period , a about 280 ng / dL , about 300 ng / dL , about 350 ng /dL , about subject's serum testosterone level may increase to about 50 400 ng / dL , about 450 ng /dL , about 500 ng / dL , about 550 ng / dL to about 100 ng / dL , about 100 ng / dL to about 150 ng / dL , or about 600 ng / dL within 90 days of the beginning ng / dL , about 150 ng / dL to about 200 ng / dL , about 200 ng /dL of the suspension period . In some embodiments after stop- 65 to about 250 ng / dL , about 250 ng / dL to about 300 ng / dL , ping once - daily administration of oral formulations of the about 300 ng /dL to about 350 ng /dL , about 350 ng / dL to disclosure for a suspension period, a subject's serum tes about 400 ng /dL , about 400 ng / dL to about 450 ng /dL , about US 10,786,501 B2 31 32 450 ng / dL to about 500 ng / dL , about 500 ng /dL to about 550 250 ng / dL to about 300 ng /dL , about 300 ng / dL to about 350 ng / dL , about 550 ng / dL to about 600 ng /dL , or about 300 ng / dL , about 350 ng /dL to about 400 ng / dL , about 400 ng /dL ng / dL to about 600 ng /dL within 4 days of the beginning of to about 450 ng / dL , about 450 ng / dL to about 500 ng / dL , the suspension period . In some embodiments after stopping about 500 ng / dL to about 550 ng / dL , about 550 ng / dL to once - daily administration of oral formulations of the disclo- 5 about 600 ng / dL , or about 300 ng / dL to about 600 ng / dL sure for a suspension period, a subject's serum testosterone within 20 days of the beginning of the suspension period . In level may increase to about 50 ng / dL to about 100 ng / dL , some embodiments after stopping once - daily administration about 100 ng / dL to about 150 ng / dL , about 150 ng / dL to of oral formulations of the disclosure for a suspension about 200 ng / dL , about 200 ng /dL to about 250 ng /dL , about period, a subject's serum testosterone level may increase to 250 ng /dL to about 300 ng /dL , about 300 ng / dL to about 350 10 about 50 ng /dL to about 100 ng / dL , about 100 ng / dL to about ng / dL , about 350 ng /dL to about 400 ng /dL , about 400 ng / dL 150 ng / dL , about 150 ng / dL to about 200 ng / dL , about 200 to about 450 ng / dL , about 450 ng / dL to about 500 ng / dL , ng / dL to about 250 ng / dL , about 250 ng / dL to about 300 about 500 ng / dL to about 550 ng / dL , about 550 ng / dL to ng/ dL , about 300 ng /dL to about 350 ng /dL , about 350 ng /dL about 600g , about 300g tabout60ng to about 400 ng / dL , about 400 ng / dL to about 450 ng / dL , within 5 days of the beginning of the suspension period . In 15 about 450 ng / dL to about 500 ng / dL , about 500 ng / dL to some embodiments after stopping once - daily administration about 550 ng / dL , about 550 ng / dL to about 600 ng / dL , or of oral formulations of the disclosure for a suspension about 300 ng / dL to about 600 ng /dL within 25 days of the period , a subject's serum testosterone level may increase to beginning of the suspension period . In some embodiments about 50ng tabut10ng , about 10gabout after stopping once - daily administration of oral formulations 150 ng / dL , about 150 ng / dL to about 200 ng / dL , about 200 20 of the disclosure for a suspension period, a subject's serum ng / dL to about 250 ng / dL , about 250 ng / dL to about 300 testosterone level may increase to about 50 ng /dL to about ng / dL , about 300 ng /dL to about 350 ng /dL , about 350 ng / dL 100 ng /dL , about 100 ng / dL to about 150 ng /dL , about 150 to about 400 ng / dL , about 400 ng / dL to about 450 ng / dL , ng / dL to about 200 ng / dL , about 200 ng / dL to about 250 about 450 ng / dL to about 500 ng / dL , about 500 ng / dL to ng /dL , about 250 ng / dL to about 300 ng / dL , about 300 ng /dL about 550 ng / dL , about 550 ng / dL to about 600 ng / dL , or 25 to about 350 ng / dL , about 350 ng / dL to about 400 ng / dL , about 300 ng / dL to about 600 ng / dL within 6 days of the about 400 ng /dL to about 450 ng /dL , about 450 ng / dL to beginning of the suspension period. In some embodiments about 500 ng /dL , about 500 ng /dL to about 550 ng/ dL , about after stopping once - daily administration of oral formulations 550 ng / dL to about 600 ng / dL , or about 300 ng /dL to about of the disclosure for a suspension period, a subject's serum 600 ng /dL within 30 days of the beginning of the suspension testosterone level may increase to about 50 ng / dL to about 30 period . In some embodiments after stopping once - daily 100 ng / dL , about 100 ng /dL to about 150 ng / dL , about 150 administration of oral formulations of the disclosure for a ng / dL to about 200 ng / dL , about 200 ng / dL to about 250 suspension period , a subject's serum testosterone level may ng / dL , about 250 ng /dL to about 300 ng /dL , about 300 ng /di increase to about 50 ng /dL to about 100 ng /dL , about 100 to about 350 ng / dL , about 350 ng / dL to about 400 ng / dL , ng / dL to about 150 ng / dL , about 150 ng / dL to about 200 about 400 ng / dL to about 450 ng / dL , about 450 ng / dL to 35 ng / dL , about 200 ng / dL to about 250 ng / dL , about 250 ng /dL about 500 ng / dL , about 500 ng /dL to about 550 ng /dL , about to about 300 ng / dL , about 300 ng / dL to about 350 ng / dL , 550 ng /dL to about 600 ng / dL , or about 300 ng /dL to about about 350 ng /dL to about 400 ng / dL , about 400 ng / dL to 600 ng / dL within 7 days of the beginning of the suspension about 450 ng / dL , about 450 ng /dL to about 500 ng /dL , about period. In some embodiments after stopping once - daily 500 ng / dL to about 550 ng / dL , about 550 ng / dL to about 600 administration of oral formulations of the disclosure forang , about 30ngt about 60ngwithin 3days suspension period, a subject's serum testosterone level may of the beginning of the suspension period . In some embodi increase to about 50 ng /dL to about 100 ng /dL , about 100 ments after stopping once -daily administration of oral for ng / dL to about 150 ng / dL , about 150 ng /dL to about 200 mulations of the disclosure for a suspension period , a ng / dL , about 200 ng /dL to about 250 ng /dL , about 250 ng / dL subject's' s serum testosterone level may increase to about 50 to about 300 ng / dL , about 300 ng / dL to about 350 ng / dL , 45 ng / dL to about 100 ng / dL , about 100 ng / dL to about 150 about 350 ng /dL to about 400 ng / dL , about 400 ng / dL to ng /dL , about 150 ng / dL to about 200 ng / dL , about 200 ng / dL about 450ng , about 450 ngabout 50g , about to about 250 ng / dL , about 250 ng / dL to about 300 ng / dL , 500 ng / dL to about 550 ng / dL , about 550 ng / dL to about 600 about 300 ng / dL to about 350 ng /dL , about 350 ng / dL to ng / dL , or about 300 ng / dL to about 600 ng / dL within 10 days about 400 ng / dL , about 400 ng / dL to about 450 ng / dL , about of the beginning of the suspension period. In some embodi- 50 450 ng / dL to about 500 ng / dL , about 500 ng / dL to about 550 ments after stopping once - daily administration of oral for ng / dL , about 550 ng / dL to about 600 ng / dL , or about 300 mulations of the disclosure for a suspension period , a ng /dL to about 600 ng / dL within 40 days of the beginning of subject's serum testosterone level may increase to about 50 the suspension period . In some embodiments after stopping ng / dL to about 100 ng / dL , about 100 ng /dL to about 150 once - daily administration of oral formulations of the disclo ng / dL , about 150 ng / dL to about 200 ng / dL , about 200 ng / dL 55 sure for a suspension period, a subject's serum testosterone to about 250 ng / dL , about 250 ng / dL to about 300 ng / dL , level may increase to about 50 ng / dL to about 100 ng / dL , about 300 ng / dL to about 350 ng / dL , about 350 ng / dL to about 100 ng /dL to about 150 ng / dL , about 150 ng / dL to about 400 ng /dL , about 400 ng /dL to about 450 ng /dL , about about 200 ng /dL , about 200 ng /dL to about 250 ng /dL , about 450 ng / dL to about 500 ng / dL , about 500 ng / dL to about 550 250 ng / dL to about 300 ng / dL , about 300 ng / dL to about 350 ng / dL , about 550 ng / dL to about 600 ng / dL , or about 300 60 ng / dL , about 350 ng / dL to about 400 ng / dL , about 400 ng /dL ng / dL to about 600 ng / dL within 15 days of the beginning of to about 450 ng / dL , about 450 ng / dL to about 500 ng / dL , the suspension period. In some embodiments after stopping about 500 ng /dL to about 550 ng / dL , about 550 ng / dL to once - daily administration of oral formulations of the disclo about 600 ng /dL , or about 300 ng / dL to about 600 ng /dL sure for a suspension period , a subject's serum testosterone within 45 days of the beginning of the suspension period . In level may increase to about 50 ng / dL to about 100 ng / dL , 65 some embodiments after stopping once - daily administration about about 150 g , about 150 ng of oral formulations of the disclosure for a suspension about 200 ng / dL , about 200 ng /dL to about 250 ng / dL , about period , a subject's serum testosterone level may increase to US 10,786,501 B2 33 34 about 50 ng / dL to about 100 ng / dL , about 100 ng / dL to about after stopping once - daily administration of oral formulations 150 ng / dL , about 150 ng /dL to about 200 ng / dL , about 200 of the disclosure for a suspension period, a subject's serum ng / dL to about 250 ng / dL , about 250 ng /dL to about 300 testosterone level may increase to about 50 ng / dL to about ng / dL , about 300 ng /dL to about 350 ng / dL , about 350 ng /dL 100 ng /dL , about 100 ng /dL to about 150 ng /dL , about 150 to about 400 ng / dL , about 400 ng / dL to about 450 ng / dL , 5 ng / dL to about 200 ng / dL , about 200 ng / dL to about 250 about 450 ng /dL to about 500 ng / dL , about 500 ng / dL to ng / dL , about 250 ng / dL to about 300 ng / dL , about 300 ng /dL about 550 ng / dL , about 550 ng / dL to about 600 ng / dL , or to about 350 ng / dL , about 350 ng / dL to about 400 ng / dL , about 300 ng /dL to about 600 ng / dL within 50 days of the about 400 ng / dL to about 450 ng /dL , about 450 ng / dL to beginning of the suspension period . In some embodiments about 500 ng / dL , about 500 ng / dL to about 550 ng / dL , about after stopping once -daily administration of oral formulations 10 550 ng /dL to about 600 ng / dL , or about 300 ng /dL to about of the disclosure for a suspension period , a subject's serum 600 ng /dL within 80 days of the beginning of the suspension testosterone level may increase to about 50 ng /dL to about period . In some embodiments after stopping once - daily 100 ng / dL , about 100 ng /dL to about 150 ng / dL , about 150 administration of oral formulations of the disclosure for a ng / dL to about 200 ng / dL , about 200 ng /dL to about 250 suspension period , a subject's serum testosterone level may ng / dL , about 250 ng / dL to about 300 ng / dL , about 300 ng / dL 15 increase to about 50 ng / dL to about 100 ng /dL , about 100 to about 350 ng / dL , about 350 ng / dL to about 400 ng / dL , ng / dL to about 150 ng / dL , about 150 ng / dL to about 200 about 400 ng / dL to about 450 ng / dL , about 450 ng / dL to ng /dL , about 200 ng / dL to about 250 ng / dL , about 250 ng /dL about 500 ng / dL , about 500 ng /dL to about 550 ng / dL , about to about 300 ng / dL , about 300 ng / dL to about 350 ng / dL , 550 ng / dL to about 600 ng / dL , or about 300 ng /dL to about about 350 ng / dL to about 400 ng / dL , about 400 ng / dL to 600 ng / dL within 50 days of the beginning of the suspension 20 about 450 ng / dL , about 450 ng /dL to about 500 ng / dL , about period . In some embodiments after stopping once - daily 500 ng / dL to about 550 ng / dL , about 550 ng /dL to about 600 administration of oral formulations of the disclosure for a ng /dL , or about 300 ng / dL to about 600 ng / dL within 85 days suspension period , a subject's serum testosterone level may of the beginning of the suspension period . In some embodi increase to about 50 ng /dL to about 100 ng / dL , about 100 ments after stopping once - daily administration of oral for ng / dL to about 150 ng / dL , about 150 ng / dL to about 200 25 mulations of the disclosure for a suspension period , a ng / dL , about 200 ng / dL to about 250 ng /dL , about 250 ng / dL subject's serum testosterone level may increase to about 50 to about 300 ng / dL , about 300 ng / dL to about 350 ng / dL , ng / dL to about 100 ng / dL , about 100 ng / dL to about 150 about 350 ng / dL to about 400 ng / dL , about 400 ng / dL to ng / dL , about 150 ng /dL to about 200 ng /dL , about 200 ng /dL about 450 ng / dL , about 450 ng /dL to about 500 ng /dL , about to about 250 ng / dL , about 250 ng / dL to about 300 ng / dL , 500 ng / dL to about 550 ng / dL , about 550 ng / dL to about 600 30 about 300 ng / dL to about 350 ng / dL , about 350 ng / dL to ng / dL , or about 300 ng / dL to about 600 ng / dL within 60 days about 400 ng / dL , about 400 ng /dL to about 450 ng/ dL , about of the beginning of the suspension period . In some embodi 450 ng / dL to about 500 ng / dL , about 500 ng / dL to about 550 ments after stopping once - daily administration of oral for ng /dL , about 550 ng / dL to about 600 ng /dL , or about 300 mulations of the disclosure for a suspension period , a ng /dL to about 600 ng / dL within 90 days of the beginning of subject's serum testosterone level may increase to about 50 35 the suspension period. In some embodiments after stopping ng / dL to about 100 ng / dL , about 100 ng / dL to about 150 once - daily administration of oral formulations of the disclo ng / dL , about 150 ng /dL to about 200 ng / dL , about 200 ng /dL sure for a suspension period , a subject's serum testosterone to about 250 ng / dL , about 250 ng / dL to about 300 ng / dL , level may increase to about 50 ng /dL to about 100 ng / dL , about 300 ng / dL to about 350 ng / dL , about 350 ng / dL to about 100 ng / dL to about 150 ng/ dL , about 150 ng / dL to about 400 ng / dL , about 400 ng /dL to about 450 ng / dL , about 40 about 200 ng /dL , about 200 ng /dL to about 250 ng /dL , about 450 ng /dL to about 500 ng / dL , about 500 ng / dL to about 550 250 ng / dL to about 300 ng /dL , about 300 ng / dL to about 350 ng / dL , about 550 ng / dL to about 600 ng /dL , or about 300 ng/ dL , about 350 ng /dL to about 400 ng / dL , about 400 ng /dL ng / dL to about 600 ng / dL within 65 days of the beginning of to about 450 ng / dL , about 450 ng / dL to about 500 ng / dL , the suspension period. In some embodiments after stopping about 500 ng / dL to about 550 ng / dL , about 550 ng / dL to once - daily administration of oral formulations of the disclo- 45 about 600 ng / dL , or about 300 ng / dL to about 600 ng / dL sure for a suspension period, a subject's serum testosterone within 95 days of the beginning of the suspension period . In level may increase to about 50 ng / dL to about 100 ng / dL , some embodiments after stopping once - daily administration about 100 ng / dL to about 150 ng / dL , about 150 ng / dL to of oral formulations of the disclosure for a suspension about 200 ng / dL , about 200 ng /dL to about 250 ng /dL , about period, a subject's serum testosterone level may increase to 250 ng /dL to about 300 ng /dL , about 300 ng / dL to about 350 50 about 50 ng /dL to about 100 ng / dL , about 100 ng / dL to about ng / dL , about 350 ng /dL to about 400 ng /dL , about 400 ng / dL 150 ng / dL , about 150 ng / dL to about 200 ng / dL , about 200 to about 450 ng / dL , about 450 ng / dL to about 500 ng / dL , ng / dL to about 250 ng / dL , about 250 ng / dL to about 300 about 500 ng / dL to about 550 ng / dL , about 550 ng / dL to ng / dL , about 300 ng / dL to about 350 ng / dL , about 350 ng / dL about 600 ng / dL , or about 300 ng / dL to about 600 ng / dL to about 400 ng / dL , about 400 ng / dL to about 450 ng / dL , within 70 days of the beginning of the suspension period. In 55 about 450 ng / dL to about 500 ng / dL , about 500 ng / dL to some embodiments after stopping once -daily administration about 550 ng / dL , about 550 ng / dL to about 600 ng / dL , or of oral formulations of the disclosure for a suspension about 300 ng / dL to about 600 ng /dL within 100 days of the period , a subject's serum testosterone level may increase to beginning of the suspension period . In some embodiments about 50 ng /dL to about 100 ng / dL , about 100 ng /dL to about after stopping once - daily administration of oral formulations 150 ng/ dL , about 150 ng /dL to about 200 ng / dL , about 200 60 of the disclosure for a suspension period, a subject's serum ng / dL to about 250 ng / dL , about 250 ng / dL to about 300 testosterone level may increase to about 300 ng /dL to about ng / dL , about 300 ng /dL to about 350 ng /dL , about 350 ng / dL 600 ng / dL after the beginning of the suspension period . to about 400 ng / dL , about 400 ng / dL to about 450 ng / dL , In some embodiments, a subject's serum testosterone about 450 ng / dL to about 500 ng / dL , about 500 ng / dL to level may be suppressed prior to and after the suspension of about 550 ng / dL , about 550 ng / dL to about 600 ng /dL , or 65 administration ( e.g. , the serum testosterone level is below about 300 ng /dL to about 600 ng /dL within 75 days of the the medical castration level, profound medical castration beginning of the suspension period. In some embodiments level , significantly lower than the subject's level prior to US 10,786,501 B2 35 36 treatment ( e.g. , less than 50 % of pre - treatment level , less administration . In some embodiments , after resuming once than 40 % , less than 30 % , less than 20 % , less than 10 % , less daily administration of an oral formulation of the disclosure than 5 % , or less than 1 % ) ) . comprising about 180 mg of Compound 1 , or a correspond With respect to onset , the present disclosure also provides ing amount of a pharmaceutically acceptable salt thereof, for resuming once - daily administration of an oral formula- 5 after a suspension period, serum testosterone levels in a tion of the disclosure or an oral load dose formulation and subject may be at or below medical castration level within an oral maintenance dose formulation of the disclosure after a suspension period to achieve a return to medical castration 4 days after commencing administration . In some embodi levels of serum testosterone. As noted previously, resuming ments , after resuming once - daily administration of an oral once - daily administration with Compound 1 , or a pharma- 10 formulation of the disclosure comprising about 180 mg of ceutically acceptable salt thereof, does not include the Compound 1 , or a corresponding amount of a pharmaceu disadvantageous clinical flare associated with GnRH ago tically acceptable salt thereof, after a suspension period, nists and therefore should not lead to worsening of symp serum testosterone levels in a subject may be at or below toms or erosion of prior gains in treatment as would restart medical castration level within 5 days after commencing ing treatment after a suspension period when treating with 15 administration . In some embodiments , after resuming once GnRH agonists . In some embodiments , within about 4 to daily administration of an oral formulation of the disclosure about 8 days of first administering once - daily an oral for comprising about 180 mg of Compound 1 , or a correspond mulation of the disclosure or an oral load dose formulation ing amount of a pharmaceutically acceptable salt thereof, and an oral maintenance dose formulation of the disclosure after a suspension period , serum testosterone levels in a after a suspension period , the serum testosterone levels in 20 subject may be at or below medical castration level within the subject may be at or below medical castration level . In 6 days after commencing administration . In some embodi some embodiments, within 4 days of first administering ments , after resuming once - daily administration of an oral once - daily an oral formulation of the disclosure or an oral formulation of the disclosure comprising about 180 mg of load dose formulation and an oral maintenance dose formu Compound 1 , or a corresponding amount of a pharmaceu lation of the disclosure after a suspension period , the serum 25 tically acceptable salt thereof, after a suspension period, testosterone levels in the subject may be at or below medical serum testosterone levels in a subject may be at or below castration level . In some embodiments , within 5 days of first medical castration level within 1 week after commencing administering once - daily an oral formulation of the disclo administration . sure or an oral load dose formulation and an oral mainte In some embodiments , after resuming once - daily admin nance dose formulation of the disclosure after a suspension 30 istration of an oral formulation of the disclosure comprising period , the serum testosterone levels in the subject may be about 80 mg to about 160 mg of Compound 1 , or a at or below medical castration level . In some embodiments , corresponding amount of a pharmaceutically acceptable salt within 6 days of first administering once - daily an oral eof, after a suspension period, serum testosterone levels formulation of the disclosure or an oral load dose formula in a subject may be at or below medical castration level tion and an oral maintenance dose formulation of the dis- 35 within 24 hours to 48 hours after commencing administra closure after a suspension period , the serum testosterone tion . In some embodiments, after resuming once - daily levels in the subject may be at or below medical castration administration of an oral formulation of the disclosure level . In some embodiments, within 7 days of first admin comprising about 80 mg to about 160 mg of Compound 1 , istering once -daily an oral formulation of the disclosure or or a corresponding amount of a pharmaceutically acceptable an oral load dose formulation and an oral maintenance dose 40 salt thereof, after a suspension period , serum testosterone formulation of the disclosure after a suspension period , the levels in a subject may be at or below medical castration serum testosterone levels in the subject may be at or below level within 3 days after commencing administration . In medical castration level. In some embodiments , within 8 some embodiments , after resuming once - daily administra days of first administering once - daily an oral formulation of tion of an oral formulation of the disclosure comprising the disclosure or an oral load dose formulation and an oral 45 about 80 mg to about 160 mg of Compound 1 , or a maintenance dose formulation of the disclosure after a corresponding amount of a pharmaceutically acceptable salt suspension period, the serum testosterone levels in the thereof, after a suspension period, serum testosterone levels subject may be at or below medical castration level . In some in a subject may be at or below medical castration level embodiments, within 3 days of first administering once within 4 days after commencing administration . In some daily an oral formulation of the disclosure or an oral load 50 embodiments, after resuming once - daily administration of dose formulation and an oral maintenance dose formulation an oral formulation of the disclosure comprising about 80 of the disclosure after a suspension period, the serum mg to about 160 mg of Compound 1 , or a corresponding testosterone levels in the subject may be at or below medical amount of a pharmaceutically acceptable salt thereof, after castration level . a suspension period, serum testosterone levels in a subject In some embodiments, after resuming once -daily admin- 55 may be at or below medical castration level within 5 days istration of an oral formulation of the disclosure comprising after commencing administration . In some embodiments, about 180 mg of Compound 1 , or a corresponding amount after resuming once -daily administration of an oral formu of a pharmaceutically acceptable salt thereof, after a sus lation of the disclosure comprising about 80 mg to about 160 pension period, serum testosterone levels in a subject may be mg of Compound 1 , or a corresponding amount of a phar at or below medical castration level within 24 hours to 48 60 maceutically acceptable salt thereof, after a suspension hours after commencing administration . In some embodi period, serum testosterone levels in a subject may be at or ments , after resuming once -daily administration of an oral below medical castration level within 6 days after commenc formulation of the disclosure comprising about 180 mg of ing administration . In some embodiments , after resuming Compound 1 , or a corresponding amount of a pharmaceu once - daily administration of an oral formulation of the tically acceptable salt thereof, after a suspension period , 65 disclosure comprising about 80 mg to about 160 mg of serum testosterone levels in a subject may be at or below Compound 1 , or a corresponding amount of a pharmaceu medical castration level within 3 days after commencing tically acceptable salt thereof, after a suspension period , US 10,786,501 B2 37 38 serum testosterone levels in a subject may be at or below amount of a pharmaceutically acceptable salt thereof, once medical castration level within 1 week after commencing daily for 1-3 days at the beginning of treatment after a administration . suspension period, and once -daily administration of an oral In some embodiments , after resuming once - daily admin maintenance dose formulation of the disclosure comprising istration of an oral formulation of the disclosure comprising 5 120 mg of Compound 1 , or a corresponding amount of a about 120 mg of Compound 1 , or a corresponding amount pharmaceutically acceptable salt thereof, starting on the day of a pharmaceutically acceptable salt thereof, after a sus after administering the last dose of the oral load dose pension period , serum testosterone levels in a subject may be formulation , and continuing for a set treatment period , at or below medical castration level within 24 hours to 48 serum testosterone levels in a subject may be at or below hours after commencing administration . In some embodi- 10 medical castration level within 3 days after commencing ments , after resuming once - daily administration of an oral administration and maintained until the end of administra formulation of the disclosure comprising about 120 mg of tion . In some embodiments, following administration of an Compound 1 , or a corresponding amount of a pharmaceu oral load dose formulation of the disclosure comprising 240 tically acceptable salt thereof, after a suspension period , mg of Compound 1 , or a corresponding amount of a phar serum testosterone levels in a subject may be at or below 15 maceutically acceptable salt thereof, on once - daily for 1-3 medical castration level within 3 days after commencing days at the beginning of treatment after a suspension period, administration . In some embodiments , after resuming once and once - daily administration of an oral maintenance dose daily administration of an oral formulation of the disclosure formulation of the disclosure comprising 120 mg of Com comprising about 120 mg of Compound 1 , or a correspond pound 1 , or a corresponding amount of a pharmaceutically