Enzalutamide: a Novel Anti-Androgen for Patients with Castrate Resistant Prostate Cancer

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Author Manuscript Published OnlineFirst on January 8, 2013; DOI: 10.1158/1078-0432.CCR-12-2910 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.

Enzalutamide: a novel anti-androgen for patients with castrate resistant prostate cancer

Jean Hoffman-Censits and Wm. Kevin Kelly

Jean Hoffman-Censits, M.D. Assistant Professor Department of Medical Oncology Thomas Jefferson University and Hospital 1025 Walnut Street, Suite 700 Philadelphia, PA 19107

Corresponding author Wm. Kevin Kelly, DO Professor Department of Medical Oncology and Urology Director, Division of Solid Tumor Oncology Thomas Jefferson University and Hospital Associate Director of Translation Research, Kimmel Cancer Center 1025 Walnut Street, Suite 700 Philadelphia, PA 19107 Office: (215)503-4490 Fax: (215)503-3408 e-mail: [email protected]

Running Title: Enzalutamide

Word Count: 2524 words Abstract Count: 190 words

Disclosure of Potential Conflicts of Interest J. Hoffman-Censits and Wm. Kevin Kelly disclosed no potential conflicts of interest.

Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2013 American Association for Cancer Research. Author Manuscript Published OnlineFirst on January 8, 2013; DOI: 10.1158/1078-0432.CCR-12-2910 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.

Abstract Enzalutamide (MDV3100, Xtandi, Medivation\Astellas) is an oral inhibitor of androgen receptor signaling which blocks androgen-receptor interaction; inhibits translocation of the androgen receptor to the nucleus; impairs androgen receptor binding to DNA; and inhibits co-activator recruitment and receptor mediated DNA transcription. In a Phase III randomized study comparing Enzalutamide to placebo in men with progressive castration resistant prostate cancer (CRPC) who were previously treated with docetaxel, Enzalutamide showed an improvement in overall survival (18.4 vs. 13.6 months, hazard ratio 0.63, p<0.001). In addition, all secondary endpoints including proportion of patients with PSA decline; soft tissue response; quality of life response; time to PSA progression; radiographic progression free survival; and the time to the first radiographic skeletal event all significantly favored patients treated with enzalutamide. Fatigue, diarrhea and hot flashes were common in patients treated with enzalutamide, with seizures reported in 5 (0.6%) of the patients. Enzalutamide is a novel therapy which very potently blocks the androgen signaling pathway that is unregulated during the development of CRPC. The preclinical studies along with the pivotal trials which led to its approval by the FDA in September of 2012 will be reviewed.

Introduction Suppression of testosterone production by medical or surgical castration is standard first line treatment for men with advanced prostate cancer. Over time, nearly all men will develop progressive prostate cancer despite castrate levels of testosterone and are considered to have castration-resistant prostate cancer (CRPC). Previous clinical dogma for this disease state was reflected in its nomenclature, with terms such as androgen independent and hormone refractory which was replaced by CRPC, as greater understanding of androgen signaling in the castrate state has been established. In 2004, docetaxel chemotherapy administered intravenously every three weeks became the first therapy that showed a survival advantage in patients with CRPC, however response was modest and median survival for patients was approximately 19 months.1, 2 To improve outcomes, an understanding of the development of CPRC was needed and work from many, showed that restoration of the androgen signaling pathway was a driving force for the development of CRPC. This could occur through amplification or overexpression of androgen receptor (AR); gain-of-function somatic mutation of AR; aberrant AR post-translational modification (frequently driven by growth factor or cytokine signaling); alternative splicing events that result in hyperactive receptors; and cofactor dysregulation and/or intracrine androgen synthesis.3 This provided the rationale for the development of several novel agents including the CYP 17 α-

hydroxylase\12,20-lyase inhibitor, abiraterone acetate (Zytiga, Johnson & Johnson), which in part inhibits intra-tumoral production of androgens.4 In men with CRPC previously treated with docetaxel, abiraterone acetate and prednisone compared with prednisone alone conferred a statistically significant improvement in overall survival (14.8 vs. 10.9 months, HR 0.65; p<0.001) which led to FDA approval of abiraterone acetate in 2011. This clinical benefit observed with abiraterone acetate by inhibiting androgen synthesis further demonstrates the critical role of androgen signaling in CRPC.5 Recently, the FDA has approved enzalutamide, which belongs to another novel class of agents which represents a very potent inhibitor of the androgen receptor signaling pathway.