ing amount of a pharmaceutically acceptable salt thereof, 20 acceptable salt thereof, starting on the day after administer after a suspension period , serum testosterone levels in a ing the last dose of the oral load dose formulation, and subject may be at or below medical castration level within continuing for a set treatment period , serum testosterone 4 days after commencing administration . In some embodi levels in a subject may be at or below medical castration ments, after resuming once - daily administration of an oral level within 4 days after commencing administration and formulation of the disclosure comprising about 120 mg of 25 maintained until the end of administration . In some embodi Compound 1 , or a corresponding amount of a pharmaceu ments , following administration of an oral load dose formu tically acceptable salt thereof, after a suspension period , lation of the disclosure comprising 240 mg of Compound 1 , serum testosterone levels in a subject may be at or below or a corresponding amount of a pharmaceutically acceptable medical castration level within 5 days after commencing salt thereof, once - daily for 1-3 days at the beginning of administration . In some embodiments, after resuming once- 30 treatment after a suspension period , and once - daily admin daily administration of an oral formulation of the disclosure istration of an oral maintenance dose formulation of the comprising about 120 mg of Compound 1 , or a correspond disclosure comprising 120 mg of Compound 1 , or a corre ing amount of a pharmaceutically acceptable salt thereof, sponding amount of a pharmaceutically acceptable salt after a suspension period , serum testosterone levels in a thereof, starting on the day after administering the last dose subject may be at or below medical castration level within 35 of the oral load dose formulation , and continuing for a set 6 days after commencing administration . In some embodi treatment period , serum testosterone levels in a subject may ments , after resuming once - daily administration of an oral be at or below medical castration level within 5 days after formulation of the disclosure comprising about 120 mg of commencing administration and maintained until the end of Compound 1 , or a corresponding amount of a pharmaceu administration . In some embodiments, following adminis tically acceptable salt thereof, after a suspension period , 40 tration of an oral load dose formulation of the disclosure serum testosterone levels in a subject may be at or below comprising 240 mg of Compound 1 , or a corresponding medical castration level within 1 week after commencing amount of a pharmaceutically acceptable salt thereof, once administration . daily for 1-3 days at the beginning of treatment after a In some embodiments , following administration of an oral suspension period , and once - daily administration of an oral load dose formulation of the disclosure comprising 240 mg 45 maintenance dose formulation of the disclosure comprising of Compound 1 , or a corresponding amount of a pharma 120 mg of Compound 1 , or a corresponding amount of a ceutically acceptable salt thereof, once -daily for 1-3 days at pharmaceutically acceptable salt thereof, starting on the day the beginning of treatment after a suspension period, and after administering the last dose of the oral load dose once - daily administration of an oral maintenance dose for formulation , and continuing for a set treatment period , mulation of the disclosure comprising 120 mg of Compound 50 serum testosterone levels in a subject may be at or below 1 , or a corresponding amount of a pharmaceutically accept medical castration level within 6 days after commencing able salt thereof, starting on the day after administering the administration and maintained until the end of administra last dose of the oral load dose formulation , and continuing tion . In some embodiments, following administration of an for a set treatment period ( e.g. , at least 4 consecutive weeks oral load dose formulation of the disclosure comprising 240 or greater, at least 8 consecutive weeks or greater, at least 12 55 mg of Compound 1 , or a corresponding amount of a phar consecutive weeks or greater, at least 16 consecutive weeks maceutically acceptable salt thereof, once - daily for 1-3 days or greater, at least 20 consecutive weeks or greater, 24 at the beginning of treatment after a suspension period , and consecutive weeks or greater, 36 consecutive weeks or once - daily administration of an oral maintenance dose for greater, 48 consecutive weeks or greater, 52 consecutive mulation of the disclosure comprising 120 mg of Compound weeks or greater, 72 consecutive weeks or greater, or 96 60 1 , or a corresponding amount of a pharmaceutically accept consecutive weeks or greater ), medical castration levels of able salt thereof, starting on the day after administering the less than or equal to 50 ng / dL ( 1.73 nmol/ L ) serum testos last dose of the oral load dose formulation , and continuing terone may be achieved within 24 to 48 hours after com for a set treatment period , serum testosterone levels in a mencing administration and maintained until the end of subject may be at or below medical castration level within administration . In some embodiments, following adminis- 65 1 week after commencing administration and maintained tration of an oral load dose formulation of the disclosure until the end of administration . In some embodiments , comprising 240 mg of Compound 1 , or a corresponding following administration of an oral load dose formulation of US 10,786,501 B2 39 40 the disclosure comprising 240 mg of Compound 1 , or a maintenance dose formulation of the disclosure comprising corresponding amount of a pharmaceutically acceptable salt 120 mg of Compound 1 , or a corresponding amount of a thereof, once - daily for 1-3 days at the beginning of treatment pharmaceutically acceptable salt thereof, starting on the day after a suspension period, and once - daily administration of after administering the last dose of the oral load dose an oral maintenance dose formulation of the disclosure 5 formulation , and continuing for a set treatment period , comprising 120 mg of Compound 1 , or a corresponding serum testosterone levels in a subject may be at or below amount of a pharmaceutically acceptable salt thereof, start medical castration level within 3 days after commencing ing on the day after administering the last dose of the oral administration and maintained until the end of administra load dose formulation , and continuing for a set treatment tion . In some embodiments, following administration of an period, serum testosterone levels in a subject may be at or 10 oral load dose formulation of the disclosure comprising 360 below medical castration level within 2 weeks after com mg of Compound 1 , or a corresponding amount of a phar mencing administration and maintained until the end of maceutically acceptable salt thereof, on once - daily for 1-3 administration . In some embodiments, following adminis days at the beginning of treatment after a suspension period , tration of an oral load dose formulation of the disclosure and once - daily administration of an oral maintenance dose comprising 240 mg of Compound 1 , or a corresponding 15 formulation of the disclosure comprising 120 mg of Com amount of a pharmaceutically acceptable salt thereof, once pound 1 , or a corresponding amount of a pharmaceutically daily for 1-3 days at the beginning of treatment after a acceptable salt thereof, starting on the day after administer suspension period , and once -daily administration of an oral ing the last dose of the oral load dose formulation , and maintenance dose formulation of the disclosure comprising continuing for a set treatment period , serum testosterone 120 mg of Compound 1 , or a corresponding amount of a 20 levels in a subject may be at or below medical castration pharmaceutically acceptable salt thereof, starting on the day level within 4 days after commencing administration and after administering the last dose of the oral load dose maintained until the end of administration . In some embodi formulation, and continuing for a set treatment period, ments , following administration of an oral load dose formu serum testosterone levels in a subject may be at or below lation of the disclosure comprising 360 mg of Compound 1 , medical castration level within 3 weeks after commencing 25 or a corresponding amount of a pharmaceutically acceptable administration and maintained until the end of administra salt thereof, once - daily for 1-3 days at the beginning of tion . In some embodiments, following administration of an treatment after a suspension period, and once - daily admin oral load dose formulation of the disclosure comprising 240 istration of an oral maintenance dose formulation of the mg of Compound 1 , or a corresponding amount of a phar disclosure comprising 120 mg of Compound 1 , or a corre maceutically acceptable salt thereof, once -daily for 1-3 days 30 sponding amount of a pharmaceutically acceptable salt at the beginning of treatment after a suspension period , and thereof, starting on the day after administering the last dose once - daily administration of an oral maintenance dose for of the oral load dose formulation , and continuing for a set mulation of the disclosure comprising 120 mg of Compound treatment period, serum testosterone levels in a subject may 1 , or a corresponding amount of a pharmaceutically accept be at or below medical castration level within 5 days after able salt thereof, starting on the day after administering the 35 commencing administration and maintained until the end of last dose of the oral load dose formulation , and continuing administration . In some embodiments, following adminis for a set treatment period, serum testosterone levels in a tration of an oral load dose formulation of the disclosure subject may be at or below medical castration level within comprising 360 mg of Compound 1 , or a corresponding 4 weeks after commencing administration and maintained amount of a pharmaceutically acceptable salt thereof, once until the end of administration . 40 daily for 1-3 days at the beginning of treatment after a In some embodiments , following administration of an oral suspension period , and once - daily administration of an oral load dose formulation of the disclosure comprising 360 mg maintenance dose formulation of the disclosure comprising of Compound 1 , or a corresponding amount of a pharma 120 mg of Compound 1 , or a corresponding amount of a ceutically acceptable salt thereof, once - daily for 1-3 days at pharmaceutically acceptable salt thereof, starting on the day the beginning of treatment after a suspension period , and 45 after administering the last dose of the oral load dose once - daily administration of an oral maintenance dose for formulation , and continuing for a set treatment period, mulation of the disclosure comprising 120 mg of Compound serum testosterone levels in a subject may be at or below 1 , or a corresponding amount of a pharmaceutically accept medical castration level within 6 days after commencing able salt thereof, starting on the day after administering the administration and maintained until the end of administra last dose of the oral load dose formulation , and continuing 50 tion . In some embodiments, following administration of an for a set treatment period ( e.g. , at least 4 consecutive weeks oral load dose formulation of the disclosure comprising 360 or greater, at least 8 consecutive weeks or greater, at least 12 mg of Compound 1 , or a corresponding amount of a phar consecutive weeks or greater, at least 16 consecutive weeks maceutically acceptable salt thereof, once - daily for 1-3 days or greater, at least 20 consecutive weeks or greater, 24 at the beginning of treatment after a suspension period, and consecutive weeks or greater, 36 consecutive weeks or 55 once -daily administration of an oral maintenance dose for greater, 48 consecutive weeks or greater, 52 consecutive mulation of the disclosure comprising 120 mg of Compound weeks or greater, 72 consecutive weeks or greater, or 96 1 , or a corresponding amount of a pharmaceutically accept consecutive weeks or greater ), medical castration levels of able salt thereof, starting on the day after administering the less than or equal to 50 ng / dL ( 1.73 nmol / L ) serum testos last dose of the oral load dose formulation , and continuing terone may be achieved within 24 to 48 hours after com- 60 for a set treatment period, serum testosterone levels in a mencing administration and maintained until the end of subject may be at or below medical castration level within administration . In some embodiments, following adminis 1 week after commencing administration and maintained tration of an oral load dose formulation of the disclosure until the end of administration . In some embodiments, comprising 360 mg of Compound 1 , or a corresponding following administration of an oral load dose formulation of amount of a pharmaceutically acceptable salt thereof, once- 65 the disclosure comprising 360 mg of Compound 1 , or a daily for 1-3 days at the beginning of treatment after a corresponding amount of a pharmaceutically acceptable salt suspension period, and once -daily administration of an oral thereof, once - daily for 1-3 days at the beginning of treatment US 10,786,501 B2 41 42 after a suspension period , and once -daily administration of after administering the last dose of the oral load dose an oral maintenance dose formulation of the disclosure formulation , and continuing for a set treatment period , comprising 120 mg of Compound 1 , or a corresponding serum testosterone levels in a subject may be at or below amount of a pharmaceutically acceptable salt thereof, start profound castration level within 3 days after commencing ing on the day after administering the last dose of the oral 5 administration and maintained until the end of administra load dose formulation , and continuing for a set treatment tion . In some embodiments, following administration of an period, serum testosterone levels in a subject may be at or oral load dose formulation of the disclosure comprising 360 below medical castration level within 2 weeks after com mg of Compound 1 , or a corresponding amount of a phar mencing administration and maintained until the end of maceutically acceptable salt thereof, on once - daily for 1-3 administration . In some embodiments , following adminis- 10 days at the beginning of treatment after a suspension period , tration of an oral load dose formulation of the disclosure and once - daily administration of an oral maintenance dose comprising 360 mg of Compound 1 , or a corresponding formulation of the disclosure comprising 120 mg of Com amount of a pharmaceutically acceptable salt thereof, once pound 1 , or a corresponding amount of a pharmaceutically daily for 1-3 days at the beginning of treatment after a acceptable salt thereof, starting on the day after administer suspension period, and once -daily administration of an oral 15 ing the last dose of the oral load dose formulation , and maintenance dose formulation of the disclosure comprising continuing for a set treatment period , serum testosterone 120 mg of Compound 1 , or a corresponding amount of a levels in a subject may be at or below profound castration pharmaceutically acceptable salt thereof, starting on the day level within 4 days after commencing administration and after administering the last dose of the oral load dose maintained until the end of administration . In some embodi formulation , and continuing for a set treatment period, 20 ments, following administration of an oral load dose formu serum testosterone levels in a subject may be at or below lation of the disclosure comprising 360 mg of Compound 1 , medical castration level within 3 weeks after commencing or a corresponding amount of a pharmaceutically acceptable administration and maintained until the end of administra salt thereof, once - daily for 1-3 days at the beginning of tion . In some embodiments, following administration of an treatment after a suspension period , and once - daily admin oral load dose formulation of the disclosure comprising 360 25 istration of an oral maintenance dose formulation of the mg of Compound 1 , or a corresponding amount of a phar disclosure comprising 120 mg of Compound 1 , or a corre maceutically acceptable salt thereof, once - daily for 1-3 days sponding amount of a pharmaceutically acceptable salt at the beginning of treatment after a suspension period , and thereof, starting on the day after administering the last dose once - daily administration of an oral maintenance dose for of the oral load dose formulation , and continuing for a set mulation of the disclosure comprising 120 mg of Compound 30 treatment period , serum testosterone levels in a subject may 1 , or a corresponding amount of a pharmaceutically accept be at or below profound castration level within 5 days after able salt thereof, starting on the day after administering the commencing administration and maintained until the end of last dose of the oral load dose formulation , and continuing administration . In some embodiments, following adminis for a set treatment period, serum testosterone levels in a tration of an oral load dose formulation of the disclosure subject may be at or below medical castration level within 35 comprising 360 mg of Compound 1 , or a corresponding 4 weeks after commencing administration and maintained amount of a pharmaceutically acceptable salt thereof, once until the end of administration . daily for 1-3 days at the beginning of treatment after a In some embodiments, following administration of an oral suspension period , and once -daily administration of an oral load dose formulation of the disclosure comprising 360 mg maintenance dose formulation of the disclosure comprising of Compound 1 , or a corresponding amount of a pharma- 40 120 mg of Compound 1 , or a corresponding amount of a ceutically acceptable salt thereof, once -daily for 1-3 days at pharmaceutically acceptable salt thereof, starting on the day the beginning of treatment after a suspension period , and after administering the last dose of the oral load dose once - daily administration of an oral maintenance dose for formulation , and continuing for a set treatment period , mulation of the disclosure comprising 120 mg of Compound serum testosterone levels in a subject may be at or below 1 , or a corresponding amount of a pharmaceutically accept- 45 profound castration level within 6 days after commencing able salt thereof, starting on the day after administering the administration and maintained until the end of administra last dose of the oral load dose formulation , and continuing tion . In some embodiments, following administration of an for a set treatment period ( e.g. , at least 4 consecutive weeks oral load dose formulation of the disclosure comprising 360 or greater, at least 8 consecutive weeks or greater, at least 12 mg of Compound 1 , or a corresponding amount of a phar consecutive weeks or greater, at least 16 consecutive weeks 50 maceutically acceptable salt thereof, once - daily for 1-3 days or greater, at least 20 consecutive weeks or greater, 24 at the beginning of treatment after a suspension period , and consecutive weeks or greater, 36 consecutive weeks or once - daily administration of an oral maintenance dose for greater, 48 consecutive weeks or greater, 52 consecutive mulation of the disclosure comprising 120 mg of Compound weeks or greater, 72 consecutive weeks or greater, or 96 1 , or a corresponding amount of a pharmaceutically accept consecutive weeks or greater ), profound castration levels of 55 able salt thereof, starting on the day after administering the less than or equal to 20 ng / dL ( 1.73 nmol/ L ) serum testos last dose of the oral load dose formulation , and continuing terone may be achieved within 24 to 48 hours after com for a set treatment period , serum testosterone levels in a mencing administration and maintained until the end of subject may be at or below profound castration level within administration . In some embodiments, following adminis 1 week after commencing administration and maintained tration of an oral load dose formulation of the disclosure 60 until the end of administration . In some embodiments , comprising 360 mg of Compound 1 , or a corresponding following administration of an oral load dose formulation of amount of a pharmaceutically acceptable salt thereof, once the disclosure comprising 360 mg of Compound 1 , or a daily for 1-3 days at the beginning of treatment after a corresponding amount of a pharmaceutically acceptable salt suspension period , and once - daily administration of an oral thereof, once -daily for 1-3 days at the beginning of treatment maintenance dose formulation of the disclosure comprising 65 after a suspension period , and once - daily administration of 120 mg of Compound 1 , or a corresponding amount of a an oral maintenance dose formulation of the disclosure pharmaceutically acceptable salt thereof, starting on the day comprising 120 mg of Compound 1 , or a corresponding US 10,786,501 B2 43 44 amount of a pharmaceutically acceptable salt thereof, start or equal to about 80 % , or greater than or equal to about 90 % ing on the day after administering the last dose of the oral of the subject's serum PSA levels prior to treatment com load dose formulation , and continuing for a set treatment mencing. In some embodiments , after resuming once - daily period, serum testosterone levels in a subject may be at or administration of oral formulations of the disclosure for 4 below profound castration level within 2 weeks after com 5 weeks following a suspension period, serum PSA levels are mencing administration and maintained until the end of reduced by greater than or equal to about 50 % of the administration . In some embodiments, following adminis subject's serum PSA levels prior to treatment commencing . tration of an oral load dose formulation of the disclosure In some embodiments , following administration of an oral comprising 360 mg of Compound 1 , or a corresponding load dose formulation of the disclosure once - daily for 1-3 amount of pharmaceutically acceptable salt thereof , ne - 10days at the beginning of treatment after a suspension period , daily for 1-3 days at the beginning of treatment after a and once - daily administration of an oral maintenance dose suspension period , and once - daily administration of an oral formulation of the disclosure starting on the day after maintenance dose formulation of the disclosure comprising administering the last dose of the oral load dose formulation , 120 mg of Compound 1 , or a corresponding amount of a and continuing for a set treatment period, median time from pharmaceutically acceptable salt thereof, starting on the day 15 commencing treatment to PSA nadir may be less than 5 after administering the last dose of the oral load dose weeks, less than 6 weeks, less than 7 , weeks , less than 8 formulation , and continuing for a set treatment period , weeks, less than 9 weeks , less than 10 weeks , less than 11 serum testosterone levels in a subject may be at or below weeks, less than 12 weeks , less than 13 weeks , less than 14 profound castration level within 3 weeks after commencing weeks, less than 15 weeks , less than 16 weeks , less than 17 administration and maintained until the end of administra- 20 weeks, less than 18 weeks , less than 19 weeks , less than 20 tion . In some embodiments, following administration of an weeks, less than 21 weeks , less than 22 weeks , less than 23 oral load dose formulation of the disclosure comprising 360 weeks, less than 24 weeks, or less than 25 weeks . In some mg of Compound 1,0 responding amount of phar embodiments, following administration of an oral load dose maceutically acceptable at thereofce - daily for13days formulation of the disclosure once - daily for 1-3 days at the at the beginning of treatment after a suspension period , and 25 beginning of treatment after a suspension period, and once ce - daily administration of an ra mantecedoor daily administration of an oral maintenance dose formula mulation of the disclosure comprising 120 mg of Compound tion of the disclosure starting on the day after administering 1 , or a corresponding amount of a pharmaceutically accept the last dose of the oral load dose formulation, and continu able salt thereof, starting on the day after administering the ing for a set treatment period , median time from commenc last dose of the oral load dose formulation , and continuing 30 ing treatment to PSA nadir may be about 5 weeks to about for a set treatment period , serum testosterone levels in a 10 weeks , about 5 weeks to about 15 weeks , about 5 weeks subject may be at or below profound castration level within to about 20 weeks , about 5 weeks to about 25 weeks , about 4 weeks after commencing administration and maintained 10 weeks about 15 weeks, about 10 weeks to about 20 until the end of administration . weeks, about 10 weeks to about 25 weeks , or about 15 weeks In some embodiments, after resuming once -daily admin- 35 to about 20 weeks. In some embodiments, following admin istration of an oral formulation of the disclosure after a istration of an oral load dose formulation of the disclosure suspension period, median time from administration of the once - daily for 1-3 days at the beginning of treatment after a first oral formulation after the suspension period to PSA suspension period , and once -daily administration of an oral nadir may be less than 5 weeks , less than 6 weeks , less than maintenance dose formulation of the disclosure starting on 7 , weeks , less than 8 weeks , less than 9 weeks, less than 10 40 the day after administering the last dose of the oral load dose weeks, less than 11 weeks, less than 12 weeks , less than 13 formulation, and continuing for a set treatment period, weeks, less than 14 weeks, less than 15 weeks , less than 16 median time from commencing treatment to PSA nadir may weeks, less than 17 weeks, less than 18 weeks , less than 19 be about 10 weeks to about 20 weeks . In some embodiments , weeks, less than 20 weeks, less than 21 weeks , less than 22 4 weeks after commencing administration of an oral load weeks, less than 23 weeks, less than 24 weeks , or less than 45 dose formulation of the disclosure once -daily for 1-3 days 25 weeks . In some embodiments , after resuming once - daily after a suspension period , and once - daily administration of administration of an oral formulation of the disclosure after an oral maintenance dose formulation of the disclosure a suspension period, median time from administration of the starting on the day after administering the last dose of the first oral formulation after the suspension period to PSA oral load dose formulation , serum PSA levels are reduced by nadir may be about 5 weeks to about 10 weeks , about 5 50 greater than or equal to about 5 % , greater than or equal to weeks to about 15 weeks, about 5 weeks to about 20 weeks , about 10 % , greater than or equal to about 20 % , greater than about 5 weeks to about 25 weeks , about 10 weeks to about or equal to about 30 % , greater than or equal to about 40 % , 15 weeks , about 10 weeks to about 20 weeks , about 10 greater than or equal to about 50 % , greater than or equal to weeks to about 25 weeks , or about 15 weeks to about 20 about 60 % , greater than or equal to about 70 % , greater than weeks. In some embodiments, after resuming once - daily 55 or equal to about 80 % , or greater than or equal to about 90 % administration of an oral formulation of the disclosure after of the subject's serum PSA levels prior to treatment com a suspension period , median time from administration of the mencing. In some embodiments, 4 weeks after commencing first oral formulation after the suspension period to PSA administration of an oral load dose formulation of the nadir may be about 10 weeks to about 20 weeks. In some disclosure once - daily for 1-3 days after a suspension period, embodiments , after resuming once - daily administration of 60 and once - daily administration of an oral maintenance dose oral formulations of the disclosure for 4 weeks following a formulation of the disclosure starting on the day after suspension period, serum PSA levels are reduced by greater administering the last dose of the oral load dose formulation , than or equal to about 5 % , greater than or equal to about serum PSA levels are reduced by greater than or equal to 10 % , greater than or equal to about 20 % , greater than or about 50 % of the subject's serum PSA levels prior to equal to about 30 % , greater than or equal to about 40 % , 65 treatment commencing. greater than or equal to about 50 % , greater than or equal to In some embodiments, after resuming once -daily admin about 60 % , greater than or equal to about 70 % , greater than istration of an oral formulation of the disclosure for 1 week , US 10,786,501 B2 45 46 4 weeks , 12 weeks , 24 weeks , or 48 weeks after a suspension illness occurring during the course of another illness , not period , serum FSH levels may be less than or equal to about related to the primary illness process ( e.g. , the illness is not 7.2 mIU /mL , about 4.8 mIU /mL , about 2.4 mIU /mL , or prostate cancer or a symptom of prostate cancer but can be , about 1.2 mIU /mL . In certain such embodiments, once - daily for example pneumonia, etc. ). In some embodiments, an administration of oral formulations comprising Compound 5 intercurrent illness is an acute illness an illness with an 1 , or a pharmaceutically acceptable salt thereof, may result abrupt onset. An intercurrent illness can result in loss of in sustained suppression of serum FSH levels. Normal FSH physical function or in muscle wasting , prolonged periods of levels in adult males are typically between 1.5 to 12.4 time in bed , prolonged inflammation , infection , or prolonged mIU /mL , but are elevated in subjects with prostate cancer . In physical therapy. An “ injury ” may impair the structure or some embodiments , after resuming once - daily administra- 10 function of the body and can result in loss of physical tion of an oral formulation of the disclosure for 1 week after function or in muscle wasting , prolonged periods of time in a suspension period , serum FSH levels may be less than or bed , prolonged inflammation , infection , prolonged physical equal to about 7.2 mIU /mL , about 4.8 mIU /mL , about 2.4 therapy , or recovery from a surgical or invasive procedure. mIU /mL , or about 1.2 mIU /mL . In some embodiments , Injury includes, but is not limited to , wounds , fractures, and resuming once - daily administration of an oral formulation of 15 burns. A “ surgical procedure ” or “ other invasive procedure ” the disclosure for 1 week , 4 weeks , 12 weeks, 24 weeks , or may refer to a procedure that is carried out by entering the 48 weeks after a suspension period may suppress serum FSH body through the skin or through a body cavity or anatomi levels by greater than or equal to about 80 % or about 90 % cal opening, and includes procedures carried out in an of the subject's serum FSH levels prior to treatment com operating room , surgical suite or procedure room . A " sur mencing. 20 gical procedure ” can include, but is not limited to , heart In some embodiments, following administration of an oral surgery, knee replacement, hip replacement, abdominal sur load dose formulation of the disclosure once - daily for 1-3 gery , pelvic surgery , vascular surgery , spine surgery, or an days at the beginning of treatment after a suspension period , emergency procedure due to injury. An “ invasive procedure ” and once - daily administration of an oral maintenance dose may include , but is not limited to , a colonoscopy , angio formulation of the disclosure starting on the day after 25 plasty, stent placement, endovascular coil placement, endo administering the last dose of the oral load dose formulation , vascular aneurysm repair, endoscopy , laparoscopy, arthros serum FSH levels may be less than or equal to about 7.2 copy, coronary catheterization, or another cathether -based mIU /mL , about 4.8 mIU /mL , about 2.4 mIU /mL , or about procedure. As noted previously, increased serum testoster 1.2 mIU /mL 1 week , 4 weeks , 12 weeks, 24 weeks , or 48 one levels can be beneficial in such subjects because tes weeks after commencing treatment . In certain such embodi- 30 tosterone has an anabolic effect, helping to rebuild tissues , ments, once - daily administration of oral formulations com increase weight and muscle mass , and promote growth and prising Compound 1 , or a pharmaceutically acceptable salt mineralization of bone , thus may help in counteracting the the of, may result in sustained suppression of serum FSH deliterious impact of the surgical procedure , intercurrent levels . In some embodiments, following administration of an illness , injury, etc. discussed above . “ Restored sexual func oral load dose formulation of the disclosure once - daily for 35 tion ” or “ recovery of sexual function ” may refer to an 1-3 days at the beginning of treatment after a suspension improvement in sexual function observed as sex hormone period, and once - daily administration of an oral mainte levels increase after suspension of once - daily administration nance dose formulation of the disclosure starting on the day of oral formulations comprising Compound 1 , or a pharma after administering the last dose of the oral load dose ceutically acceptable salt thereof. For example, when serum formulation , serum FSH levels may be less than or equal to 40 testosterone levels are normalized to above medical castra about 7.2 mIU /mL , about 4.8 mIU /mL , about 2.4 mIU /mL , tion levels of > 50 ng / dL because once - daily administration or about 1.2 mIU /mL 1 week after commencing treatment. of oral formulations comprising Compound 1 , or a pharma In some embodiments, following administration of an oral ceutically acceptable salt thereof, is suspended, sexual func load dose formulation of the disclosure once -daily for 1-3 tion is improved . Sexual function and libido will continue to days at the beginning of treatment after a suspension period , 45 improve as serum testosterone levels increase to above 50 and once -daily administration of an oral maintenance dose ng /dL and return to normal ( pre - treatment) levels . Improve formulation of the disclosure starting on the day after ment of sexual function may include, but is not limited to , administering the last dose of the oral load dose formulation , improvements in libido , erectile dysfunction , arousal, serum FSH levels may be suppressed by greater than or orgasm , nocturnal erections , sexual desire , penile morphol equal to about 80 % or about 90 % of the subject's serum FSH 50 ogy , ejaculation , quality of life , overall self - esteem , and levels prior to treatment commencing 1 week , 4 weeks, 12 overall relationships. weeks, 24 weeks , or 48 weeks after commencing treatment. Once -daily administration may also be suspended to Because of the return to serum testosterone levels to a improve the subject's quality of life and energy levels; to level above 50 ng /dL after the last dose of an oral formu help with healing after injury, intercurrent illness , surgery , or lation comprising Compound 1 , or a pharmaceutically 55 radiation therapy ; to aid subjects in remaining in control of acceptable salt thereof, and the rapid onset of the oral their lifestyles , including an improvement in sexual func formulations of the disclosure once once - daily administra tion ; and to assist in regaining strength and mobility after tion is restarted after a suspension period, administration intercurrent illness or injury. Once administration is sus may be suspended for a suspension period as necessary to pended , it may or may not resume as needed . In some allow for an increase in serum testosterone levels . In certain 60 embodiments , once - daily administration resumes after the embodiments, the subject is in need of an increase in serum subject is recovered from an intercurrent illness, is no longer testosterone levels to a level above 50 ng /dL . Increases in bedridden , has resumed normal activities of daily living , or serum testosterone level may be needed due to an intercur has regained a normal level of function ( e.g. , returns to the rent illness , receiving radiation therapy, while bedridden , level of function the subject experience prior to the illness ) . having suffered an injury, having a surgical procedure or 65 The present disclosure provides for suspension of the other invasive procedure , or a desire for a period of restored once - daily administration of oral formulations of the disclo sexual function . An " intercurrent illness” may refer to an sure prior to a surgical procedure or other invasive procedure US 10,786,501 B2 47 48 or radiation therapy. In some embodiments, once - daily after a suspension of administration after radiation therapy. administration may be suspended prior to a surgical proce In some embodiments , once - daily administration may be dure or other invasive procedure. In some embodiments , resumed when there is rise in PSA of “ nadir + 2 ng/ mL ” after once - daily administration of oral formulations of the disclo radiation therapy. In some embodiments, once - daily admin sure may be suspended after a surgical procedure or other 5 istration may be resumed after radiation therapy when the invasive procedure, injury, or radiation therapy . In certain subject's PSA level rises to 23 ng /mL , 210 ng /mL , 220 embodiments, once - daily administration of oral formula ng /mL , or 230 ng /mL . tions of the disclosure occurs prior to and during the surgical In some embodiments, once -daily administration may be procedure or other invasive procedure or radiation therapy suspended during an intercurrent illness or while the subject and once - daily administration may be suspended after the 10 is bedridden . In some embodiments, once -daily administra surgical procedure or other invasive procedure or radiation tion may be suspended after an intercurrent illness . In certain therapy. In some embodiments, once - daily administration of embodiments, once - daily administration of the oral formu oral formulations of the disclosure may be suspended during lations of the disclosure may be suspended because the a surgical procedure or other invasive procedure, injury, or subject is in need of an increase in serum testosterone levels radiation therapy . In certain embodiments , once - daily 15 due to an intercurrent illness with a projected full recovery administration of the oral formulations of the disclosure may time of at least about 1 week , about 2 weeks , about 3 weeks , be suspended because the subject is in need of an increase about 4 weeks, about 5 weeks , about 6 weeks, about 7 in serum testosterone levels due to a surgical procedure or weeks, about 8 weeks , about 9 weeks, about 10 weeks, about other invasive procedure with a projected full recovery time 12 weeks, about 16 weeks , about 20 weeks , about 24 weeks, of at least about 1 week , about 2 weeks , about 3 weeks , 20 about 36 weeks , about 48 weeks , or about 52 weeks . In about 4 weeks , about 5 weeks , about 6 weeks , about 7 certain such embodiments, the recovery time is about 2 weeks, about 8 weeks , about 9 weeks, about 10 weeks , about weeks. In some embodiments , once - daily administration of 12 weeks , about 16 weeks, about 20 weeks , about 24 weeks , oral formulations of the disclosure is not resumed after a about 36 weeks , about 48 weeks , or about 52 weeks . In suspension of administration after or during an intercurrent certain such embodiments, the recovery time is about 2 25 illness . In certain such embodiments, once -daily adminis weeks . In some embodiments, once -daily administration of tration is not resumed after a suspension of administration oral formulations of the disclosure is not resumed after a after an intercurrent illness . In some embodiments , once suspension of administration prior to , after, or during a daily administration of oral formulations of the disclosure surgical procedure or other invasive procedure. In certain may be suspended for an intercurrent illness, wherein the such embodiments, once - daily administration is not resumed 30 illness is stroke or cerebral hemorrhage . In certain embodi after a suspension of administration after a surgical proce ments, once -daily administration may be suspended for an dure or other invasive procedure. In some embodiments , the intercurrent illness , wherein the illness is myocardial infarc surgical procedure is heart surgery , knee replacement, hip tion or congestive heart failure. In some embodiments, replacement, abdominal surgery , pelvic surgery , vascular once - daily administration is suspended following an acci surgery, spine surgery , or an emergency procedure due to 35 dent or injury requiring prolonged recovery. In some injury . In certain embodiments of the methods and uses embodiments, once -daily administration is suspended fol described herein , the subject receiving prostate cancer treat lowing a stroke, cerebral hemorrhage, myocardial infarction , ment is identified as at risk for acute postoperative frailty . congestive heart failure, hip fracture or other event resulting The present disclosure provides for suspension of once in limited mobility and requiring prolonged recovery . daily administration of oral formulations of the disclosure 40 In certain embodiments, once - daily administration of the prior to radiation therapy . In some embodiments, once - daily oral formulations of the disclosure may be suspended administration of oral formulations of the disclosure may be because the subject is in need of an increase in serum suspended after radiation therapy . Suspension of once - daily testosterone levels due to an injury with a projected full administration of oral formulations of the disclosure after recovery time of at least about 1 week , about 2 weeks , about radiation therapy may aid in recovery from the radiation 45 3 weeks, about 4 weeks , about 5 weeks , about 6 weeks, therapy yet permit therapeutic treatment with oral formula about 7 weeks , about 8 weeks, about 9 weeks, about 10 tions comprising Compound 1 , or a pharmaceutically weeks, about 12 weeks, about 16 weeks, about 20 weeks, acceptable salt thereof, during radiation therapy, enabling about 24 weeks, about 36 weeks , about 48 weeks, or about intensive treatment of prostate cancer. In certain embodi 52 weeks. In certain such embodiments, the recovery time is ments , once - daily administration of oral formulations of the 50 about 2 weeks . In some embodiments, once - daily adminis disclosure occurs prior to and during radiation therapy and tration of oral formulations of the disclosure may be sus administration may be suspended after radiation therapy. In pended for an injury, wherein the injury is a bone fracture. some embodiments, once - daily administration of oral for In certain embodiments, once - daily administration may be mulations of the disclosure may be suspended during radia suspended for an injury, wherein the injury is a hip fracture . tion therapy. In certain embodiments , once - daily adminis- 55 In some embodiments, once - daily administration of oral tration of the oral formulations of the disclosure may be formulations of the disclosure may be suspended for an suspended because the subject is in need of an increase in injury, wherein the injury is a knee injury. serum testosterone levels due to radiation therapy for at least The formulations of this disclosure may allow for a rise of about 1 week , about 2 weeks , about 3 weeks, about 4 weeks , serum testosterone when medically needed . Stopping once about 5 weeks , about 6 weeks , about 7 weeks, about 8 60 daily administration of the oral formulations of the disclo weeks, about 9 weeks , about 10 weeks, about 12 weeks , sure comprising Compound 1 , or a pharmaceutically accept about 16 weeks, about 20 weeks , about 24 weeks , about 36 able salt thereof, may decrease the catabolic effect of weeks, about 48 weeks, or about 52 weeks . In some embodi intercurrent / acute illness and bedrest in men with prostate ments, once -daily administration of oral formulations of the cancer, thereby allowing for serum testosterone levels to rise disclosure is not resumed after a suspension of administra- 65 to assist in regaining strength and mobility after an inter tion prior to , after, or during radiation therapy. In certain current/ acute illness . This benefit cannot be achieved with such embodiments, once - daily administration is not resumed the depot GnRH agonist /antagonist formulations. This inter US 10,786,501 B2 49 50 mittent androgen deprivation therapy may minimize adverse completed at least 48 consecutive weeks of treatment. As events associated with continuous androgen deprivation with duration , depending on one or more of the following: therapy while providing comparable efficacy for patients symptom severity, subject age , weight and sensitivity, the with prostate cancer. time for taking the suspension period during the treatment The duration of the suspension period should be such that 5 period can be altered . there is minimal adverse effect on the treatment due to the With respect to onset, within about 4 to about 8 days of temporary stoppage of once -daily administration of oral first administering once - daily an oral formulation of the formulations of the disclosure . In some embodiments, the disclosure or an oral load dose formulation and an oral suspension period is from 4 weeks or less to 12 weeks or maintenance dose formulation of the disclosure, the serum greater. Longer suspension periods may be possible as long 10 testosterone levels in the subject may be at or below medical as the subject's PSA levels remain low , such as < 4 ng /mL or castration level . In some embodiments, within 4 days of first < 0.2 ng /mL . In some embodiments, once -daily administra administering once -daily an oral formulation of the disclo tion may be resumed when there is rise in PSA of “ nadir + 2 sure or an oral load dose formulation and an oral mainte ng/ mL ” during the suspension period . In some embodi nance de formulation of the disclosure , therum test ments, once - daily administration may be resumed when the 15 terone levels in the subject may be at or below medical subject's PSA level rises to 23 ng /mL , 210 ng /mL , 220 castration level . me embodiment , within 5daysoffrst ng /mL , or 230 ng /mL during the suspension period . In some administering once -daily an oral formulation of the disclo embodiments, the suspension period may be up to 60 weeks . sure or an oral load dose formulation and an oral mainte In some embodiments, the suspension period may be up to nance de formulation of the disclosure , therum test 52 weeks . In some embodiments, the suspension period may 20 terone levels in the subject may be at or below medical be up to 48 weeks. In some embodiments, the suspension castration level.me embodiment , within daysofirst period may be up to 36 weeks . In some embodiments, the administering once -daily an oral formulation of the disclo suspension period may be up to 24 weeks . In some embodi sure or an oral load dose formulation and an oral mainte ments , the suspension period may be up to 20 weeks . In nance dose formulation of the disclosure , the serum testos some embodiments, the suspension period may be up to 16 25 terone levels in the subject may be at or below medical weeks . In some embodiments, the suspension period may be castration level . In some embodiments , within 7 days of first up to 12 weeks. In some embodiments , the suspension administering once - daily an oral formulation of the disclo period may be up to 4 weeks . In some embodiments, the sure or an oral load dose formulation and an oral mainte suspension period may be up to 8 weeks. nance dose formulation of the disclosure , the serum testos Depending on one or more of the following: symptom 30 terone levels in the subject may be at or below medical severity , subject age , weight and sensitivity , the duration of castration level . In some embodiments, within 8 days of first the suspension period can be altered. In some embodiments, administering once -daily an oral formulation of the disclo as long as the PSA level is < 4 ng /mL or < 0.2 ng /mL , the sure or an oral load dose formulation and an oral mainte subject may be off therapy . In some embodiments , the nance dose formulation of the disclosure , the serum testos suspension period is discontinued when the subject's pros- 35 terone levels in the subject may be at or below medical tate - specific antigen ( PSA ) level is 20 % of the subject's castration level . In some embodiments , within 3 days of first PSA level of the nadir during treatment. In some embodi administering once - daily an oral formulation of the disclo ments , the suspension period is discontinued when the urranraadde formulation and anal mainte subject's PSA level is 250 % of the subject's PSA level prior nance dose formulation of the disclosure , the serum testos to treatment. In certain embodiments , the suspension period 40 terone levels in the subject may be at or below medical is discontinued when the subject’s PSA level is greater than castration level . the subject's PSA level at the beginning of the suspension With further respect to onset , in some embodiments , period . In some embodiments, the suspension period is following administration of an oral load dose formulation of discontinued when the subject experiences return of symp the disclosure once -daily for 1-3 days at the beginning of toms of prostate cancer . In certain embodiments , the sus- 45 treatment, and once - daily administration of an oral mainte pension period is discontinued when the subject's PSA level nance dose formulation of the disclosure starting on the day is 23 ng /mL . In other embodiments , the suspension period is after administering the last dose of the oral load dose discontinued when the subject's PSA level is 210 ng /mL . In formulation , and continuing for a set treatment period ( e.g. , some embodiments, the suspension period is discontinued at least 4 consecutive weeks or greater, at least 8 consecutive when the subject's PSA level is 20 ng /mL . In other 50 weeks or greater, at least 12 consecutive weeks or greater, at embodiments , the suspension period is discontinued when least 16 consecutive weeks or greater, at least 20 consecutive the subject’s PSA level is 230 ng /mL . weeks or greater, 24 consecutive weeks or greater, 36 In some embodiments, the time as to when a suspension consecutive weeks or greater, 48 consecutive weeks or period during the treatment period can be taken by a subject greater, 52 consecutive weeks or greater, 72 consecutive should be such that there is a minimal adverse effect on the 55 weeks or greater, or 96 consecutive weeks or greater ), treatment due to the suspension period . In some embodi medical castration levels of less than or equal to 50 ng /dL ments, before a suspension period can be taken , a subject ( 1.73 nmol / L ) serum testosterone may be achieved within 24 must have completed at least 4 consecutive weeks , at least 48 hours after commencing administration and main 8 consecutive weeks , at least 12 consecutive weeks , at least tained until the end of administration . In some embodiments, 16 consecutive weeks , at least 20 consecutive weeks , at least 60 following administration of an oral load dose formulation of 24 consecutive weeks , at least 36 consecutive weeks , at least the disclosure once - daily for 1-3 days at the beginning of 48 consecutive weeks , at least 52 consecutive weeks , at least treatment, and once - daily administration of an oral mainte 72 consecutive weeks, or at least 96 consecutive weeks of nance dose formulation of the disclosure starting on the day treatment. In some embodiments , before a suspension period after administering the last dose of the oral load dose can be taken , a subject must have completed at least 24 65 formulation , and continuing for a set treatment period , consecutive weeks of treatment. In some embodiments, serum testosterone levels in a subject may be at or below before a suspension period can be taken , a subject must have medical castration level within 3 days after commencing US 10,786,501 B2 51 52 administration and maintained until the end of administra may be at or below medical castration level within 4 weeks tion . In some embodiments, following administration of an after commencing administration and maintained until the oral load dose formulation of the disclosure once - daily for end of administration . 