Preclinical Data Based upon the better understanding of the crystal structure of androgen receptor (AR)/bicalutamide interaction, Sawyers and colleagues modified and optimized the chemical scaffolding of the more potent anti-androgen, RU59063, to develop two oral diaryl-thiohydantoins, RD 162 and MDV3100 (enzalutamide) (6,7). Both of these agents bound the AR 5-8 fold greater than biclutamide and demonstrated no agonist activity in LNCaP/AR cell lines. Importantly, MDV3100 (enzalutamide) and RD162 and not biclutamide, decreased cell growth and induced apoptosis in the VCaP cell line which has an endogenous AR gene amplification. In a mutated cell line derived from a patient with bicalutamide resistance and where bicalutamide potentiated androgen dependent signaling, enzalutamide inhibited cell growth. Unlike biclutamide, neither of these novel anti-androgens recruited AR to the enhancer regions and co-activators to nuclear transcription complexes. Further studies in live LNCaP cells have shown that RD162 and enzalutamide reduced the nuclear to cytoplasmic AR ratio when compared with bicalutamide and that these drugs appear to inhibit the binding of AR to DNA. The nuclear localization of ligand bound AR with subsequent conformational changes allowing for cofactor recruitment and formation of the AR transcription complex and AR dependent DNA transcription, was impaired by enzalutamide in AR upregulated cell lines , This action was enhanced by bicalutamide6 Enzalutamide was selected for further clinical testing based on these and other pre-clinical studies, coupled with a more favorable pharmacokinetic profile of this agent versus others in early development.

Early Clinical Development In animal models of castrate resistant cell line derived LNCaP/AR tumors in castrate male mice, enzalutamide led to superior tumor responses over bicalutamide in a dose dependent fashion. These and other data led to the initial Phase I/II study which was initiated in 2007 and conducted at 5 centers

through the Prostate Cancer Clinical Trials Consortium.7 Men with progressive CRPC and a rising PSA with or without radiographic metastasis were eligible to participate. In the phase I portion, dose exposure ranged from 30 mg up to 600 mg orally daily, with only patients refractory to chemotherapy in the 480 and 600 mg cohorts. Pharmacokinetic analyses revealed rapid drug absorption and peak serum concentration from 30 minutes to 4 hours, with an approximate 7 day half-life. At all dose levels and in a dose dependent fashion up to 150 mg, significant decreases in PSA were demonstrated regardless of prior chemotherapy exposure. It was observed in this phase I study that chemotherapy naive men had a higher proportion of PSA decline of >50% at 12 weeks, and patients with prior exposure to ketoconazole had a diminished PSA response when administered Enzalutamide.

In these early studies, time to PSA progression (Prostate Cancer Working Group 2 (PCWG2) definition of PSA progression, 25% or greater increase from nadir PSA) was 41, 32, and 21 weeks respectively for chemonaive men, all men, and men previously exposed to chemotherapy. The median time to radiographic progression was 47 weeks for all participants, and the time to progression was significantly different in men previously treated with chemotherapy compared to chemonaive men (29 weeks vs. not yet reached, p=0.01). Exploratory studies using 16b-[18F] fluoro-5a-dihydrotestosterone (FDHT) imaging and circulating tumor cells showed improvement post treatment in subsets of patients which correlated with clinical outcomes. Long term follow up data presented in 2011 demonstrated median time to radiographic progression of 56 weeks in chemotherapy naive men and 24 weeks in men previously treated with chemotherapy.8

Fatigue was the most common reported toxicity, and led to dose reductions at levels of 240 mg and above. No dose reductions for fatigue were required in men receiving 150 mg or less, and the most common reported toxicities were grade 2 fatigue, nausea, dyspnea, anorexia, and back pain. Witnessed seizures were reported in 1 patient each at the 360 and 600 mg dose levels, and a possible seizure event at the 480 mg dose level was also reported. Other adverse events which lead to treatment discontinuation were rash, nausea and vomiting, fatigue and myocardial infarction, none of which occurred at the 150 mg and below dose levels. Other grade 3 and 4 events were anemia, arthralgia and asthenia which generally occurred at higher rates in the elevated dose levels. The maximum tolerated dose selected for phase II study was 240 mg daily. In all dose levels, partial responses in soft tissue disease were observed in 22% of the men , and stable bone scan at 12 weeks in 56% of the men , with chemonaive men having higher rates of radiographic responses than those with previous chemotherapy exposure.

Late Clinical Development AFFIRM, a phase III study evaluating the efficacy and safety of Investigational drug enzalutamide (NCT00974311), compared enzalutamide to placebo and randomized (in a 2:1 ratio)1199 men with CRPC that progressed on at least one prior chemotherapy from September 2009 through November 2010 at 156 centers in 15 countries.9 Patients with castrate levels of testosterone, disease progression by PCWG2 criteria, with ECOG performance status 0, 1 or 2 and adequate hematologic, hepatic and renal function were eligible to participate. Men were administered enzalutamide 160 mg orally daily or matched placebo and the use of prednisone was allowed but not required. The dose of 160 mg per day of enzalutamide was chosen for this registration study as there was comparable clinical benefit seen in the phase I/II study amongst men treated in the 150 mg and 240 mg cohorts, but increased incidence of adverse events with the higher dose.