1-3 days at the beginning of treatment, and once - daily With further respect to onset , as described herein , follow administration of an oral maintenance dose formulation of 5 ing once - daily administration of an oral formulation com the disclosure starting on the day after administering the last prising about 180 mg of Compound 1 , or a corresponding dose of the oral load dose formulation , and continuing for a amount of a pharmaceutically acceptable salt thereof, medi set treatment period, serum testosterone levels in a subject cal castration levels of less than or equal to 50 ng / dL ( 1.73 may be at or below medical castration level within 4 days nmol/ L ) serum testosterone may be achieved within 24 to 48 after commencing administration and maintained until the 10 hoursments , afterfollowing commencing once - daily administration administration . In ofsome an oralembodi for end of administration . In some embodiments, following mulation of the disclosure comprising about 180 mg of administration of an oral load dose formulation of the Compound 1 , or a corresponding amount of a pharmaceu disclosure once - daily for 1-3 days at the beginning of tically acceptable salt thereof, serum testosterone levels in a treatment, and once - daily administration of an oral mainte 15 subject may be at or below medical castration level within nance dose formulation of the disclosure starting on the day 3 days after commencing administration . In some embodi after administering the last dose of the oral load dose ments, following once - daily administration of an oral for formulation , and continuing for a set treatment period, mulation of the disclosure comprising about 180 mg of serum testosterone levels in a subject may be at or below Compound 1 , or a corresponding amount of a pharmaceu medical castration level within 5 days after commencing 20 tically acceptable salt thereof, serum testosterone levels in a administration and maintained until the end of administra subject may be at or below medical castration level within tion . In some embodiments, following administration of an 4 days after commencing administration . In some embodi oral load dose formulation of the disclosure once - daily for ments, following once - daily administration of an oral for 1-3 days at the beginning of treatment, and once - daily mulation of the disclosure comprising about 180 mg of administration of an oral maintenance dose formulation of 25 Compound 1 , or a corresponding amount of a pharmaceu the disclosure starting on the day after administering the last tically acceptable salt thereof, serum testosterone levels in a dose of the oral load dose formulation , and continuing for a subject may be at or below medical castration level within set treatment period, serum testosterone levels in a subject 5 days after commencing administration . In some embodi may be or below medical castration level within 6 days ments , following once - daily administration of an oral for after commencing administration and maintained until the 30 mulationCompound of 1 ,the or adisclosure corresponding comprising amount about of a pharmaceu180 mg of end of administration . In some embodiments , following tically acceptable salt thereof, serum testosterone levels in a administration of an oral load dose formulation of the subject may be at or below medical castration level within disclosure once - daily for 1-3 days at the beginning of 6 days after commencing administration . In some embodi treatment, and once - daily administration of an oral mainte 35 ments , following once - daily administration of an oral for nance dose formulation of the disclosure starting on the day mulation of the disclosure comprising about 180 mg of after administering the last dose of the oral load dose Compound 1 , or a corresponding amount of a pharmaceu formulation , and continuing for a set treatment period, tically acceptable salt thereof, serum testosterone levels in a serum testosterone levels in a subject may be at or below subject may be at or below medical castration level within medical castration level within 1 week after commencing 40 1 week after commencing administration . administration and maintained until the end of administra With further respect to onset , as described herein , follow tion . In some embodiments, following administration of an ing once - daily administration of an oral formulation com oral load dose formulation of the disclosure once - daily for prising about 80 mg to about 160 mg of Compound 1 , or a 1-3 days at the beginning of treatment, and once - daily corresponding amount of a pharmaceutically acceptable salt administration of an oral maintenance dose formulation of 45 thereof, medical castration levels of less than or equal to 50 the disclosure starting on the day after administering the last ng / dL ( 1.73 nmol / L ) serum testosterone may be achieved dose of the oral load dose formulation , and continuing for a within 24 to 48 hours after commencing administration . In set treatment period , serum testosterone levels in a subject some embodiments, following once -daily administration of may be at or below medical castration level within 2 weeks an oral formulation of the disclosure comprising about 80 after commencing administration and maintained until the 50 mg to about 160 mg of Compound 1 , or a corresponding end of administration . In some embodiments , following amount of a pharmaceutically acceptable salt thereof, serum administration of an oral load dose formulation of the testosterone levels in a subject may be at or below medical disclosure once - daily for 1-3 days at the beginning of castration level within 3 days after commencing adminis treatment, and once - daily administration of an oral mainte tration . In some embodiments, following once - daily admin nance dose formulation of the disclosure starting on the day 55 istration of an oral formulation of the disclosure comprising after administering the last dose of the oral load dose about 80 mg to about 160 mg of Compound 1 , or a formulation , and continuing for a set treatment period , corresponding amount of a pharmaceutically acceptable salt serum testosterone levels in a subject may be at or below thereof, serum testosterone levels in a subject may be at or medical castration level within 3 weeks after commencing below medical castration level within 4 days after commenc administration and maintained until the end of administra- 60 ing administration . In some embodiments , following once tion . In some embodiments, following administration of an daily administration of an oral formulation of the disclosure oral load dose formulation of the disclosure once - daily for comprising about 80 mg to about 160 mg of Compound 1 , 1-3 days at the beginning of treatment, and once - daily or a corresponding amount of a pharmaceutically acceptable administration of an oral maintenance dose formulation of salt thereof, serum testosterone levels in a subject may be at the disclosure starting on the day after administering the last 65 or below medical castration level within 5 days after com dose of the oral load dose formulation , and continuing for a mencing administration . In some embodiments , following set treatment period, serum testosterone levels in a subject once - daily administration of an oral formulation of the US 10,786,501 B2 53 54 disclosure comprising about 80 mg to about 160 mg of serum testosterone may be achieved within 24 to 48 hours Compound 1 , or a corresponding amount of a pharmaceu after commencing administration and maintained until the tically acceptable salt thereof, serum testosterone levels in a end of administration . In some embodiments, following subject may be at or below medical castration level within administration of an oral load dose formulation of the 6 days after commencing administration . In some embodi- 5 disclosure comprising 240 mg of Compound 1 , or a corre ments , following once -daily administration of an oral for sponding amount of a pharmaceutically acceptable salt mulation of the disclosure comprising about 80 mg to about thereof, once - daily for 1-3 days at the beginning of treat 160 mg of Compound 1 , or a corresponding amount of a ment, and once - daily administration of an oral maintenance pharmaceutically acceptable salt thereof, serum testosterone dose formulation of the disclosure comprising 120 mg of levels in a subject may be at or below medical castration 10 Compound 1 , or a corresponding amount of a pharmaceu level within 1 week after commencing administration . tically acceptable salt thereof, starting on the day after With further respect to onset , as described herein , follow administering the last dose of the oral load dose formulation , ing once -daily administration of an oral formulation com and continuing for a set treatment period, serum testosterone prising about 120 mg of Compound 1 , or a corresponding levels in a subject may be at or below medical castration amount of a pharmaceutically acceptable salt thereof , medi- 15 level within 3 days after commencing administration and cal castration levels of less than or equal to 50 ng / dL ( 1.73 maintained until the end of administration . In some embodi nmol / L ) serum testosterone may be achieved within 24 to 48 ments, following administration of an oral load dose formu hours after commencing administration . In some embodi lation of the disclosure comprising 240 mg of Compound 1 , ments , following once -daily administration of an oral for or a corresponding amount of a pharmaceutically acceptable mulation of the disclosure comprising about 120 mg of 20 salt thereof, once- daily for 1-3 days at the beginning of Compound 1 , or a corresponding amount of a pharmaceu treatment, and once -daily administration of an oral mainte tically acceptable salt thereof, serum testosterone levels in a nance dose formulation of the disclosure comprising 120 mg subject may be at or below medical castration level within of Compound 1 , or a corresponding amount of a pharma 3 days after commencing administration . In some embodi ceutically acceptable salt thereof, starting on the day after ments, following once - daily administration of an oral for- 25 administering the last dose of the oral load dose formulation , mulation of the disclosure comprising about 120 mg of and continuing for a set treatment period , serum testosterone Compound 1 , or a corresponding amount of a pharmaceu levels in a subject may be at or below medical castration tically acceptable salt thereof, serum testosterone levels in a level within 4 days after commencing administration and subject may be at or below medical castration level within maintained until the end of administration . In some embodi 4 days after commencing administration . In some embodi- 30 ments, following administration of an oral load dose formu ments , following once -daily administration of an oral for lation of the disclosure comprising 240 mg of Compound 1 , mulation of the disclosure comprising about 120 mg of or a corresponding amount of a pharmaceutically acceptable Compound 1 , or a corresponding amount of a pharmaceu salt thereof, once -daily for 1-3 days at the beginning of tically acceptable salt thereof, serum testosterone levels in a treatment, and once -daily administration of an oral mainte subject may be at or below medical castration level within 35 nance dose formulation of the disclosure comprising 120 mg 5 days after commencing administration . In some embodi of Compound 1 , or a corresponding amount of a pharma ments , following once -daily administration of an oral for ceutically acceptable salt thereof, starting on the day after mulation of the disclosure comprising about 120 mg of administering the last dose of the oral load dose formulation, Compound 1 , or a corresponding amount of a pharmaceu and continuing for a set treatment period, serum testosterone tically acceptable salt thereof, serum testosterone levels in a 40 levels in a subject may be at or below medical castration subject may be at or below medical castration level within level within 5 days after commencing administration and 6 days after commencing administration . In some embodi maintained until the end of administration . In some embodi ments , following once - daily administration of an oral for ments, following administration of an oral load dose formu mulation of the disclosure comprising about 120 mg of lation of the disclosure comprising 240 mg of Compound 1 , Compound 1 , or a corresponding amount of a pharmaceu- 45 or a corresponding amount of a pharmaceutically acceptable tically acceptable salt thereof, serum testosterone levels in a salt thereof, once - daily for 1-3 days at the beginning of subject may be at or below medical castration level within treatment, and once -daily administration of an oral mainte 1 week after commencing administration . nance dose formulation of the disclosure comprising 120 mg With further respect to onset , in some embodiments , of Compound 1 , or a corresponding amount of a pharma following administration of an oral load dose formulation of 50 ceutically acceptable salt thereof, starting on the day after the disclosure comprising 240 mg of Compound 1 , or a administering the last dose of the oral load dose formulation , corresponding amount of a pharmaceutically acceptable salt and continuing for a set treatment period, serum testosterone thereof, once -daily for 1-3 days at the beginning of treat levels in a subject may be at or below medical castration ment, and once -daily administration of an oral maintenance level within 6 days after commencing administration and dose formulation of the disclosure comprising 120 mg of 55 maintained until the end of administration . In some embodi Compound 1 , or a corresponding amount of a pharmaceu ments, following administration of an oral load dose formu tically acceptable salt thereof, starting on the day after lation of the disclosure comprising 240 mg of Compound 1 , administering the last dose of the oral load dose formulation , or a corresponding amount of a pharmaceutically acceptable and continuing for a set treatment period ( e.g. , at least 4 salt thereof, once - daily for 1-3 days at the beginning of consecutive weeks or greater, at least 8 consecutive weeks or 60 treatment, and once - daily administration of an oral mainte greater, at least 12 consecutive weeks or greater, at least 16 nance dose formulation of the disclosure comprising 120 mg consecutive weeks or greater, at least 20 consecutive weeks of Compound 1 , or a corresponding amount of a pharma or greater, 24 consecutive weeks or greater, 36 consecutive ceutically acceptable salt thereof, starting on the day after weeks or greater, 48 consecutive weeks or greater, 52 administering the last dose of the oral load dose formulation , consecutive weeks or greater, 72 consecutive weeks or 65 and continuing for a set treatment period , serum testosterone greater, or 96 consecutive weeks or greater ), medical cas levels in a subject may be at or below medical castration tration levels of less than or equal to 50 ng /dL ( 1.73 nmol / L ) level within 1 week after commencing administration and US 10,786,501 B2 55 56 maintained until the end of administration . In some embodi dose formulation of the disclosure comprising 120 mg of ments, following administration of an oral load dose formu Compound 1 , or a corresponding amount of a pharmaceu lation of the disclosure comprising 240 mg of Compound 1 , tically acceptable salt thereof, starting on the day after or a corresponding amount of a pharmaceutically acceptable administering the last dose of the oral load dose formulation , salt thereof, once - daily for 1-3 days at the beginning of 5 and continuing for a set treatment period , serum testosterone treatment, and once - daily administration of an oral mainte levels in a subject may be at or below medical castration nance dose formulation of the disclosure comprising 120 mg level within 3 days after commencing administration and of Compound 1 , or a corresponding amount of a pharma maintained until the end of administration . In some embodi ceutically acceptable salt thereof, starting on the day after ments , following administration of an oral load dose formu administering the last dose of the oral load dose formulation , 10 lation of the disclosure comprising 360 mg of Compound 1 , and continuing for a set treatment period , serum testosterone or a corresponding amount of a pharmaceutically acceptable levels in a subject may be at or below medical castration salt thereof, once - daily for 1-3 days at the beginning of level within 2 weeks after commencing administration and treatment, and once -daily administration of an oral mainte maintained until the end of administration . In some embodi nance dose formulation of the disclosure comprising 120 mg ments, following administration of an oral load dose formu- 15 of Compound 1 , or a corresponding amount of a pharma lation of the disclosure comprising 240 mg of Compound 1 , ceutically acceptable salt thereof, starting on the day after or a corresponding amount of a pharmaceutically acceptable administering the last dose of the oral load dose formulation , salt thereof, once - daily for 1-3 days at the beginning of and continuing for a set treatment period , serum testosterone treatment, and once - daily administration of an oral mainte levels in a subject may be at or below medical castration nance dose formulation of the disclosure comprising 120 mg 20 level within 4 days after commencing administration and of Compound 1 , or a corresponding amount of a pharma maintained until the end of administration . In some embodi ceutically acceptable salt thereof, starting on the day after ments, following administration of an oral load dose formu administering the last dose of the oral load dose formulation , lation of the disclosure comprising 360 mg of Compound 1 , and continuing for a set treatment period , serum testosterone or a corresponding amount of a pharmaceutically acceptable levels in a subject may be at or below medical castration 25 salt thereof, once - daily for 1-3 days at the beginning of level within 3 weeks after commencing administration and treatment, and once -daily administration of an oral mainte maintained until the end of administration . In some embodi nance dose formulation of the disclosure comprising 120 mg ments , following administration of an oral load dose formu of Compound 1 , or a corresponding amount of a pharma lation of the disclosure comprising 240 mg of Compound 1 , ceutically acceptable salt thereof, starting on the day after or a corresponding amount of a pharmaceutically acceptable 30 administering the last dose of the oral load dose formulation , salt thereof, once - daily for 1-3 days at the beginning of and continuing for a set treatment period, serum testosterone treatment, and once - daily administration of an oral mainte levels in a subject may be at or below medical castration nance dose formulation of the disclosure comprising 120 mg level within 5 days after commencing administration and of Compound 1 , or a corresponding amount of a pharma maintained until the end of administration . In some embodi ceutically acceptable salt thereof, starting on the day after 35 ments , following administration of an oral load dose formu administering the last dose of the oral load dose formulation , lation of the disclosure comprising 360 mg of Compound 1 , and continuing for a set treatment period , serum testosterone or a corresponding amount of a pharmaceutically acceptable levels in a subject may be at or below medical castration salt thereof, once - daily for 1-3 days at the beginning of level within 4 weeks after commencing administration and treatment, and once -daily administration of an oral mainte maintained until the end of administration . 40 nance dose formulation of the disclosure comprising 120 mg With further respect to onset , in some embodiments , of Compound 1 , or a corresponding amount of a pharma following administration of an oral load dose formulation of ceutically acceptable salt thereof, starting on the day after the disclosure comprising 360 mg of Compound 1 , or a administering the last dose of the oral load dose formulation , corresponding amount of a pharmaceutically acceptable salt and continuing for a set treatment period, serum testosterone thereof, once - daily for 1-3 days at the beginning of treat- 45 levels in a subject may be at or below medical castration ment, and once - daily administration of an oral maintenance level within 6 days after commencing administration and dose formulation of the disclosure comprising 120 mg of maintained until the end of administration . In some embodi Compound 1 , or a corresponding amount of a pharmaceu ments, following administration of an oral load dose formu tically acceptable salt thereof, starting on the day after lation of the disclosure comprising 360 mg of Compound 1 , administering the last dose of the oral load dose formulation , 50 or a corresponding amount of a pharmaceutically acceptable and continuing for a set treatment period ( e.g. , at least 4 salt thereof, once - daily for 1-3 days at the beginning of consecutive weeks or greater, at least 8 consecutive weeks or treatment, and once -daily administration of an oral mainte greater, at least 12 consecutive weeks or greater, at least 16 nance dose formulation of the disclosure comprising 120 mg consecutive weeks or greater, at least 20 consecutive weeks of Compound 1 , or a corresponding amount of a pharma or greater, 24 consecutive weeks or greater, 36 consecutive 55 ceutically acceptable salt thereof, starting on the day after weeks or greater, 48 consecutive weeks or greater, 52 administering the last dose of the oral load dose formulation , consecutive weeks or greater, 72 consecutive weeks or and continuing for a set treatment period, serum testosterone greater, or 96 consecutive weeks or greater ), medical cas levels in a subject may be at or below medical castration tration levels of less than or equal to 50 ng /dL ( 1.73 nmol / L ) level within 1 week after commencing administration and serum testosterone may be achieved within 24 to 48 hours 60 maintained until the end of administration . In some embodi after commencing administration and maintained until the ments, following administration of an oral load dose formu end of administration . In some embodiments, following lation of the disclosure comprising 360 mg of Compound 1 , administration of an oral load dose formulation of the or a corresponding amount of a pharmaceutically acceptable disclosure comprising 360 mg of Compound 1 , or a corre salt thereof, once - daily for 1-3 days at the beginning of sponding amount of a pharmaceutically acceptable salt 65 treatment, and once - daily administration of an oral mainte thereof, once -daily for 1-3 days at the beginning of treat nance dose formulation of the disclosure comprising 120 mg ment, and once - daily administration of an oral maintenance of Compound 1 , or a corresponding amount of a pharma US 10,786,501 B2 57 58 ceutically acceptable salt thereof, starting on the day after ments, following administration of an oral load dose formu administering the last dose of the oral load dose formulation , lation of the disclosure comprising 360 mg of Compound 1 , and continuing for a set treatment period , serum testosterone or a corresponding amount of a pharmaceutically acceptable levels in a subject may be at or below medical castration salt thereof, once - daily for 1-3 days at the beginning of level within 2 weeks after commencing administration and 5 treatment, and once - daily administration of an oral mainte maintained until the end of administration . In some embodi nance dose formulation of the disclosure comprising 120 mg ments , following administration of an oral load dose formu of Compound 1 , or a corresponding amount of a pharma lation of the disclosure comprising 360 mg of Compound 1 , ceutically acceptable salt thereof, starting on the day after or a corresponding amount of a pharmaceutically acceptable administering the last dose of the oral load dose formulation , salt thereof, once - daily for 1-3 days at the beginning of 10 and continuing for a set treatment period , serum testosterone treatment, and once - daily administration of an oral mainte levels in a subject may be at or below profound castration nance dose formulation of the disclosure comprising 120 mg level within 4 days after commencing administration and of Compound 1 , or a corresponding amount of a pharma maintained until the end of administration . In some embodi ceutically acceptable salt thereof, starting on the day after ments, following administration of an oral load dose formu administering the last dose of the oral load dose formulation , 15 lation of the disclosure comprising 360 mg of Compound 1 , and continuing for a set treatment period , serum testosterone or a corresponding amount of a pharmaceutically acceptable levels in a subject may be at or below medical castration salt thereof, once - daily for 1-3 days at the beginning of level within 3 weeks after commencing administration and treatment, and once -daily administration of an oral mainte maintained until the end of administration . In some embodi nance dose formulation of the disclosure comprising 120 mg ments, following administration of an oral load dose formu- 20 of Compound 1 , or a corresponding amount of a pharma lation of the disclosure comprising 360 mg of Compound 1 , ceutically acceptable salt thereof, starting on the day after or a corresponding amount of a pharmaceutically acceptable administering the last dose of the oral load dose formulation , salt thereof, once - daily for 1-3 days at the beginning of and continuing for a set treatment period, serum testosterone treatment, and once - daily administration of an oral mainte levels in a subject may be at or below profound castration nance dose formulation of the disclosure comprising 120 mg 25 level within 5 days after commencing administration and of Compound 1 , or a corresponding amount of a pharma maintained until the end of administration . In some embodi ceutically acceptable salt thereof, starting on the day after ments , following administration of an oral load dose formu administering the last dose of the oral load dose formulation , lation of the disclosure comprising 360 mg of Compound 1 , and continuing for a set treatment period , serum testosterone or a corresponding amount of a pharmaceutically acceptable levels in a subject may be at or below medical castration 30 salt thereof, once - daily for 1-3 days at the beginning of level within 4 weeks after commencing administration and treatment, and once -daily administration of an oral mainte maintained until the end of administration . nance dose formulation of the disclosure comprising 120 mg With further respect to onset , in some embodiments, of Compound 1 , or a corresponding amount of a pharma following administration of an oral load dose formulation of ceutically acceptable salt thereof, starting on the day after the disclosure comprising 360 mg of Compound 1 , or a 35 administering the last dose of the oral load dose formulation , corresponding amount of a pharmaceutically acceptable salt and continuing for a set treatment period, serum testosterone thereof, once - daily for 1-3 days at the beginning of treat levels in a subject may be at or below profound castration ment, and once - daily administration of an oral maintenance level within 6 days after commencing administration and dose formulation of the disclosure comprising 120 mg of maintained until the end of administration . In some embodi Compound 1 , or a corresponding amount of a pharmaceu- 40 ments, following administration of an oral load dose formu tically acceptable salt thereof, starting on the day after lation of the disclosure comprising 360 mg of Compound 1 , administering the last dose of the oral load dose formulation , or a corresponding amount of a pharmaceutically acceptable and continuing for a set treatment period ( e.g. , at least 4 salt thereof, once - daily for 1-3 days at the beginning of consecutive weeks or greater, at least 8 consecutive weeks or treatment, and once -daily administration of an oral mainte greater, at least 12 consecutive weeks or greater, at least 16 45 nance dose formulation of the disclosure comprising 120 mg consecutive weeks or greater, at least 20 consecutive weeks of Compound 1 , or a corresponding amount of a pharma or greater, 24 consecutive weeks or greater, 36 consecutive ceutically acceptable salt thereof, starting on the day after weeks or greater, 48 consecutive weeks or greater, 52 administering the last dose of the oral load dose formulation , consecutive weeks or greater, 72 consecutive weeks or and continuing for a set treatment period, serum testosterone greater, or 96 consecutive weeks or greater ), profound 50 levels in a subject may be at or below profound castration castration levels of less than or equal to 20 ng / dL ( 1.73 level within 1 week after commencing administration and nmol/ L ) serum testosterone may be achieved within 24 to 48 maintained until the end of administration . In some embodi hours after commencing administration and maintained until ments , following administration of an oral load dose formu the end of administration . In some embodiments , following lation of the disclosure comprising 360 mg of Compound 1 , administration of an oral load dose formulation of the 55 or a corresponding amount of a pharmaceutically acceptable disclosure comprising 360 mg of Compound 1 , or a corre salt thereof, once - daily for 1-3 days at the beginning of sponding amount of a pharmaceutically acceptable salt treatment, and once - daily administration of an oral mainte thereof, once - daily for 1-3 days at the beginning of treat nance dose formulation of the disclosure comprising 120 mg ment, and once -daily administration of an oral maintenance of Compound 1 , or a corresponding amount of a pharma dose formulation of the disclosure comprising 120 mg of 60 ceutically acceptable salt thereof, starting on the day after Compound 1 , or a corresponding amount of a pharmaceu administering the last dose of the oral load dose formulation , tically acceptable salt thereof, starting on the day after and continuing for a set treatment period, serum testosterone administering the last dose of the oral load dose formulation , levels in a subject may be at or below profound castration and continuing for a set treatment period , serum testosterone level within 2 weeks after commencing administration and levels in a subject may be at or below profound castration 65 maintained until the end of administration . In some embodi level within 3 days after commencing administration and ments , following administration of an oral load dose formu maintained until the end of administration . In some embodi lation of the disclosure comprising 360 mg of Compound 1 , US 10,786,501 B2 59 60 or a corresponding amount of a pharmaceutically acceptable than or equal to about 90 % of the subject’s serum PSA levels salt thereof, once - daily for 1-3 days at the beginning of prior to treatment commencing. In some embodiments, after treatment, and once - daily administration of an oral mainte once - daily administration of oral formulations of the disclo nance dose formulation of the disclosure comprising 120 mg sure for 4 weeks , serum PSA levels are reduced by greater of Compound 1 , or a corresponding amount of a pharma- 5 than or equal to about 50 % of the subject's serum PSA levels ceutically acceptable salt thereof, starting on the day after prior to treatment commencing. administering the last dose of the oral load dose formulation , In some embodiments, following administration of an oral and continuing for a set treatment period , serum testosterone load dose formulation of the disclosure once - daily for 1-3 levels in a subject may be at or below profound castration days at the beginning of treatment, and once - daily admin level within 3 weeks after commencing administration and 10 istration of an oral maintenance dose formulation of the maintained until the end of administration . In some embodi disclosure starting on the day after administering the last ments, following administration of an oral load dose formu dose of the oral load dose formulation , and continuing for a lation of the disclosure comprising 360 mg of Compound 1 , set treatment period, median time from commencing treat or a corresponding amount of a pharmaceutically acceptable ment to PSA nadir may be less than 5 weeks , less than 6 salt thereof, once -daily for 1-3 days at the beginning of 15 weeks, less than 7 , weeks , less than 8 weeks, less than 9 treatment, and once - daily administration of an oral mainte weeks, less than 10 weeks , less than 11 weeks , less than 12 nance dose formulation of the disclosure comprising 120 mg weeks, less than 13 weeks , less than 14 weeks , less than 15 of Compound 1 , or a corresponding amount of a pharma weeks, less than 16 weeks , less than 17 weeks , less than 18 ceutically acceptable salt thereof, starting on the day after weeks, less than 19 weeks , less than 20 weeks , less than 21 administering the last dose of the oral load dose formulation , 20 weeks, less than 22 weeks , less than 23 weeks, less than 24 and continuing for a set treatment period , serum testosterone weeks, or less than 25 weeks . In some embodiments, fol levels in a subject may be at or below profound castration lowing administration of an oral load dose formulation of level within 4 weeks after commencing administration and the disclosure once -daily for 1-3 days at the beginning of maintained until the end of administration . treatment, and once - daily administration of an oral mainte In some embodiments of the methods and uses described 25 nance dose formulation of the disclosure starting on the day herein , PSA may be suppressed in the subject to a level less after administering the last dose of the oral load dose than or equal to 4 ng /mL or less than or equal to 2 ng /mL . formulation, and continuing for a set treatment period, During a treatment period ( e.g. , at least 4 consecutive median time from commencing treatment to PSA nadir may weeks or greater, at least 8 consecutive weeks or greater, at be about 5 weeks to about 10 weeks, about 5 weeks to about least 12 consecutive weeks or greater, at least 16 consecutive 30 15 weeks , about 5 weeks to about 20 weeks , about 5 weeks weeks or greater, at least 20 consecutive weeks or greater, 24 to about 25 weeks , about 10 weeks to about 15 weeks , about consecutive weeks or greater, 36 consecutive weeks or 10 weeks to about 20 weeks, about 10 weeks to about 25 greater, 48 consecutive weeks or greater, 52 consecutive eks, or about 15 weeks to about 20 weeks . In some weeks or greater, 72 consecutive weeks or greater, or 96 embodiments, following administration of an oral load dose consecutive weeks or greater ) of once - daily administration 35 formulation of the disclosure once - daily for 1-3 days at the of oral formulations comprising Compound 1 , or a pharma beginning of treatment, and once -daily administration of an ceutically acceptable salt thereof, median time from admin oral maintenance dose formulation of the disclosure starting istration of the first oral formulation to PSA nadir may be on the day after administering the last dose of the oral load less than 5 weeks, less than 6 weeks , less than 7 , weeks , less dose formulation , and continuing for a set treatment period, than 8 weeks , less than 9 weeks , less than 10 weeks , less 40 median time from commencing treatment to PSA nadir may than 11 weeks , less than 12 weeks, less than 13 weeks , less be about 10 weeks to about 20 weeks . In some embodiments, than 14 weeks, less than 15 weeks , less than 16 weeks , less 4 weeks after commencing administration of an oral load than 17 weeks, less than 18 weeks , less than 19 weeks , less dose formulation of the disclosure once - daily for 1-3 days , than 20 weeks, less than 21 weeks , less than 22 weeks , less and once - daily administration of an oral maintenance dose than 23 weeks, less than 24 weeks , or less than 25 weeks . In 45 formulation of the disclosure starting on the day after some embodiments , during a treatment period of once - daily administering the last dose of the oral load dose formulation , administration of oral formulations comprising Compound serum PSA levels are reduced by greater than or equal to 1 , or a pharmaceutically acceptable salt thereof, median time about 5 % , greater than or equal to about 10 % , greater than from administration of the first oral formulation to PSA or equal to about 20 % , greater than or equal to about 30 % , nadir may be about 5 weeks to about 10 weeks , about 5 50 greater than or equal to about 40 % , greater than or equal to weeks to about 15 weeks, about 5 weeks to about 20 weeks , about 50 % , greater than or equal to about 60 % , greater than about 5 weeks to about 25 weeks , about 10 weeks to about or equal to about 70 % , greater than or equal to about 80 % , 15 weeks , about 10 weeks to about 20 weeks , about 10 or greater than or equal to about 90 % of the subject's serum weeks to about 25 weeks , or about 15 weeks to about 20 PSA levels prior to treatment commencing. In some embodi weeks. In some embodiments, during a treatment period of 55 ments, 4 weeks after commencing administration of an oral once - daily administration of oral formulations comprising load dose formulation of the disclosure once - daily for 1-3 Compound 1 , or a pharmaceutically acceptable salt thereof, days, and once - daily administration of an oral maintenance median time from administration of the first oral formulation dose formulation of the disclosure starting on the day after to PSA nadir may be about 10 weeks to about 20 weeks . In administering the last dose of the oral load dose formulation , some embodiments , after once - daily administration of oral 60 serum PSA levels are reduced by greater than or equal to formulations of the disclosure for 4 weeks , serum PSA levels about 50 % of the subject's serum PSA levels prior to are reduced by greater than or equal to about 5 % , greater treatment commencing . than or equal to about 10 % , greater than or equal to about After once - daily administration of oral formulations com 20 % , greater than or equal to about 30 % , greater than or prising Compound 1 , or a pharmaceutically acceptable salt equal to about 40 % , greater than or equal to about 50 % , 65 thereof, for 1 week , 4 weeks, 12 weeks , 24 weeks , or 48 greater than or equal to about 60 % , greater than or equal to weeks, serum FSH levels may be less than or equal to about about 70 % , greater than or equal to about 80 % , or greater 7.2 mIU /mL , about 4.8 mIU /mL , about 2.4 mIU /mL , or US 10,786,501 B2 61 62 about 1.2 mIU /mL . In certain such embodiments , once - daily dependent prostate cancer , advanced prostate cancer, meta administration of oral formulations comprising Compound static , non -metastatic , locally advanced , advanced hormone 1 , or a pharmaceutically acceptable salt thereof, may result sensitive , advanced castration resistant, recurrent, castra in sustained suppression of serum FSH levels . Normal FSH tion - resistant metastatic prostate cancer , castration - resistant levels in adult males are typically between 1.5 to 12.45 non - metastatic prostate cancer , hormone - sensitive meta mIU /mL , but are elevated in subjects with prostate cancer . In static prostate cancer, or hormone - sensitive non - metastatic some embodiments , after once - daily administration of oral prostate cancer . In some embodiments, the medicament formulations comprising Compound 1 , or a pharmaceuti comprises 80 mg to about 480 mg of Compound 1 , or a cally acceptable salt thereof, for 1 week , serum FSH levels corresponding amount of the pharmaceutically acceptable may be less than or equal to about 7.2 mIU /mL , about 4.8 10 salt thereof. mIU /mL , about 2.4 mIU /mL , or about 1.2 mIU /mL . In some Methods and uses described herein may provide androgen embodiments , once -daily administration of oral formula deprivation in prostate cancer without increasing risk of tions comprising Compound 1 , or a pharmaceutically hyperglycemia and diabetes as compared to GnRH agonists acceptable salt thereof, for 1 week , 4 weeks , 12 weeks , 24 ( e.g. , Lupron ). Unlike other GnRH antagonists ( e.g. , weeks, or 48 weeks, may suppress serum FSH levels by 15 degarelix ), oral formulations of the disclosure provide greater than or equal to about 80 % or about 90 % of the androgen deprivation without need for injection . subject's serum FSH levels prior to treatment commencing. Methods and uses described herein may delay progression In some embodiments, following administration of an oral of castration resistant disease . In particular, Compound 1 , or load dose formulation of the disclosure once - daily for 1-3 a pharmaceutically acceptable salt thereof, may offer days at the beginning of treatment, and once -daily admin- 20 improved disease control when compared with a GnRH istration of an oral maintenance dose formulation of the agonist in terms of superior FSH suppression and PSA disclosure starting on the day after administering the last progression - free survival. dose of the oral load dose formulation , serum FSH levels Methods and uses described herein may be used to may be less than or equal to about 7.2 mIU /mL , about 4.8 achieve the anti- androgen withdrawal syndrome. An “ anti mIU /mL , about 2.4 mIU /mL , or about 1.2 mIU /mL 1 week , 25 androgen ” may refer to any drug or substance that decreases 4 weeks , 12 weeks , 24 weeks, or 48 weeks after commenc the levels or activity of androgens. Anti -androgens tend to ing treatment . In certain such embodiments, once - daily inhibit the production, activity , or effects of a male sex administration of oral formulations comprising Compound hormone or prevent androgens like testosterone or dihy 1 , or a pharmaceutically acceptable salt thereof, may result drotestosterone from mediating their biological effects in the in sustained suppression of serum FSH levels . In some 30 body. The anti - androgen withdrawal syndrome is a well embodiments, following administration of an oral load dose established phenomenon in prostate cancer. It is widely formulation of the disclosure once -daily for 1-3 days at the accepted that a subset of patients will benefit from the beginning of treatment, and once - daily administration of an withdrawal of anti - androgen or steroidal hormone from oral maintenance dose formulation of the disclosure starting hormonal therapy, exhibiting decreasing PSA values and on the day after administering the last dose of the oral load 35 clinical improvement. dose formulation , serum FSH levels may be less than or Methods and uses described herein may be employed to equal to about 7.2 mIU /mL , about 4.8 mIU /mL , about 2.4 provide heart benefits . The cardiac benefits may be linked to mIU /mL , or about 1.2 mIU /mL 1 week after commencing better FSH suppression compared to agonists . Methods and treatment. In some embodiments, following administration uses described herein may be employed to provide ADT of an oral load dose formulation of the disclosure once - daily 40 with lower rates of cardiovascular side effects compared to for 1-3 days at the beginning of treatment, and once - daily agonists . Also , the formulations of the present disclosure administration of an oral maintenance dose formulation of may be useful in sexual reassignment /cross gender transition the disclosure starting on the day after administering the last protocols. Further, the formulations of the present disclosure dose of the oral load dose formulation , serum FSH levels may be useful in preserving fertility during chemotherapy. may be suppressed by greater than or equal to about 80 % or 45 Dosing and Administration about 90 % of the subject's serum FSH levels prior to Although GnRH agonists and antagonists are typically treatment commencing 1 week , 4 weeks , 12 weeks , 24 given either subcutaneously , intramuscularly or intranasally , weeks, or 48 weeks after commencing treatment . including by depot formulations, Compound 1 , or a phar The disclosure also provides oral formulations compris maceutically acceptable salt thereof, may be administered ing about 80 mg to about 480 mg of Compound 1 , or a 50 orally and once - daily, making dose administration easier and corresponding amount of a pharmaceutically acceptable salt more convenient. thereof, for use in a method of treating prostate cancer in a For treatment of prostate cancer , Compound 1 , or a subject in need thereof. pharmaceutically acceptable salt thereof, may be adminis The disclosure provides oral formulations comprising tered orally once -daily , and formulated with a pharmaceu about 80 mg to about 480 mg of Compound 1 , or a 55 tically acceptable carrier or excipients . In some embodi corresponding amount of a pharmaceutically acceptable salt ments , the dosage formulation is a solid preparation, such as thereof, for use in a method for treating prostate cancer in a a tablet, capsule, granule, or powder, for oral administration . subject in need thereof, the method comprising: administer In some embodiments, the oral formulations comprising ing the oral formulation to the subject once daily ; suspend Compound 1 , or a pharmaceutically acceptable salt thereof, ing administration of the oral formulation for a suspension 60 have an immediate release profile . However, the oral for period to allow for an increase of serum testosterone levels ; mulation may have other release profiles including , for and resuming administering to the subject once daily the oral example, sustained release, controlled release, delayed formulation at the end of the suspension period. release and extended release . The disclosure also provides for use of Compound 1 , or In some embodiments, the periods of once -daily admin a pharmaceutically acceptable salt thereof, for the manufac- 65 istration for oral formulations comprising Compound 1 , or a ture of a medicament for the treatment of prostate cancer. In pharmaceutically acceptable salt thereof, in the methods and certain such embodiments, the prostate cancer is hormone uses described herein are : at least 4 consecutive weeks or US 10,786,501 B2 63 64 greater, at least 8 consecutive weeks or greater, at least 12 able salt thereof. In some embodiments, the oral formulation consecutive weeks or greater, at least 16 consecutive weeks comprises about 160 mg of Compound 1 , or a corresponding or greater, at least 20 consecutive weeks or greater, 24 amount of a pharmaceutically acceptable salt thereof . In consecutive weeks or greater, 36 consecutive weeks or some embodiments, the oral formulation comprises about greater, 48 consecutive weeks or greater, 52 consecutive 5 180 mg of Compound 1 , or a corresponding amount of a weeks or greater, 72 consecutive weeks or greater, or 96 pharmaceutically acceptable salt thereof. In some embodi consecutive weeks or greater me embodiments, the ments , the oral formulation comprises about 360 mg of periods of once -daily administration are 4 consecutive Compound 1 , or a corresponding amount of a pharmaceu weeks or greater. In some embodiments, the periods of tically acceptable salt thereof. In some embodiments , the once - daily administration are 8 consecutive weeks or 10 oral formulation comprises about 240 mg of Compound 1 , greater. In some embodiments, the periods of once - daily or a corresponding amount of a pharmaceutically acceptable administration are 12 consecutive weeks or greater. In some salt thereof. embodiments, the periods of once - daily administration are The present disclosure provides once - daily administration 16 consecutive weeks or greater. In some embodiments, the of oral formulations such as an oral load dose formulation periods of once - daily administration are 20 consecutive 15 comprising Compound 1 , or a pharmaceutically acceptable weeks or greater. In some embodiments, the periods of salt thereof, and an oral maintenance dose formulation once - daily administration are 24 consecutive weeks or comprising Compound 1 , or a pharmaceutically acceptable greater. In some embodiments, the periods of once - daily salt thereof, to a subject in need of treatment for prostate administration are 36 consecutive weeks or greater. In some cancer. In some embodiments , the oral load dose formula embodiments, the periods of daily administration are 48 20 tion is a tablet or capsule and the oral maintenance dose consecutive weeks or greater membodiments, the formulations are a tablet or capsule . In some embodiments, periods of once - daily administration are 52 consecutive the oral load dose formulation has an immediate release weeks or greater. In some embodiments , the periods of profile. However, the oral load dose formulation can have once - daily administration are 72 consecutive weeks or other release profiles including, for example, sustained greater. In some embodiments , the periods of once - daily 25 release , controlled release, delayed release and extended administration are 96 consecutive weeks or greater. release . In some embodiments , the oral maintenance dose The methods and uses described herein include chronic formulation has an immediate release profile. However, the administration . For example, the treatment periods using oral maintenance dose formulation can have other release oral formulations comprising Compound 1 , or a pharmaceu profiles including, for example, sustained release , controlled tically acceptable salt thereof, for treating prostate cancer in 30 release , delayed release and extended release . In some a subject and suppressing PSA and / or one or more sex embodiments , both the oral load and oral maintenance dose hormones in a subject, including testosterone , LH , and FSH , formulations are immediate release formulations . may be of a long du such as , once - daily administra In some embo ts , an oral load dose formulation tion for consecutive day periods of 48 weeks or greater, comprising Compound 1 , or a pharmaceutically acceptable once - daily administration for consecutive day periods of 52 35 salt thereof, may be administered once - daily to begin treat consecutive weeks or greater, once - daily administration for ment of prostate cancer and the duration of administration is consecutive day periods of 72 consecutive weeks or greater, between 1 and 3 days . In some embodiments, an oral load once - daily administration for consecutive day periods of 76 dose formulation comprising Compound 1 , or a pharmaceu weeks or greater, once - daily administration for consecutive tically acceptable salt thereof, may be administered once day periods of 96 weeks or greater, once - daily administra- 40 daily to begin treatment of prostate cancer and the duration tion for consecutive day periods of 104 weeks or greater, or of administration is 1 day . In some embodiments , an oral once - daily administration for consecutive day periods of 128 load dose formulation comprising Compound 1 , or a phar weeks or greater. In certain such embodiments, the treatment maceutically acceptable salt thereof, may be administered period is once - daily administration for consecutive day once - daily to begin treatment of prostate cancer and the periods of 48 weeks or greater. 45 duration of administration is 2 days. In some embodiments, The methods and uses described herein include adminis an oral load dose formulation comprising Compound 1 , or a tering , once - daily , oral formulations comprising Compound pharmaceutically acceptable salt thereof, may be adminis 1 , or a pharmaceutically acceptable salt thereof, to a subject tered once -daily to begin treatment of prostate cancer and in need thereof for the treatment of prostate cancer. In the duration of administration is 3 days. certain such embodiments , the oral formulation comprises at 50 Oral load dose formulations of the disclosure may com least about 80 mg to about 480 mg of Compound 1 , or a prise about 240 to about 480 mg of Compound 1 , or a corresponding amount of a pharmaceutically acceptable salt corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments , the oral formulation com thereof, such as about 320 mg to about 400 mg . In some prises about 80 mg , about 120 mg , about 160 mg , about 180 embodiments , the oral load dose formulation of the disclo mg , or about 360 mg of Compound 1 , or a corresponding 55 sure comprises about 240 mg , about 320 mg , about 360 mg , amount of a pharmaceutically acceptable salt thereof. In or about 480 mg of Compound 1 , or a corresponding amount some embodiments, the oral formulation comprises about 80 of a pharmaceutically acceptable salt thereof . In some mgt about 10mg of Compu1, corresponding embodiments , the oral load dose formulation of the disclo amount of a pharmaceutically acceptable salt thereof. In sure comprises about 360 mg of Compound 1 , or a corre certain embodiments , the oral formulation comprises about 60sponding amount of pharmaceutically acceptable salt 240 mg to about 480 mg of Compound 1 , or a corresponding thereof. In some embodiments, the oral load dose formula amount of a pharmaceutically acceptable salt thereof . In tion of the disclosure comprises about 240 mg of Compound some embodiments, the oral formulation comprises about 80 1 , or a corresponding amount of a pharmaceutically accept mg of Compound 1 , or a corresponding amount of a phar able salt thereof. In some embodiments , the oral load dose maceutically acceptable salt thereof. In some embodiments, 65 formulation of the disclosure comprises about 320 mg of theral formulation comprises about 120mgofCompound Compound 1 , or a corresponding amount of a pharmaceu 1 , or a corresponding amount of a pharmaceutically accept tically acceptable salt thereof. In some embodiments, the US 10,786,501 B2 65 66 oral load dose formulation of the disclosure comprises about amount of a pharmaceutically acceptable salt thereof. In 480 mg of Compound 1 , or a corresponding amount of a some embodiments , the oral load dose formulation of the pharmaceutically acceptable salt thereof. disclosure may be administered once -daily for 1 day at the Thereafter, and sometimes combined during the duration beginning of treatment and each dose comprises about 360 of the oral load dose formulation , there is once - daily admin- 5 mg of Compound 1 , or a corresponding amount of a phar istration of an oral maintenance dose formulation . In some maceutically acceptable salt thereof. In some embodiments, embodiments , the oral maintenance dose formulation once the oral load dose formulation of the disclosure may be daily administration begins on the day after administering administered once - daily for 1 day at the beginning of the last dose of the oral load dose formulation . In some treatment and each dose comprises about 240 mg of Com embodiments, the oral maintenance dose formulation of the 10 pound 1 , or a corresponding amount of a pharmaceutically disclosure comprises about 80 mg to about 160 mg of acceptable salt thereof . In some embodiments , the oral load Compound 1 , or a corresponding amount of a pharmaceu dose formulation of the disclosure may be administered tically acceptable salt thereof, such as about 100 mg to about once - daily for 1 day at the beginning of treatment and each 140 mg . In some embodiments , the oral maintenance dose dose comprises about 320 mg of Compound 1 , or a corre formulation of the disclosure comprises about 120 mg of 15 sponding amount of a pharmaceutically acceptable salt Compound 1 , or a corresponding amount of a pharmaceu thereof. In some embodiments, the oral load dose formula tically acceptable salt thereof . In some embodiments, the tion of the disclosure may be administered once - daily for 1 oral maintenance dose formulation of the disclosure com day at the beginning of treatment and each dose comprises prises about 160 mg of Compound 1 , or a corresponding about 480 mg of Compound 1 , or a corresponding amount amount of a pharmaceutically acceptable salt thereof . In 20 of a pharmaceutically acceptable salt thereof. some embodiments, the oral maintenance dose formulation In some embodiments , the oral load dose formulation of of the disclosure comprises about 80 mg of Compound 1 , or the disclosure may be administered once - daily for 2 days at a corresponding amount of a pharmaceutically acceptable the beginning of treatment and each dose comprises about salt thereof. In some embodiments, the oral maintenance 240 to about 480 mg of Compound 1 , or a corresponding dose formulation of the disclosure comprises about 180 mg 25 amount of a pharmaceutically acceptable salt thereof, such of Compound 1 , or a corresponding amount of a pharma as about 320 mg to about 400 mg . In some embodiments , the ceutically acceptable salt thereof. oral load dose formulation of the disclosure may be admin In some embodiments , the oral load dose formulation of istered once - daily for 2 days at the beginning of treatment the disclosure may be administered once -daily for 1-3 days and each dose comprises about 240 mg , about 320 mg , about at the beginning of treatment and each dose comprises about 30 360 mg , or about 480 mg of Compound 1 , or a correspond 240 to about 480 mg of Compound 1 , or a corresponding ing amount of a pharmaceutically acceptable salt thereof. In amount of a pharmaceutically acceptable salt thereof, such some embodiments, the oral load dose formulation of the as about 320 mg to about 400 mg . In some embo ts , the disclosure may be administered once -daily for 2 days at the oral load dose formulation of the disclosure may be admin beginning of treatment and each dose comprises about 360 istered once - daily for 1-3 days at the beginning of treatment 35 mg of Compound 1 , or a corresponding amount of a phar and each dose comprises about 240 mg , about 320 mg , about maceutically acceptable salt thereof. In some embodiments, 360 mg , or about 480 mg of Compound 1 , or a correspond the oral load dose formulation of the disclosure may be ing amount of a pharmaceutically acceptable salt thereof. In administered once - daily for 2 days at the beginning of some embodiments , the oral load dose formulation of the treatment and each dose comprises about 240 mg of Com disclosure may be administered once - daily for 1-3 days at 40 pound 1 , or a corresponding amount of a pharmaceutically the beginning of treatment and each dose comprises about acceptable salt thereof. In some embodiments, the oral load 360 mg of Compound 1 , or a corresponding amount of a dose formulation of the disclosure may be administered pharmaceutically acceptable salt thereof. In some embodi once - daily for 2 days at the beginning of treatment and each ments, the oral load dose formulation of the disclosure may dose comprises about 320 mg of Compound 1 , or a corre be administered once - daily for 1-3 days at the beginning of 45 sponding amount of a pharmaceutically acceptable salt treatment and each dose comprises about 240 mg of Com thereof. In some embodiments, the oral load dose formula pound 1 , or a corresponding amount of a pharmaceutically tion of the disclosure may be administered once - daily for 2 acceptable salt thereof. In some embodiments, the oral load days at the beginning of treatment and each dose comprises dose formulation of the disclosure may be administered about 480 mg of Compound 1 , or a corresponding amount once - daily for 1-3 days at the beginning of treatment and 50 of a pharmaceutically acceptable salt thereof. each dose comprises about 320 mg of Compound 1 , or a In some embodiments , the oral load dose formulation of corresponding amount of a pharmaceutically acceptable salt the disclosure may be administered once - daily for 3 days at thereof. In some embodiments , the oral load dose formula the beginning of treatment and each dose comprises about tion of the disclosure may be administered once - daily for 240 to about 480 mg of Compound 1 , such as about 320 mg 1-3 days at the beginning of treatment and each dose 55 to about 400 mg, or a corresponding amount of a pharma comprises about 480 mg of Compound 1 , or a corresponding ceutically acceptable salt thereof . In some embodiments, the amount of a pharmaceutically acceptable salt thereof. oral load dose formulation of the disclosure may be admin In some embodiments, the oral load dose formulation of istered once - daily for 3 days at the beginning of treatment the disclosure may be administered once - daily for 1 day at and each dose comprises about 240 mg , about 320 mg , about the beginning of treatment and each dose comprises about 60 360 mg , or about 480 mg of Compound 1 , or a correspond 240 to about 480 mg of Compound 1 , or a corresponding ing amount of a pharmaceutically acceptable salt thereof. In amount of a pharmaceutically acceptable salt thereof, such some embodiments , the oral load dose formulation of the as about 320 mg to about 400 mg . In some embodiments, the disclosure may be administered once - daily for 3 days at the oral load dose formulation of the disclosure may be admin beginning of treatment and each dose comprises about 360 istered once - daily for 1 day at the beginning of treatment and 65 mg of Compound 1 , or a corresponding amount of a phar each dose comprises about 240 mg , about 320 mg , about 360 maceutically acceptable salt thereof. In some embodiments, mg , or about 480 mg of Compound 1 , or a corresponding the oral load dose formulation of the disclosure may be US 10,786,501 B2 67 68 administered once - daily for 3 days at the beginning of 72 consecutive weeks or greater. In some embodiments, the treatment and each dose comprises about 240 mg of Com oral maintenance dose formulations of the disclosure may be pound 1 , or a corresponding amount of a pharmaceutically administered once -daily for 96 consecutive weeks or greater. acceptable salt thereof . In some embodiments, the oral load For chronic administration, the oral maintenance dose for dose formulation of the disclosure may be administered 5 mulations of the disclosure may be administered once - daily once - daily for 3 days at the beginning of treatment and each for : consecutive day periods of 48 weeks or greater, con dose comprises about 320 mg of Compound 1 , or a corre secutive day periods of 52 consecutive weeks or greater, sponding amount of a pharmaceutically acceptable salt consecutive day periods of 72 consecutive weeks or greater, thereof. In some embodiments , the oral load dose formula consecutive day periods of 76 weeks or greater, consecutive tion of the disclosure may be administered once - daily for 3 10 day periods of 96 weeks or greater, consecutive day periods days at the beginning of treatment and each dose comprises of 104 weeks or greater, or consecutive day periods of 128 about 480 mg of Compound 1 , or a corresponding amount weeks or greater. In certain such embodiments, the oral of a pharmaceutically acceptable salt thereof. maintenance dose formulations of the disclosure may be In some embodiments, an oral maintenance dose formu administered once - daily for consecutive day periods of 48 lation of the disclosure may be administered once - daily and 15 weeks or greater. comprises about 80 mg to about 160 mg of Compound 1 , or In some embodiments , the oral load dose formulation of a corresponding amount of a pharmaceutically acceptable the disclosure comprises about 360 mg of Compound 1 , or salt thereof, such as about 100 mg to about 140 mg . In some a corresponding amount of a pharmaceutically acceptable embodiments, the oral maintenance dose formulation of the salt thereof, and may be administered once on day 1 of the disclosure may be administered once - daily and comprises 20 treatment period, and the oral maintenance dose formula about 120 mg of Compound 1 , or a corresponding amount tions of the disclosure comprise about 120 mg of Compound of a pharmaceutically acceptable salt thereof. In some 1 , or a corresponding amount of a pharmaceutically accept embodiments , the oral maintenance dose formulation of the able salt thereof, and may be administered once -daily start disclosure may be administered once - daily and comprises ing on day 2 of the treatment period . In certain such about 160 mg of Compound 1 , or a corresponding amount 25 embodiments , the daily oral maintenance dose formulations of a pharmaceutically acceptable salt thereof. In some may be administered once - daily for a 12 consecutive weeks embodiments, the oral maintenance dose formulation of the or greater treatment period . In some embodiments , the daily disclosure may be administered once - daily and comprises oral maintenance dose formulations of the disclosure may be about 80 mg of Compound 1 , or a corresponding amount of administered once - daily for a 48 consecutive weeks or a pharmaceutically acceptable salt thereof. In some embodi- 30 greater treatment period . ments, the oral maintenance dose formulation of the disclo In some embodiments, the oral load dose formulation of sure may be administered once - daily and comprises about the disclosure comprises about 240 mg of Compound 1 , or 180 mg of Compound or a corresponding amount of a a corresponding amount of a pharmaceutically acceptable pharmaceutically acceptable salt thereof. salt thereof, and may be administered once on day 1 of the In some embodiments, the oral maintenance dose formu- 35 treatment period , and the oral maintenance dose formula lations of the disclosure may be administered once - daily for tions of the disclosure comprise about 120 mg of Compound 4 consecutive weeks or greater, 8 consecutive weeks or 1 , or a corresponding amount of a pharmaceutically accept greater, 12 consecutive weeks or greater, 16 consecutive able salt thereof, and may be administered once - daily start weeks or greater, 20 consecutive weeks or greater, 24 ing on day 2 of the treatment period. In certain such consecutive weeks or greater, 36 consecutive weeks or 40 embodiments , the daily oral maintenance dose formulations greater, 48 consecutive weeks or greater, 52 consecutive may be administered once - daily for a 12 consecutive weeks weeks or greater, 72 consecutive weeks or greater, or 96 or greater treatment period . In some embodiments, the daily consecutive weeks or greater. In some embodiments , the oral oral maintenance dose formulations of the disclosure may be maintenance dose formulations of the disclosure may be administered once - daily for a 48 consecutive weeks or administered once - daily for 4 consecutive weeks or greater. 45 greater treatment period . In some embodiments, the oral maintenance dose formula In some embodiments , the oral load dose formulation of tions of the disclosure may be administered once - daily for 8 the disclosure comprises about 360 mg of Compound 1 , or consecutive weeks or greater. In some embodiments, the oral a corresponding amount of a pharmaceutically acceptable maintenance dose formulations of the disclosure may be salt thereof, and may be administered once on day 1 of a first administered once - daily for 12 consecutive weeks or greater. 50 treatment period , and the oral maintenance dose formula In some embodiments, the oral maintenance dose formula tions of the disclosure comprise about 120 mg of Compound tions of the disclosure may be administered once - daily for 1 , or a corresponding amount of a pharmaceutically accept 16 consecutive weeks or greater. In some embodiments , the able salt thereof, and may be administered once - daily start oral maintenance dose formulations of the disclosure may be ing on day 1 or day 2 of a second treatment period. In certain administered once -daily for 20 consecutive weeks or greater. 55 such embodiments , the daily oral maintenance dose formu In some embodiments, the oral maintenance dose formula lations may be administered once - daily for a 12 consecutive tions of the disclosure may be administered once - daily for weeks or greater treatment period. In some embodiments , 24 consecutive weeks or greater. In some embodiments, the the daily oral maintenance dose formulations of the disclo oral maintenance dose formulations of the disclosure may be sure may be administered once - daily for a 48 consecutive administered once - daily for 36 consecutive weeks or greater. 60 weeks or greater treatment period . In some embodiments , the oral maintenance dose formula In some embodiments , the oral load dose formulation of tions of the disclosure may be administered once - daily for the disclosure comprises about 240 mg of Compound 1 , or 48 consecutive weeks or greater. In some embodiments, the a corresponding amount of a pharmaceutically acceptable oral maintenance dose formulations of the disclosure may be salt thereof, and may be administered once on day 1 of a first administered once - daily for 52 consecutive weeks or greater. 65 treatment period , and the oral maintenance dose formula In some embodiments , the oral maintenance dose formula tions of the disclosure comprise about 120 mg of Compound tions of the disclosure may be administered once - daily for 1 , or a corresponding amount of a pharmaceutically accept US 10,786,501 B2 69 70 able salt thereof, and may be administered once - daily start ments , the suspension period may be up to 12 weeks . In ing on day 1 or day 2 of a second treatment period . In certain some embodiments , the suspension period may be up to 4 such embodiments , the daily oral maintenance dose formu weeks. In some embodiments, the suspension period may be lations may be administered once -daily for a 12 consecutive up to 8 weeks . weeks or greater treatment period . In some embodiments, 5 In some embodiments , the once - daily administration of the daily oral maintenance dose formulations of the disclo oral formulations of the disclosure comprising Compound 1 , sure may be administered once - daily for a 48 consecutive or a pharmaceutically acceptable salt thereof, for all methods weeks or greater treatment period . and uses disclosed herein can be suspended for a period of The present disclosure further provides that once - daily 4 weeks or less , after at least 24 consecutive weeks of administration of oral formulations comprising Compound 10 once -daily administration . In some embodiments , the once 1 , or a pharmaceutically acceptable salt thereof, can be daily administration of oral formulations of the disclosure suspended for a suspension period , thereby allowing for an comprising Compound 1 , or a pharmaceutically acceptable increase in a subject's serum testosterone levels . Increased salt thereof, for all methods and uses disclosed herein can be serum testosterone levels during the suspension period may suspended for a period of 4 weeks or less to 8 weeks or enable subjects remain in control of their lifestyle and 15 greater, after at least 24nsecutive weeks fonce - daily quality of life ( e.g. , maintenance of sexual activity ). In some administration . In some embodiments, the once - daily embodiments , the suspension occurs after the oral formula administration of oral formulations comprising Compound tion of the disclosure is administered once -daily for 4 1 , or a pharmaceutically acceptable salt thereof, for all consecutive weeks or greater. In some embodiments, the methods and uses disclosed herein can be suspended for a suspension occurs after the oral formulation of the disclo- 20 period of 4 weeks or less to 12 weeks or greater, after at least sure is administered once - daily for 8 consecutive weeks or 24 consecutive weeks of once - daily administration . In some greater . In some embodiments, the suspension occurs after embodiments , the once - daily administration of oral formu the oral formulation of the disclosure is administered once lations comprising Compound 1 , or a pharmaceutically daily for 12 consecutive weeks or greater. In some embodi acceptable salt thereof, for all methods and uses disclosed ments, the suspension occurs after the oral formulation of 25 herein can be suspended for a period of 4 weeks or less to the disclosure is administered once -daily for 16 consecutive 16 weeks or greater, after at least 24 consecutive weeks of weeks or greater. In some embodiments, the suspension once - daily administration . In some embodiments , the once occurs after the oral formulation of the disclosure is admin daily administration of oral formulations comprising Com istered once - daily for 20 consecutive weeks or greater. In pound 1 , or a pharmaceutically acceptable salt thereof , for me embodiment , the suspension occurs after the ra3almethods and uses disclosed herein abesspended for formulation of the disclosure is administered once - daily for a period of 4 weeks or less to 20 weeks or greater, after at 24 consecutive weeks or greater. In some embodiments, the least 24 consecutive weeks of once - daily administration. In suspension occurs after the oral formulation of the disclo some embodiments , the once - daily administration of oral sure is administered once - daily for 36 consecutive weeks or formulations comprising Compound 1 , or a pharmaceuti greater. In some embodiments , the suspension occurs after 35 cally acceptable salt thereof, for all methods and uses the oral formulation of the disclosure is administered once disclosed herein can be suspended for a period of 4 weeks daily for 48 consecutive weeks or greater. In some embodi or less to 24 weeks or greater, after at least 24 consecutive ments, the suspension occurs after the oral formulation of weeks of once - daily administration . In some embodiments, the disclosure is administered once -daily for 52 consecutive the once -daily administration of oral formulations compris weeks or greater. In some embodiments, the suspension 40 ing Compound 1 , or a pharmaceutically acceptable salt occurs after the oral formulation of the disclosure is admin thereof, for all methods and uses disclosed herein can be istered once - daily for 72 consecutive weeks or greater. In suspended for a period of 4 weeks or less to 36 weeks or some embodiments , the suspension occurs after the oral greater, after at least 24 consecutive weeks of once - daily formulation of the disclosure is administered once - daily for administration . In some embodiments, the once - daily consecutive weeks or greater. In membodiments, the 45 administration fra formulations comprising Compound administration of the oral formulation of the disclosure is 1 , or a pharmaceutically acceptable salt thereof, for all suspended after at least 24 consecutive weeks of once -daily methods and uses disclosed herein can be suspended for a administration . In some embodiments , the administration of period of 4 weeks or less to 48 weeks or greater, after at least the oral formulation of the disclosure is suspended after at 24 consecutive weeks of once - daily administration . In some least 48 consecutive weeks of once - daily administration . 50 embodiments , the once - daily administration of oral formu The suspension period may last until the desired increase lations comprising Compound 1 , or a pharmaceutically in a subject's serum testosterone levels is achieved or may acceptable salt thereof, for all methods and uses disclosed last as long as required . In some embodiments, the suspen herein can be suspended for a period of 4 weeks or less to sion period may last until the PSA begins to rise . In some 52 weeks or greater, after at least 24 consecutive weeks of embodiments, once -daily administration may be resumed 55 once - daily administration . In some embodiments, the once when there is rise in PSA of “ nadir + 2 ng / mL . ” In some daily administration of oral formulations comprising Com embodiments , once - daily administration may be resumed pound 1 , or a pharmaceutically acceptable salt thereof, for when the subject's PSA level is 3 ng /mL , 210 ng /mL , 220 all methods and uses disclosed herein can be suspended for ng /mL , or 230 ng /mL . In some embodiments , the suspen a period of 4 weeks or less to 60 weeks or greater, after at sion period may be up to 60 weeks . In some embodiments, 60 least 24 consecutive weeks of once - daily administration. the suspension period may be up to 52 weeks . In some The present disclosure provides for resumption of once embodiments, the suspension period may be up to 48 weeks . daily administration of oral formulations of the disclosure In some embodiments, the suspension period may be up to following a suspension period. In some embodiments , once 36 weeks . In some embodiments, the suspension period may daily administration of oral formulations of the disclosure be up to 24 weeks. In some embodiments, the suspension 65 comprising about 80 mg to about 480 mg of Compound 1 , period may be up to 20 weeks . In some embodiments , the or a corresponding amount of a pharmaceutically acceptable suspension period may be up to 16 weeks . In some embodi salt thereof, is resumed at the end of the suspension period . US 10,786,501 B2 71 72 The present disclosure also provides for once - daily once - daily for 24 consecutive weeks or greater following a administration of oral load dose formulations after a sus suspension period. In some embodiments , the oral formu pension period. In some embodiments, an oral load dose lations or oral maintenance dose formulations of the disclo formulation of the disclosure comprising about 240 mg to sure may be administered once - daily for 36 consecutive about 480 mg of Compound 1 , or a corresponding amount 5 weeks or greater following a suspension period . In some of a pharmaceutically acceptable salt thereof, may be admin embodiments, the oral formulations or oral maintenance istered once - daily for 1-3 days at the beginning of the dose formulations of the disclosure may be administered treatment period after the suspension period . In some once - daily for 48 consecutive weeks or greater following a embodiments , the oral load dose formulation of the disclo suspension period . In some embodiments, the oral formu suresuspension may be period administered. In some embodimentsonce -daily for, the 1 oralday loadafter dose the 10 lations or oral maintenance dose formulations of the disclo formulation of the disclosure may be administered once sure may be administered once -daily for 52 consecutive daily for 2 days after the suspension period . In some weeks or greater following a suspension period . In some embodiments , the oral load dose formulation of the disclo embodiments, the oral formulations or oral maintenance sure may be administered once - daily for 3 days after the 15 dose formulations of the disclosure may be administered suspension period. once -daily for 72 consecutive weeks or greater following a After a suspension period , the present disclosure provides suspension period . In some embodiments, the oral formu for administration of a once -daily oral maintenance dose lations or oral maintenance dose formulations of the disclo formulation of the disclosure comprising about 80 mg to sure may be administered once - daily for 96 consecutive about 160 mg of Compound 1 , or a corresponding amount 20 weeks or greater following a suspension period . For chronic of a pharmaceutically acceptable salt thereof, beginning administration after a suspension period , the oral formula after administering the last dose of the oral load dose tions or oral maintenance dose formulations of the disclo formulation of the disclosure . In some embodiments follow sure may be administered once - daily for : consecutive day ing a suspension period , administration of the once - daily periods of 48 weeks or greater, consecutive day periods of oral maintenance dose formulation of the disclosure com- 25 52 consecutive weeks or greater, consecutive day periods of prising about 80 mg to about 160 mg of Compound 1 , or a 72 consecutive weeks or greater, consecutive day periods of corresponding amount of a pharmaceutically acceptable salt 76 weeks or greater, consecutive day periods of 96 weeks or thereof, begins on the day after administering the last dose greater, consecutive day periods of 104 weeks or greater, or of the oral load dose formulation of the disclosure . consecutive day periods of 128 weeks or greater. In certain In certain embodiments with intermittent dosing involv- 30 such embodiments, the oral formulations or oral mainte ing separate treatment periods , the oral load dose formula nance dose formulations of the disclosure may be adminis tion of the disclosure may be administered once - daily for tered once - daily for consecutive day periods of 48 weeks or 1-3 days at the beginning of each treatment period . In certain greater. embodiments with intermittent dosing involving separate In some embodiments , the once - daily administration of treatment periods, the oral maintenance dose formulation of 35 oral formulations comprising Compound 1 , or a pharmaceu the disclosure may be administered once - daily at the begin tically acceptable salt thereof, is suspended for a subsequent ning of each treatment period. suspension period after completion of an initial suspension After resuming administration of oral formulations or oral period and resumption of administration . In certain such maintenance dose formulations of the disclosure following a embodiments, the subsequent suspension period occurs at suspension period , the oral formulations or oral maintenance 40 least 12 weeks after resuming once - daily administration of dose formulations may be administered once - daily for 4 an oral formulation comprising about 80 mg to about 480 mg consecutive weeks or greater, 8 consecutive weeks or of Compound 1 , or a corresponding amount of a pharma greater, 12 consecutive weeks or greater, 16 consecutive ceutically acceptable salt thereof. weeks or later, 20 consecutive weeks or greater , 24 con The present disclosure also provides for not resuming secutive weeks or greater, 36 consecutive weeks or greater, 45 administration once it is suspended . For example , in some 48 consecutive weeks or greater, 52 consecutive weeks or embodiments, administration may be suspended after radia greater, 72 consecutive weeks or greater, or 96 consecutive tion therapy is completed and not resumed . In some embodi weeks or greater. In some embodiments , the oral formula ments, administration after radiation therapy is completed tions or oral maintenance dose formulations of the disclo will not be resumed until the PSA rises . In some embodi sure may be administered once -daily for 4 consecutive 50 ments, once - daily administration may be resumed when weeks or greater following a suspension period . In some there is rise in PSA of “ nadir + 2 ng / mL ” after radiation embodiments , the oral formulations or oral maintenance therapy. In some embodiments, once - daily administration dose formulations of the disclosure may be administered may resumed after radiation therapy when the subject’s PSA once - daily for 8 consecutive weeks or greater following a level is z3 ng /mL , > 10 ng /mL , 220 ng /mL , or 230 ng /mL . suspension period . In some embodiments, the oral formu- 55 In some embodiments , administration of the oral formu lations or oral maintenance dose formulations of the disclo lations of the present disclosure is food dependent. In certain sure may be administered once - daily for 12 consecutive such embodiments , administration is preferably before any weeks or greater following a suspension period. In some meal . In some embodiments, the oral formulation compris embodiments, the oral formulations or oral maintenance ing Compound 1 , or a pharmaceutically acceptable salt dose formulations of the disclosure may be administered 60 thereof, may be administered pre - prandial. In some embodi once - daily for 16 consecutive weeks or greater following a ments , administration is at least 1 hour before eating or at suspension period. In some embodiments, the oral formu least 2 hours after eating. In other embodiments, adminis lations or oral maintenance dose formulations of the disclo tration can also be at least 30 minutes before eating or while sure may be administered once - daily for 20 consecutive the subject is fasting. In some embodiments , administration weeks or greater following a suspension period . In some 65 is about 2 hours before eating or 1 hour after eating. In some embodiments, the oral formulations or oral maintenance embodiments, administration is at least 30 minutes before dose formulations of the disclosure may be administered eating, 1 hour before eating , or 2 hours before eating . In US 10,786,501 B2 73 74 some embodiments, administration is at least 30 minutes vidone , acacia , sodium alginate, and carboxymethylcellu after eating, 1 hour after eating , or 2 hours after eating. lose . In some embodiments, the diluent is D -mannitol . In In some embodiments, the administration of the oral some embodiments , the diluent is microcrystalline cellulose . formulations of the disclosure is without any fasting or In some embodiments , the diluent is lactose . eating schedule requirement. In some embodiments, the 5 Binders for use in the present disclosure include, but are administration is without any fasting requirement. In certain not limited to , hydroxypropyl cellulose , crystalline cellulose such embodiments , the administration of the oral formula ( e.g. , CEOLUS KG - 802 ( grade: KG - 802 ) and CEOLUS tion can be food independent. In some embodiments , admin PH - 302 ( grade : PH - 302 ) ) , crystalline cellulose ( particles ), istration can be during a meal . crystalline cellulose ( fine particles ), microcrystalline cellu The present disclosure provides that the administration for 10 lose , hydroxypropyl methylcellulose ( e.g. , hypromellose all methods and uses described herein is such that there is no 2910 ) , starch , gelatin , sucrose , dextrin , lactose , povidone stimulation of sex hormones, and thereby flare is prevented ( polyvinylpyrrolidone ), and copolyvidone. Natural and syn or minimized in subjects. thetic gums that can be used as binders include , but are not Depending on one or more of the following: symptom limited to , acacia , sodium alginate, and carboxymethylcel severity, subject age , weight and sensitivity, and risk factors, 15 lulose . In some embodiments, the binder is hydroxypropyl such as whether a smoker, and existing medications , the methylcellulose. In some embodiments, the binder is duration and intervals of administration can be altered . hydroxypropyl cellulose . Dosage Forms of the Disclosure Disintegrants for use in the present disclosure include , but As used herein , the oral formulations of the disclosure are not limited to , crosslinked polymers, such as crosslinked may include, but are not limited to , tablets, capsules , caplets, 20 polyvinylpyrrolidone ( crospovidone ), crosslinked sodium pills , oral dissolving films, lozenges, gums, granules, and carboxylmethyl cellulose ( croscarmellose sodium ) , cross powders. In some embodiments, the oral formulation is a linked carmellose sodium , microcrystalline cellulose , car tablet or a capsule. boxymethyl cellulose , carboxylmethyl cellulose calcium , In some embodiments , the oral formulations, including carboxylmethyl starch sodium , and sodium starch glycolate . the oral load and maintenance dose formulations, disclosed 25 Additional disintegrants for use in the present disclosure herein have an immediate release profile. However, the oral include , but are not limited to , corn starch , sodium car formulations can have other release profiles including, for boxymethyl starch , low - substituted hydroxypropylcellulose example, sustained release , controlled release , delayed ( L - HPC ), hydroxypropyl starch , and magnesium alumino release and extended release . In some embodiments, the oral metasilicate . In some embodiments, the disintegrant is formulations disclosed herein have a sustained release pro- 30 sodium starch glycolate. In some embodiments, the disin file . In some embodiments , the oral formulations disclosed tegrant is crosslinked sodium carboxylmethyl cellulose . herein have controlled release profile. In some embodi Lubricants for use in the present disclosure include , but ments , the oral formulations disclosed herein have a delayed are not limited to , magnesium stearate ; stearic acid ; sodium release profile. In some embodiments, the oral formulations stearyl fumarate ; triethyl citrate ; inorganic lubricants , disclosed herein have an extended release profile . 35 namely talc , colloidal silica and fumed silicon dioxide ; The excipients of the oral formulations of the disclosure polymeric lubricants, such as polyethylene glycol , PEG are a blend of excipients, and amounts, that help to optimize 4000 , and PEG 6000 ; mineral oils ; and hydrogenated veg the efficacy of the formulation . The following are core etable oils . However, other compounds, such as fatty acids excipients and include various organic or inorganic excipi and metallic salts thereof, fatty acid esters and salts thereof, ents or carrier substances , including, but not limited to , one 40 organic waxes , polymers and inorganic substances, can be or more fillers or diluents , lubricants, binders, surfactants, employed . Useful fatty acids include , but are not limited to , pH adjusters, sweeteners , flavors, and disintegrants. There lauric acid , palmitic acid and stearic acid . Useful metallic can be a film coat with pharmaceutical additives, including, salts include , but are not limited to , those of calcium , but not limited to , one or more film formers , coating bases , magnesium and zinc . Useful fatty acid esters include, but are coating additives , plasticizers, organic acids , pigments or 45 not limited to , glyceride esters , such as glyceryl monoste antioxidants, light shielding agents , flow - aids or polishing arate , glyceryl tribehenate, glyceryl palmitostearate and agents, and colorants. glyceryl dibehenate . Useful sugar esters include, but are not Diluents or fillers for use in the present disclosure include limited to , sucrose esters of fatty acids , sorbitan monoste organic materials and inorganic materials including, but not arate , and sucrose monopalmitate . Useful salts thereof limited to , dextrose, lactose , mannitol, D -mannitol ( e.g. , 50 include , but are not limited to , sodium oleate , sodium PEARLITOL 50C , PEARLITOL 100SD , PEARLITOL benzoate , sodium acetate , magnesium lauryl sulfate , and 200SD , PEARLITOL 300 DC , and PEARLITOL 400DC ) , sodium lauryl sulfate . In some embodiments, lubricants sodium starch , sucrose , calcium phosphate, anhydrous cal include magnesium stearate , calcium stearate, talc , and cium phosphate , precipitated calcium carbonate , calcium colloidal silica . In some embodiments, the lubricant is sulfate, calcium carbonate, calcium silicate, sorbitol, corn 55 magnesium stearate. As used herein, polyethylene glycol is starch , potato starch , wheat starch , rice starch , partly prege a generic term of compounds represented by the formula latinized starch , pregelatinized starch , porous starch , and HOCH2CH2 ) , OH wherein n is a natural number ( com calcium carbonate starch . In some embodiments , the diluent pound wherein n is not less than 2000 is sometimes referred is mannitol. Diluents or fillers for use in the present disclo to as polyethylene oxide ) . sure include organic materials and inorganic materials also 60 Examples of colorants used in the formulations of the include , but are not limited to , hydroxypropyl cellulose , disclosure include , but are not limited to , food colors such as crystalline cellulose ( e.g. , CEOLUS KG - 802 ( grade: Food Color Yellow No. 5 , Food Color Red No. 2 , Food KG - 802 ) and CEOLUS PH - 302 ( grade : PH - 302 ) ), crystal Color Blue No. 2 and the like , food lake colors , red ferric line cellulose ( particles ), crystalline cellulose ( fine par oxide , and yellow ferric oxide . ticles ) , microcrystalline cellulose , hydroxypropyl methyl- 65 Examples of pH adjusters used in the formulations of the cellulose ( e.g. , hypromellose 2910 ), starch , gelatin , sucrose , disclosure include , but are not limited to , citric acid or a salt dextrin , lactose , povidone ( polyvinylpyrrolidone ), copoly thereof, phosphoric acid or a salt thereof, carbonic acid or a US 10,786,501 B2 75 76 salt thereof, tartaric acid or a salt thereof, fumaric acid or a cancer, the oral formulations provided by this disclosure that salt thereof, acetic acid or a salt thereof, and amino acid or include sodium starch glycolate have improved stability and a salt thereof. greater load capacity of Compound 1 , or a pharmaceutically Examples of surfactants used in the formulations of the acceptable salt thereof, so that Compound 1 , or a corre disclosure include , but are not limited to , sodium lauryl 5 sponding amount of a pharmaceutically acceptable salt sulfate, polysorbate 80 , and polyoxyethylene ( 160 ) polyoxy thereof, can be as high as about 360 mg in an oral load dose propylene ( 30 )glycol . formulation and about 120 mg in an oral maintenance dose Examples of sweeteners used in the formulations of the formulation . disclosure include , but are not limited to , aspartame ( trade The present disclosure provides oral formulations com namerin sodium) , acesulfame , and dipotassium potassium ,glycyrrhizinate sucralose , thaumatin . , saccha- 10 prising Compound 1 , or a pharmaceutically acceptable salt Examples of the flavors used in the formulations of the thereof, for the treatment of prostate cancer . In certain such disclosure include, but are not limited to , menthol, pepper embodiments, the oral formulations comprise about 80 mg mint oil , lemon oil , and vanillin . or about 120 mg or about 160 mg or about 180 mg of In some embodiments, the pigments for use herein 15 Compound 1 , or a corresponding amount of a pharmamaceu include , but are not limited to , titanium dioxide . tically acceptable salt thereof, and core excipients , such as In some embodiments, the film former / film coating base one or more diluents , one or more binders , one or more is a sugar coating base . Sugar coating bases for use herein disintegrants, one or more lubricants, or combinations include , but are not limited to , sucrose in combination with thereof. In certain such embodiments, the diluent comprises one or more of talc , precipitated calcium carbonate , gelatin , 20 mannitol, the binder comprises hydroxypropyl cellulose , the gum arabic , pullulan , or carnauba wax . disintegrant comprises sodium starch glycolate , and the In some embodiments , the film former / film coating base lubricant comprises hydroxypropyl cellulose . In some is a water - soluble film coating base . Water - soluble film embodiments , the oral formulations further comprise one or coating bases for use herein include , but are not limited to , more film formers /film coating bases , one or more pigments, cellulose polymers such as hydroxypropylcellulose , 25 one or more colorants, one or more flow aids / polishing hydroxypropyl methylcellulose ( e.g. , hypromellose 2910 , agents, or combinations thereof. In certain such embodi TC - 5 ) , hydroxyethylcellulose , methylhydroxyethylcellulose ments , the film former / film coating base comprises and the like ; synthetic polymers such as polyvinyl acetaldi hypromellose 2910 , the pigment comprises titanium diox ethylaminoacetate, aminoalkylmethacrylate copolymer E , ide , the colorant comprises ferric oxide , and the flow aid / polyvinylpyrrolidone and the like; and polysaccharides such 30 polishing agent comprises carnauba wax . as pullulan and the like. In some embodiments, the water In some embodiments, the oral formulations of the dis soluble film coating base is hydroxypropyl methylcellulose closure comprise about 240 mg to about 480 mg of Com ( e.g. , hypromellose 2910 , TC - 5 ) . In some embodiments, the pound 1 , or a corresponding amount of a pharmaceutically film former /film coating base is hydroxypropyl methylcel acceptable salt thereof, such as about 360 mg or about 240 lulose ( HPMC ) . In some embodiments, the hydroxypropyl 35 mg , and core excipients such as one or more diluents, one or methylcellulose is hypromellose 2910 . more binders, one or more disintegrants, one or more In some embodiments , the film former /film coating base lubricants, or combinations thereof. In certain such embodi comprises cellulose polymers such as hydroxypropylmeth ments, the diluent comprises mannitol, the binder comprises ylcellulose phthalate , ethylcellulose , hydroxypropylmethyl hydroxypropyl cellulose , the disintegrant comprises sodium cellulose acetate succinate, carboxymethylethylcellulose, 40 starch glycolate , and the lubricant comprises hydroxypropyl cellulose acetate phthalate and the like ; acrylic acid poly cellulose . In some embodiments, the oral formulations of the mers such as methacrylic acid copolymer L , methacrylic disclosure further comprise one or more film formers / film acid copolymer LD , methacrylic acid copolymer S , amino coating bases , one or more pigments, one or more colorants , alkylmethacrylate copolymer RS , ethyl acrylate -methyl one or more flow aids / polishing agents, or combinations methacrylate copolymer suspension , and the like ; and natu- 45 thereof. In certain such embodiments, the film formers / film rally occurring substances such as shellac and the like . coating base comprises hypromellose 2910 , the pigment In some embodiments , the flow aid / polishing agent is comprises titanium dioxide , the colorant comprises ferric carnauba wax . In some embodiments, the flow aid / polishing oxide , and the flow aid / polishing agent comprises carnauba agent is talc . wax . In some embodiments , colorants for use herein include , 50 In some embodiments, the present disclosure provides but are not limited to , ferric oxide . In some embodiments, oral formulations comprising about 80 mg or about 120 mg the colorant is red ferric oxide . In some embodiments , the or about 160 mg or about 180 mg of Compound 1 , or a colorant is yellow ferric oxide . In some embodiments, the corresponding amount of a pharmaceutically acceptable salt colorant is a combination of yellow ferric oxide and red thereof, and core excipients, namely, 51 mg to 244 mg of ferric oxide . 55 mannitol, 3 mg to 12 mg of hydroxypropyl cellulose , 10 mg In some embodiments , the plasticizers for use herein to 20 mg of sodium starch glycolate , and 2 mg to 4 mg of include , but are not limited to , polyethylene glycol ( e.g. , magnesium stearate . In some embodiments, the oral formu macrogol 6000 ) , triethyl citrate, castor oil , polysorbates, and lations of the disclosure can comprise 80 mg or 120 mg or the like . 160 mg of Compound 1 , or a corresponding amount of a In some embodiments , the organic acids for use herein 60 pharmaceutically acceptable salt thereof, and core excipi include , but are not limited to , citric acid , tartaric acid , malic ents, namely, 51 mg to 244 mg of mannitol, 3 mg to 12 mg acid , ascorbic acid , and the like . of hydroxypropyl cellulose , 10 mg to 20 mg of sodium In some embodiments , the oral formulations of the dis starch glycolate , and 2 mg to 4 mg of magnesium stearate . closure , including the oral load dose formulations and the The present disclosure still further provides that such oral oral maintenance dose formulations, comprise at least one 65 formulations include a film coat having film excipients, excipient that improves stability while maintaining load namely, 7.12 to 14.24 mg of hypromellose 2910 ( i.e. , capacity. It has been found that for the treatment of prostate hydroxypropyl methylcellulose ), 0.8 mg to 1.6 mg of tita US 10,786,501 B2 77 78 nium dioxide, a sufficient quantity of carnauba wax , and 160 mg of Compound 1 , or a corresponding amount of a 0.08 mg to 0.16 mg of ferric oxide . pharmaceutically acceptable salt thereof , such as about 120 In some embodiments , the oral formulations of the dis mg , and core excipients , such as one or more diluents, one closure comprise 80 mg or 120 mg or 160 mg of Compound or more binders , one or more disintegrants, one or more 1 , or a corresponding amount of a pharmaceutically accept- 5 lubricants, or combinations thereof. In certain such embodi able salt thereof, and core excipients, namely, 102 mg to 204 ments, the diluent comprises mannitol, the binder comprises mg of mannitol, 6 mg to 12 mg of hydroxypropyl cellulose , hydroxypropyl cellulose, the disintegrant comprises sodium 10 mg to 20 mg of sodium starch glycolate , and 2 mg to 4 starch glycolate , and the lubricant comprises hydroxypropyl mg of magnesium stearate . The present disclosure still cellulose . In some embodiments, the oral maintenance dose further provides that such oral formulations include a film 10 formulations further comprise one or more film formers / film coat having film excipients, namely , 7.12 to 14.24 mg of coating bases , one or more pigments, one or more colorants, hypromellose 2910 ( i.e. , hydroxypropyl methylcellulose ), one or more flow aids /polishing agents, or combinations 0.8 mg to 1.6 mg of titanium dioxide , a sufficient quantity of thereof. In certain such embodiments , the film former / film carnaubaIn some wax embodiments , and 0.08 ,mg the to oral 0.16 formulations mg of ferric of oxide the .dis- 15 coating base comprises hypromellose 2910 , the pigment closure comprise about 240 mg to about 480 mg of Com comprises titanium dioxide , the colorant comprises ferric pound 1 , or a corresponding amount of a pharmaceutically oxide, and the flow aid / polishing agent comprises carnauba acceptable salt thereof. Further, in certain such embodi wax . Further, in some embodiments, the oral maintenance ments, the oral formulations of the disclosure can include : dose formulations of the disclosure can include : from 244 from 306 mg to 612 mg ofmannitol ( including D -mannitol ) ; 20 mg to 488 mg ofmannitol ( including D -mannitol ) ; from 80 from 30 mg to 60 mg of sodium starch glycolate; from 18 mg mg to 160 mg of microcrystalline cellulose ; from 12 mg to to 36 mg of hydroxypropyl cellulose ; and from 6 mg to 12 24 mg of hydroxypropyl cellulose ; from 20 mg to 40 mg of mg of magnesium stearate , as core excipients; as well as croscarmellose sodium ; from 4 mg to 8 mg of magnesium from 21.36 mg to 42.72 mg of hypromellose 2910 ; from 2.4 stearate ; from 14.24 mg to 28.48 mg of hypromellose 2910 ; mg to 4.8 mg of titanium dioxide ; from 0.24 mg to 0.48 mg 25 from 1.6 mg to 3.2 mg of titanium dioxide ; and from 0.16 of ferric oxide ; and a sufficient quantity of carnauba wax . mg to 0.32 mg of ferric oxide . With this and other oral In some embodiments , the oral formulations of the dis formulations of the disclosure , water is removed during closure comprise about 240 mg to about 480 mg of Com processing of the oral maintenance dose formulation . pound 1 , or a corresponding amount of a pharmaceutically In some embodiments , the oral maintenance dose formu acceptable salt thereof. Further, in certain such embodi- 30 lation of the disclosure includes: 17.54 wt % of Compound ments, the oral formulations of the disclosure can include : 1 , or a corresponding amount of a pharmaceutically accept from 306 mg to 612 mg of mannitol ( including D -mannitol ) ; able salt thereof; 53.51 wt % of mannitol; 17.54 wt % of from 30 mg to 60 mg of sodium starch glycolate ; from 18 mg microcrystalline ose ; 2.63 wt % of hydroxypropyl to 36 mg of hydroxypropyl cellulose ; and from 6 mg to 12 cellulose ; 4.39 wt % of croscarmellose sodium , and 0.88 wt mg of magnesium stearate . In certain such embodiments , the 35 % of magnesium stearate, as core excipients. In certain such oral formulations of the disclosure further comprise from embodiments, the oral maintenance dose formulation of the 21.36 mg to 42.72 mg of hypromellose 2910 ; from 2.4 mg disclosure also includes the following other excipients: 3.12 to 4.8 mg of titanium dioxide ; from 0.24 mg to 0.48 mg of wt % of hypromellose 2910 ; 0.35 wt % of titanium dioxide ; ferric oxide ; and a sufficient quantity of carnauba wax . and 0.04 wt % of ferric oxide . In some embodiments, the oral load dose formulations of 40 In some embodiments, the oral maintenance dose formu the disclosure comprise about 240 mg , about 320 mg , about lations provided by this disclosure comprise about 80 mg to 360 mg , or about 480 mg of Compound 1 , or a correspond about 160 mg of Compound 1 , or a corresponding amount ing amount of a pharmaceutically acceptable salt thereof, of a pharmaceutically acceptable salt thereof. Further, in and may be administered once - daily . In some embodiments, certain such embodiments, the oral maintenance dose for the oral load dose formulations comprise about 360 mg of 45 mulations of the disclosure can include : from 102 mg to 204 Compound 1 , or a corresponding amount of a pharmaceu mg of mannitol ( including D -mannitol ); from 10 mg to 20 tically acceptable salt thereof . About 360 mg of Compound mg of sodium starch glycolate ; from 6 mg to 12 mg of 1 , or a corresponding amount of a pharmaceutically accept hydroxypropyl cellulose ; from 2 mg to 4 mg of magnesium able salt thereof, is used because it optimizes stability in the stearate ; from 7.12 mg to 14.24 mg of hypromellose 2910 ; composition , as well as maintains an efficacious load dose . 50 from 0.8 mg to 1.6 mg of titanium dioxide ; from 0.08 mg to In some embodiments, the oral maintenance dose formula 0.16 mg of ferric oxide ; and a sufficient quantity of carnauba tions of the disclosure comprise about 80 mg , about 120 mg , wax . about 160 mg , or about 180 mg of Compound 1 , or a In some embodiments , the oral maintenance dose formu corresponding amount of a pharmaceutically acceptable salt lations provided by this disclosure comprise about 80 mg to thereof, and may be administered once -daily . In some 55 about 160 mg of Compound 1 , or a corresponding amount embodiments , the oral maintenance dose formulations of the of a pharmaceutically acceptable salt thereof. Further , in disclosure comprise about 120 mg of Compound 1 , or a certain such embodiments , the oral maintenance dose for corresponding amount of a pharmaceutically acceptable salt mulations of the disclosure can include : from 102 mg to 204 thereof. About 120 mg of Compound 1 , or a corresponding mg of mannitol ( including D -mannitol ) ; from 10 mg to 20 amount of a pharmaceutically acceptable salt thereof, is used 60 mg of sodium starch glycolate ; from 6 mg to 12 mg of because it optimizes stability in the composition , as well as hydroxypropyl cellulose ; and from 2 mg to 4 mg of mag maintains an efficacious load dose. nesium stearate . In certain such embodiments , the oral Oral maintenance dose formulations of the disclosure maintenance dose formulations of the disclosure further comprising Compound 1 , or a pharmaceutically acceptable comprise from 7.12 mg to 14.24 mg of hypromellose 2910 ; salt thereof, can be used for treating prostate cancer . In 65 from 0.8 mg to 1.6 mg of titanium dioxide ; from 0.08 mg to certain such embodiments , the oral maintenance dose for 0.16 mg of ferric oxide ; and a sufficient quantity of carnauba mulations of the disclosure comprise about 80 mg to about wax . US 10,786,501 B2 79 80 In some embodiments, the oral maintenance dose formu 2910 ; 1.6 mg of titanium dioxide ; 0.16 mg of ferric oxide ; lations of the disclosure include : 38.46 wt % of Compound and a sufficient quantity of carnauba wax . 1 , or a corresponding amount of a pharmaceutically accept The disclosure provides oral load dose formulations com able salt thereof; 49.04 wt % of mannitol; 4.81 wt % of prising Compound 1 , or pharmaceutically acceptable salt sodium starch glycolate ( Type A ) ; 2.88 wt % of hydroxy- 5 thereof, for treatment of prostate cancer. In certain such propyl cellulose ; and 0.96 wt % of magnesium stearate, as embodiments , the oral load dose formulations of the disclo core excipients. In certain such embodiments , the oral sure comprise about 240 mg to about 480 mg of Compound maintenance dose formulations of the disclosure also 1 , or a corresponding amount of a pharmaceutically accept include the following other excipients: 3.42 wt % of able salt thereof, such as about 360 mg or 240 mg , and core hypromellose 2910 ; 0.38 wt % of titanium dioxide ; 0.04 wt 10 excipients such as one or more diluents, one or more binders , % of ferric oxide ; and a sufficient quantity of carnauba wax . one or more disintegrants, one or more lubricants , or com In some embodiments, the oral maintenance dose formu binations thereof. In certain such embodiments, the diluent lations of the disclosure include : 80 mg of Compound 1 , or comprises mannitol, the binder comprises hydroxypropyl a corresponding amount of a pharmaceutically acceptable cellulose , the disintegrant comprises sodium starch glyco salt thereof; 244 mg of mannitol; 80 mg of microcrystalline 15 late , and the lubricant comprises hydroxypropyl cellulose . In cellulose ; 12 mg of hydroxypropyl cellulose ; 20 mg of some embodiments, the oral load dose formulations of the croscarmellose sodium ; 4 mg of magnesium stearate as core disclosure further comprise one or more film formers / film excipients . In certain such embodiments, the oral mainte coating bases , one or more pigments, one or more colorants, nance dose formulations of the disclosure also include a film one or more flow aids /polishing agents, or combinations coat including 14.24 mg of hypromellose 2910 ; 1.6 mg of 20 thereof. In certain such embodiments, the film former / film titanium dioxide ; and 0.16 mg of ferric oxide . coating base comprises hypromellose 2910 , the pigment In some embodiments , the oral maintenance dose formu comprises titanium dioxide , the colorant comprises ferric lations of the disclosure include : 120 mg of Compound 1 , or oxide, and the flow aid /polishing agent comprises carnauba a corresponding amount of a pharmaceutically acceptable wax . Further, in some embodiments the oral load dose salt thereof; 366 mg of mannitol ( filler / diluent ); 120 mg of 25 formulations of the disclosure can include: from 732 mg to microcrystalline cellulose ( filler /diluent ) ; 18 mg ofhydroxy 1464 mg of mannitol ( including D - mannitol) ; from 240 mg propyl cellulose (binder ); 30 mg of croscarmellose sodium to 480 mg of microcrystalline cellulose ; from 36 mg to 72 ( disintegrant ), and 6 mg of magnesium stearate ( lubricant ), mg of hydroxypropyl cellulose ; from 60 mg to 120 mg of as core excipients. In certain such embodiments , the oral croscarmellose sodium ; from 12 mg to 24 mg of magnesium maintenance dose formulations of the disclosure also 30 stearate ; from 42.72 mg to 85.44 mg of hypromellose 2910 ; include the following other excipients: 21.36 mg of from 4.8 mg to 9.6 mg of titanium dioxide ; and from 0.48 hypromellose 2910 ( film coating base ) ; 2.4 mg of titanium mg to 0.96 mg of ferric oxide . With this and other oral dioxide ( pigment) ; and 0.24 mg of ferric oxide ( colorant ). formulations of the disclosure, water is removed during In some embodiments, the oral maintenance dose formu processing of the oral load dose formulation. lations of the disclosure include: 160 mg of Compound 1 , or 35 In some embodiments, the oral load dose formulations of a corresponding amount of a pharmaceutically acceptable the disclosure include: 17.54 wt % of Compound 1 , or a salt thereof; 488 mg of mannitol; 160 mg of microcrystalline corresponding amount of a pharmaceutically acceptable salt cellulose ; 24 mg of hydroxypropyl cellulose ; 40 mg of thereof; 53.51 wt % of mannitol; 17.54 wt % of microcrys croscarmellose sodium ; 8 mg of magnesium stearate as core talline cellulose ; 2.63 wt % ofhydroxypropyl cellulose ; 4.39 excipients. In certain such embodiments , the maintenance 40 wt % of croscarmellose sodium ; and 0.88 wt % of magne dose formulations of the disclosure also include as a film sium stearate , as core excipients. In certain such embodi coat 28.48 mg of hypromellose 2910 ; 3.2 mg of titanium ments , the oral load dose formulations of the disclosure also dioxide ; and 0.32 mg of ferric oxide . include the following other excipients: 3.12 wt % of In some embodiments , the oral maintenance dose formu hypromellose 2910 ; 0.35 wt % of titanium dioxide ; and 0.04 lations provided by this disclosure include : 80 mg of Com- 45 wt % of ferric oxide . pound 1 , or a corresponding amount of a pharmaceutically In some embodiments, the oral load dose formulations of acceptable salt thereof; 102 mg of mannitol; 10 mg of the disclosure comprise about 240 mg to about 480 mg of sodium starch glycolate ; 6 mg of hydroxypropyl cellulose; 2 Compound 1 , or a corresponding amount of a pharmaceu mg of magnesium stearate; 7.12 mg of hypromellose 2910 ; tically acceptable salt thereof. In certain such embodiments, 0.8 mg of titanium dioxide ; 0.08 mg of ferric oxide ; and a 50 the oral load dose formulations of the disclosure can include : sufficient quantity of carnauba wax . from 306 mg to 612 mg ofmannitol ( including D -mannitol ); In some embodiments, the oral maintenance dose formu from 30 mg to 60 mg of sodium starch glycolate; from 18 mg lations provided by this disclosure include: 120 mg of to 36 mg of hydroxypropyl cellulose ; and from 6 mg to 12 Compound 1 , or a corresponding amount of a pharmaceu mg of magnesium stearate , as core excipients; as well as tically acceptable salt thereof; 153 mg of mannitol ( filler/ 55 from 21.36 mg to 42.72 mg ofhypromellose 2910 ; from 2.4 diluent ); 15 mg of sodium starch glycolate ( disintegrant ); 9 mg to 4.8 mg of titanium dioxide ; from 0.24 mg to 0.48 mg mg of hydroxypropyl cellulose ( binder ); 3 mg of magnesium of ferric oxide ; and a sufficient quantity of carnauba wax . stearate ( lubricant ); 10.68 mg of hypromellose 2910 ( film In some embodiments, the oral load dose formulations of coating base ) ; 1.2 mg of titanium dioxide (pigment ); 0.12 the disclosure comprise about 240 mg to about 480 mg of mg of ferric oxide ( colorant) ; and a sufficient quantity of 60 Compound 1 , or a corresponding amount of a pharmaceu carnauba wax ( tablet flow aid / polishing agent ). tically acceptable salt thereof . In certain such embodiments, In some embodiments, the oral maintenance dose formu the oral load dose formulations of the disclosure can include : lations provided by this disclosure include: 160 mg of from 306 mg to 612 mg of mannitol ( including D -mannitol ); Compound 1 , or a corresponding amount of a pharmaceu from 30 mg to 60 mg of sodium starch glycolate ; from 18 mg tically acceptable salt thereof; 204 mg ofmannitol ; 20 mg of 65 to 36 mg of hydroxypropyl cellulose ; and from 6 mg to 12 sodium starch glycolate ; 12 mg of hydroxypropyl cellulose ; mg of magnesium stearate . In certain such embodiments , the 4 mg of magnesium stearate ; 14.24 mg of hypromellose oral load dose formulations of the disclosure further com US 10,786,501 B2 81 82 prise from 21.36 mg to 42.72 mg of hypromellose 2910 ; mg of titanium dioxide ; 0.48 mg of ferric oxide ; and a from 2.4 mg to 4.8 mg of titanium dioxide ; from 0.24 mg to sufficient quantity of carnauba wax . 0.48 mg of ferric oxide; and a sufficient quantity of carnauba Dosage Packs of the Disclosure wax . The present disclosure provides for dosage packs com In some embodiments , the oral load dose formulations of 5 prising the oral load and maintenance dose formulations the disclosure include : 38.46 wt % of Compound 1 , or a disclosed herein . The dosage pack of the disclosure includes corresponding amount of a pharmaceutically acceptable salt an oral load dose formulation that is separate from an oral thereof; 49.04 wt % of mannitol; 4.81 wt % of sodium starch maintenance dose formulation . In certain such embodi glycolate ( Type A ) ; 2.88 wt % of hydroxypropyl cellulose ; ments , the dosage pack is used for treating prostate cancer . andcertain 0.96 such wt % embodiments of magnesium , the stearate oral load, as coredose excipientsformulations. In 10 In some embodiments, the oral load dose formulation in the of the disclosure also include the following other excipients : dosage pack has a different color, shape , and / or size than the 3.42 wt % of hypromellose 2910 ; 0.38 wt % of titanium oral maintenance dose formulation . dioxide ; 0.04 wt % of ferric oxide ; and a sufficient quantity In some embodiments, the dosage pack provided by this of carnauba wax . 15 disclosure includes : an oral load dose formulation compris In some embodiments , the oral load dose formulations of ing excipients and from about 240 mg to about 480 mg of the disclosure include: 240 mg of the Compound 1 , or a Compound 1 , or a corresponding amount of a pharmaceu corresponding amount of a pharmaceutically acceptable salt tically acceptable salt thereof; and an oral maintenance dose thereof; 732 mg of mannitol; 240 mg of microcrystalline formulation comprising excipients and about 80 mg to about cellulose ; 36 mg of hydroxypropyl cellulose ; 60 mg of 20 160 mg of Compound 1 , or a corresponding amount of a croscarmellose sodium ; 12 mg ofmagnesium stearate ; 42.72 pharmaceutically acceptable salt thereof. In certain such mg of hypromellose 2910 ; 4.8 mg of titanium dioxide ; and embodiments, the oral load dose and maintenance formula 0.48 mg of ferric oxide . tions independently comprise excipients such as one or more In some embodiments, the oral load dose formulations of diluents, one or more binders, one or more disintegrants, one the disclosure include : 360 mg of Compound 1 , or a corre- 25 or more lubricants, or combinations thereof . In certain such sponding amount of a pharmaceutically acceptable salt embodiments , the diluent comprises mannitol, the binder thereof; 1098 mg of mannitol ( filler / diluent ); 360 mg of comprises hydroxypropyl cellulose , the disintegrant com microcrystalline cellulose ( filler / diluent ); 54 mg of hydroxy prises sodium starch glycolate, and the lubricant comprises propyl cellulose ( binder ); 90 mg of croscarmellose sodium hydroxypropyl cellulose . In some embodiments , the oral ( disintegrant ); and 18 mg of magnesium stearate ( lubricant ), 30 load dose and maintenance formulations independently fur as core excipients. In certain such embodiments , the oral ther comprise one or more film formers / film coating bases , load dose formulations of the disclosure also include the one or more pigments, one or more colorants, one or more following other excipients : 64.08 mg of hypromellose 2910 flow aids / polishing agents, or combinations thereof . In cer ( film coating base ) ; 7.2 mg of titanium dioxide ( pigment) ; tain such embodiments , the film former / film coating base and 0.72 mg of ferric oxide ( colorant ). 35 comprises hypromellose 2910 , the pigment comprises tita In some embodiments , the oral load dose formulation of nium dioxide , the colorant comprises ferric oxide , and the the disclosure include : 480 mg of the Compound 1 , or a flow aid / polishing agent comprises carnauba wax . corresponding amount of a pharmaceutically acceptable salt In some embodiments , the oral load dose formulation of thereof; 1464 mg of mannitol; 480 mg of microcrystalline the dosage pack of the disclosure comprises 306 mg to 612 cellulose ; 72 mg of hydroxypropyl cellulose ; 120 mg of 40 mg ofmannitol , 18 mg to 36 mg of hydroxypropyl cellulose , croscarmellose sodium ; 24 mg ofmagnesium stearate ; 85.44 30 mg to 60 mg of sodium starch glycolate , and 6 mg to 12 mg of hypromellose 2910 ; 9.6 mg of titanium dioxide ; and mg of magnesium stearate . 0.96 mg of ferric oxide . In some embodiments , the oral load dose formulation of In some embodiments, the oral load dose formulations the dosage pack of the disclosure further comprises 21.36 provided by this disclosure include: 240 mg of Compound 1 , 45 mg to 42.72 mg of hypromellose 2910 , 2.4 mg to 4.8 mg of or a corresponding amount of a pharmaceutically acceptable titanium dioxide , 0.24 mg to 0.48 mg of ferric oxide , and a salt thereof; 306 mg of mannitol; 30 mg of sodium starch sufficient quantity of carnauba wax . glycolate ; 18 mg of hydroxypropyl cellulose ; 6 mg of In some embodiments , the oral maintenance dose formu magnesium stearate ; 21.36 mg of hypromellose 2910 ; 2.4 lation of the dosage pack of the disclosure comprises 102 mg mg of titanium dioxide ; 0.24 mg of ferric oxide ; and a 50 to 204 mg of mannitol, 6 mg to 12 mg of hydroxypropyl sufficient quantity of carnauba wax . cellulose , 10 mg to 20 mg of sodium starch glycolate , and 2 In some embodiments, the oral load dose formulations mg to 4 mg of magnesium stearate . provided by this disclosure include : 360 mg of Compound 1 , In some embodiments, the oral maintenance dose formu or a corresponding amount of a pharmaceutically acceptable lation of the dosage pack of the disclosure further comprises salt thereof; 459 mg of mannitol ( filler /diluent ); 45 mg of 55 7.12 mg to 14.24 mg of hypromellose 2910 , 0.8 mg to 1.6 sodium starch glycolate ( disintegrant ); 27 mg of hydroxy mg of titanium dioxide , 0.08 mg to 0.16 mg of ferric oxide , propyl cellulose ( binder ); 9 mg of magnesium stearate and a sufficient quantity of carnauba wax . ( lubricant ); 32.04 mg of hypromellose 2910 ( film coating In certain aspects of the disclosure , the oral load dose base ) ; 3.6 mg of titanium dioxide ( pigment ); 0.36 mg of formulation and the oral maintenance dose formulation of ferric oxide ( colorant) ; and a sufficient quantity of carnauba 60 the dosage pack include at least one excipient that improves wax ( tablet flow aid / polishing agent ). stability while maintaining load capacity. In some embodi In some embodiments , the oral load dose formulations ments , the sodium starch glycolate in the oral load dose provided by this disclosure include : 480 mg of Compound 1 , formulation and the oral maintenance dose formulation of or a corresponding amount of a pharmaceutically acceptable the dosage pack of the disclosure improves stability and load salt thereof; 612 mg of mannitol; 60 mg of sodium starch 65 capacity of Compound 1 , or a pharmaceutically acceptable glycolate; 36 mg of hydroxypropyl cellulose ; 12 mg of salt thereof, in the oral load dose formulation and the oral magnesium stearate; 42.72 mg of hypromellose 2910 ; 4.8 maintenance dose formulation . US 10,786,501 B2 83 84 In some embodiments , the oral load dose formulation of In accordance with this disclosure, methods and uses the dosage pack of the disclosure comprises about 240 mg , comprising administration of oral formulations of the dis about 320 mg , about 360 mg , or about 480 mg of Compound closure comprising Compound 1 , or a pharmaceutically 1 , or a corresponding amount of a pharmaceutically accept acceptable salt thereof, can further comprise administration able salt thereof . In some embodiments, the oral load dose 5 of chemotherapy . “ Chemotherapy” may refer to a category of treatment using agents / drugs that are destructive to tumor formulation of the dosage pack of the disclosure comprises cells and certain tissues . Examples of such agents /drugs about 360 mg of Compound 1 , or a corresponding amount include small molecule compounds and biologic drugs, such of a pharmaceutically acceptable salt thereof. In some as an antibody or a polypeptide. Chemotherapy drugs that embodiments, the oral load dose formulation of the dosage 10 can be used with the methods and uses described herein pack of the disclosure comprises about 240 mg of Com include, but are not limited to , alkylating agents, antime pound 1 , or a corresponding amount of a pharmaceutically tabolites , anti - tumor antibiotics, topoisomerase inhibitors, acceptable salt thereof. mitotic inhibitors, corticosteroids, differentiating agents, In some embodiments , the oral maintenance dose formu proteasome inhibitors , immunotherapeutics, and hormone lation of the dosage pack of the disclosure comprises about 15 therapeutics. Chemotherapy drugs may include, but are not 80 mg , about 120 mg , or about 160 mg of Compound 1 , or limited to , abiraterone acetate with or without prednisone , a corresponding amount of a pharmaceutically acceptable enzalutamide, docetaxel , cabazitaxel, mitoxantrone, estra salt thereof. In some embodiments, the oral maintenance mustine, doxorubicin , etoposide, vinblastine, and inhibitors dose formulation of the dosage pack of the disclosure of the enzyme poly adenosine diphosphate ribose poly comprises about 120 mg of Compound 1 , or a corresponding 20 merase ( PARP ) . amount of a pharmaceutically acceptable salt thereof. In accordance with this disclosure, oral formulations of In some embodiments , the oral load dose formulation of the disclosure comprising Compound 1 , or a pharmaceuti the dosage pack of the disclosure comprises about 360 mg cally acceptable salt thereof, can be given daily together of Compound 1 , or a corresponding amount of a pharma with an anti- androgen . The anti -androgen can be given on ceutically acceptable salt thereof, and the oral maintenance 25 and off throughout treatment to provide benefit of an anti dose formulation comprises about 120 mg of Compound 1 , androgen withdrawal syndrome. Alternatively, oral formu or a corresponding amount of a pharmaceutically acceptable lations comprising Compound 1 , or a pharmaceutically salt thereof. acceptable salt thereof, can be given on and off throughout In some embodiments , the oral load dose formulation of the treatment cycle to provide an anti- androgen withdrawal the dosage pack of the disclosure comprises about 240 mg 30 syndrome by itself. To help treat clinical flare in subjects of Compound 1 , or a corresponding amount of a pharma with prostate cancer, an anti -androgen can be co -adminis ceutically acceptable salt thereof, and the oral maintenance tered with an oral formulation of the disclosure comprising dose formulation comprises about 120 mg of Compound 1 , Compound 1 , or a pharmaceutically acceptable salt thereof. or a corresponding amount of a pharmaceutically acceptable Illustrative anti - androgens include , but are not limited to , salt thereof. 35 flutamide, nilutamide, bicalutamide , enzalutamide , apaluta In some embodiments, the oral load dose formulation and mide , cyproterone acetate , megestrol acetate, chlormadi the oral maintenance dose formulation of the dosage pack of none acetate , spironolactone, canrenone , drospirenone, keto the disclosure are tablets . conazole , topilutamide ( fluridil) , and cimetidine. Such anti In some embodiments, the oral load dose formulation and androgens are typically administered for the first 2 to 4 the oral maintenance dose formulation of the dosage pack of 40 weeks of treatment. An illustrative dosage is an oral formu the disclosure have an immediate release profile . lation comprising about 120 mg of Compound 1 , or a In some embodiments, the dosage pack of the disclosure corresponding amount of a pharmaceutically acceptable salt further comprises at least one of an anti -androgen or CYP17 thereof, and 160 mg of enzalutamide. lyase inhibitor . In certain such embodiments, the anti - an In some embodiments , an oral formulation of the disclo drogen comprises enzalutamide, bicalutamide , enzalutamide 45 sure comprising Compound 1 , or a pharmaceutically accept or flutamide , and the CYP17 lyase inhibitor comprises able salt thereof, may be administered with a CYP17 lyase abiraterone. inhibitor. In some embodiments, the CYP17 lysase inhibitor Combination Therapy is abiraterone or salts thereof, galeterone or salts thereof, The administration mode of oral formulations of the ketoconazole or salts thereof, or seviteronel or salts thereof. disclosure comprising Compound 1 , or a pharmaceutically 50 In certain such embodiments, the CYP17 lyase inhibitor acceptable salt thereof, and a concomitant medicament can , comprises abiraterone or salts thereof. In some embodi for example, be ( 1 ) an administration of a single oral ments, the CYP17 lyase inhibitor and oral formulation formulation obtained by formulating Compound 1 , or a comprising Compound 1 , or a pharmaceutically acceptable pharmaceutically acceptable salt thereof, and a concomitant salt thereof, may be administered with a glucocorticoid . In medicament, simultaneously , ( 2 ) a simultaneous administra- 55 certain such embodiments, the glucocorticoid is prednisone. tion via an identical route of two formulations obtained by An illustrative dosing regime is abiraterone acetate given formulating Compound 1 , or a pharmaceutically acceptable daily in combination with prednisone given daily . In certain salt thereof, and a concomitant medicament separately, and such embodiments, 1000 mg of abiraterone acetate is given ( 3 ) a sequential and intermittent administration via an iden orally once - daily in combination with 5 mg prednisone ticalCompound route of1 , ortwo a pharmaceutically formulations obtained acceptable by saltformulating thereof, 60 givenlyase inhibitororally twice and dailyoral . formulationIn some embodiments comprising, theCompound CYP17 and a concomitant medicament separately. 1 , or a pharmaceutically acceptable salt thereof, may be In accordance with this disclosure, methods and uses administered in the absence of a glucocorticoid . comprising administration of oral formulations of the dis In accordance with the treatment methods and uses of this closure comprising Compound 1 , or a pharmaceutically 65 disclosure , if a prostate cancer is growth hormone depen acceptable salt thereof, can further comprise radiation dent, an oral formulation of the disclosure comprising Com therapy. pound 1 , or a pharmaceutically acceptable salt thereof, may US 10,786,501 B2 85 86 be administered in combination with a growth hormone pharmaceutically acceptable salt thereof Pharmacokinetic ( receptor) antagonist, or Prolactin ( receptor) antagonist, or characteristics were determined in healthy subjects after other drugs that may decrease growth hormone or IGF - 1 . single or repeat - dose administration ( once per day, until Still another benefit of this disclosure is that an oral pharmacokinetic steady - state is reached , at least as long as formulation of the disclosure comprising Compound 1 , or a 5 5 half - lives ). The effect of food or meals was determined pharmaceutically acceptable salt thereof, may be adminis after a single - dose administration , where the pharmacoki tered to a subject in conjunction with one or more interven netics of Compound 1 before /with / after food is compared to tions that mitigate or avoid side - effects normally associated administration in the fasted state ( no food for at least 8 hours with a GnRH antagonist, such as bone mineral density prior to dosing and for 4 hours after dosing ) . After admin ( BMD ) loss . Interventions include life style interventions 10 istration of Compound 1 , blood samples at prespecified and pharmacologic interventions. Such life style interven intervals were collected , plasma is harvested , and the con tions include , but are not limited to , exercise, smoking centration of Compound 1 is determined using analytical abstinence , and alcohol abstinence . Such pharmacologic methods such as high -performance liquid chromatography interventions include , but are not limited to , calcium supple with tandem mass - spectrometry. Pharmacokinetic param mentation , vitamin D supplementation , bisphosphonates, 15 eters ( such as Cmax. AUC and half- life ) were determined denosumab , calcitonin , SERMs , and strontium . from plasma concentration - time data for each individual In some embodiments, the methods and uses provided subject using noncompartmental analysis methods, as imple herein do not include administering Compound 1 or a mented in software such as Phoenix WinNonlin . These pharmaceutically acceptable salt thereof within 6 hours of parameters may then be summarized or compared using administering a P - glycoprotein ( P - gp ) inhibitor, CYP3A 20 statistical methods. inducer, or a P - gp inducer, or any combinations thereof. In some embodiments, a “ high -bioavailability formula P - gp mediates the export of drugs from certain cells , such as tion” dosage form comprising about 120 mg of Compound those located in the small intestine , blood - brain barrier, 1 , or a corresponding amount of a pharmaceutically accept hepatocytes, and kidney proximal tube . P - gp may be able salt thereof, taken orally pre - prandially may provide a affected by P - gp inducers or inhibitors, which impair P - gp 25 blood plasma concentration of at least about 22.68 ng /mL at mediated uptake or efflux , or enhance P - gp activity , respec 1 hour after dose administration . In some embodiments, it tively . CYP3A is a subfamily of monooxygenases which may provide a blood plasma concentration of about 48.6 may be involved in drug metabolism . P - gp or CYP3A ng /mL at 1 hour after dose administration . In certain inducers may include carbamazepine, rifampin , St. John's embodiments, it may provide a blood plasma concentration wort, bosentan , efavirenz, mitotane , modafinil, or nafcillin . 30 of about 84 ng /mL at 1 hour after dose administration . In P - gp inhibitors may include amiodarone, azithromycin , cap some embodiments, the high - bioavailability formulation topril, carvedilol, clarithromycin , conivaptan , cyclosporine, may have a lower dose of Compound 1 , or a pharmaceuti diltiazem , dronedarone , eliglustat, erythromycin , felodipine , cally acceptable salt thereof, yet may achieve the same itraconazole, ketoconazole, lapatinib , lopinavir/ ritonavir, average drug exposure in subjects . propafenone, quercetin , quinidine, reserpine, ranolazine , 35 In some embodiments , Compound 1 , or a pharmaceuti saquinavir , telaprevir, tipranavir, ticagrelor, tacrolimus, and cally acceptable salt thereof, may be formulated to achieve verapamil. A discussion of the P - gp transport system may be a low variability of pharmacokinetic and pharmacodynamic found in J. D. Wesslery , et al . JACC ( 2013 ) 61 ( 25 ) : 2495 effects in subjects. In some embodiments, a " low variability 502. In some embodiments , Compound 1 or a pharmaceu formulation ” dosage form comprising about 40 mg of Com tically acceptable salt thereof is administered no less than 6 40 pound 1 , or a corresponding amount of a pharmaceutically hours, no less than 8 hours , no less than 10 hours , or no less acceptable salt thereof, taken orally pre - prandially may than 12 hours before a P - gp inhibitor, CYP3A inducer, or a provide pharmacodynamic effects that are less subject to P - gp inducer, or any combinations thereof is administered . variation in subjects, yet may achieve the same average drug In some embodiments, Compound 1 or a pharmaceutically exposure in subjects as in other embodiments described acceptable salt thereof is administered no less than 6 hours , 45 herein . no less than 8 hours , no less than 10 hours , or no less than In some embodiments, an oral load dose formulation 12 hours after a P - gp inhibitor, CYP3A inducer, or a P - gp tablet comprising about 240 mg to about 480 mg of Com inducer, or any combinations thereof is administered . In pound 1 , or a corresponding amount of a pharmaceutically certain embodiments, for example when beginning a treat acceptable salt thereof, and an oral maintenance dose for ment comprising administration of Compound 1 or a phar- 50 mulation tablet comprising about about 80 mg to about 160 maceutically acceptable salt thereof, Compound 1 or a mg of Compound 1 , or a corresponding amount of a phar pharmaceutically acceptable salt thereof is administered no maceutically acceptable salt thereof, are formulated so that less than 16 hours , no less than 20 hours , or no less than 24 both are high -bioavailability and food -independent , and may hours before a P - gp inhibitor, CYP3A inducer, or a P - gp provide pharmacokinetic and pharmacodynamic effects that inducer, or any combinations thereof is administered . In 55 are less subject to variation in subjects. other embodiments, for example when beginning a treat In some embodiments, an oral load dose formulation ment comprising administration of Compound 1 or a phar tablet comprising about 360 mg of Compound 1 , or a maceutically acceptable salt thereof, Compound 1 or a corresponding amount of a pharmaceutically acceptable salt pharmaceutically acceptable salt thereof is administered no thereof, and an oral maintenance dose formulation tablet less than 16 hours, no less than 20 hours , or no less than 24 60 comprising about 120 mg of Compound 1 , or a correspond hours after a P - gp inhibitor, CYP3A inducer, or a P - gp ing amount of a pharmaceutically acceptable salt thereof, are inducer, or any combinations thereof is administered . formulated so that both are high - bioavailability and food Pharmacokinetics independent, and may provide pharmacokinetic and phar In some embodiments , Compound 1 , or a pharmaceuti macodynamic effects that are less subject to variation in cally acceptable salt thereof, is formulated to achieve a 65 subjects . desired PK profile, such as effective plasma levels for In some embodiments , a patient can take an oral formu once - daily treatment with a low dose of Compound 1 , or a lation comprising Compound 1 , or a pharmaceutically