Baseline patient and disease characteristics were well balanced between placebo and enzalutamide treated men . The median age of men on study was 69 years (range 41-92), median Gleason score was 8 in both groups, and the majority of patients had reported ECOG performance status of 0 or 1. Over 70% of men in each group had received only one prior chemotherapy regimen with median of 8.5 and 8 prior cycles of docetaxel in the enzalutamide and placebo arms, respectively. At the planned interim analysis, following 520 deaths on study, the median overall survival of patients in the enzalutamide arm was 18.4 months (95% CI 17.3 months – not yet reached), compared to 13.6 months (95% CI 11.3 – 15.8 months) in the placebo treated patients, translating to a 37% reduction in the risk of death in the enzalutamide treated group when compared to placebo treated men (HR for death 0.63; 95% CI, 0.53 – 0.75; p<0.001). Based on these data, the study was unblinded, and placebo-treated men were offered treatment with enzalutamide. The statistically significant benefit in overall survival derived from enzalutamide treatment was conserved among all pre-specified subgroups analyzed, and was not affected by baseline ECOG PS of 0/1 vs 2, mean pain score, type of progression at study entry, presence of visceral disease at screening, baseline LDH, or baseline hemoglobin. The survival benefit of enzalutamide was also maintained even when accounting for post-study therapy, as 38% of placebo treated men versus 31% of enzalutamide treated men went on to receive either abiraterone acetate or cabazitaxel, both agents with a survival benefit in men with chemotherapy refractory CRPC as well. Statistically significant improvements in all pre-specified secondary endpoints were also observed, including PSA response rate (54% vs 2%, p< 0.001), soft tissue response rate (29% vs 4%; p< 0.001), FACT-P validated quality of life response rate (43% vs 18%; p < 0/001), time to PSA progression (8.3 vs 3.0 months; p< 0.001), radiographic

progression free survival (8.3 vs 2.9 months; p < 0.001), and time to first skeletal related event (16.7 vs 13.3 months; p < 0.001).

Strikingly, the proportion of overall grade >3 adverse events was higher in the placebo treated men compared to men that received enzalutamide , suggesting a significant cause of on-study adverse events was related to underlying disease progression. Fatigue was the most commonly reported adverse event in both groups, with 34% of enzalutamide treated and 29% of placebo treated men reporting any grade of fatigue, with similar rates of > grade 3 fatigue, 6 and 7% respectively. More frequent rates of diarrhea, hot flashes, musculoskeletal pain and headache were reported in the enzalutamide treated men , with no significant differences reported in the infrequent metabolic and hepatic function related events between the groups. Hypertension was noted in 6.6% of enzalutamide compared to 3.3% of placebo treated men , with no clinically significant electrocardiographic changes in either group.

Seizure, which was noted at the higher dosages in the Phase I/II study which is an uncommon adverse event in prostate cancer therapeutic studies, was reported in this trial as well. Five of the 800 enzalutamide treated men (0.6%), compared with none of the placebo treated men , experienced a witnessed or unwitnessed seizure on study. Predisposing dural or brain metastases and concomitant medications are speculated to have contributed to the seizure events. Animal studies suggest seizure mechanism is partly explained by CNS drug concentration and off-target gamma-amino butyric acid-A (GABA-A) inhibition by enzalutamide. Similar animal data supporting this mechanism of seizure were reported for another novel AR antagonist BMS-641988, the development of which was halted following phase I data demonstrating only modest clinical effect and seizure activity in one patient.10, 11

Advantage over Antiandrogens and other agents Enzalutamide lacks the partial agonist activity notable with other non-steroidal anti-androgens, and given its activity not just as an inhibitor of the androgen receptor, but pre-clinically to inhibit nuclear translocation of the AR and inhibit the association of AR with DNA, further differentiates it from other anti-androgens (figure1). Enzalutamide represents the third pharmaceutical agent to significantly increase survival in men with CRPC following docetaxel (table 1). While there have been no comparative studies between the other two agents, cabazitaxel (Jevtana, Sanofi-Avnetis) and abiraterone acetate (Zytigia, Johnson & Johnson), the hazards ratios are similar between all three of the agents. It is important to note that the abiraterone acetate and cabazitaxel studies had control arms which included agents with anti-

tumor activity (prednisone and mitoxantrone\predinsone respectively) compared with placebo controlled arm in the AFFIRM study. Although approximately 30 percent of patients in both the AFFIRM enzalutamide and placebo arms were receiving corticosteroids at baseline which was associated with reduced survival regardless of study treatment.12Overall , enzalutamide has a favorable toxicity profile. Unlike cabazitaxel, enzalutamide was not reported to cause neuropathy or myelosuppression, two significant toxicities which can lead to morbidity and limit additional therapy in CRPC patients.13 Enzalutamide also lacks the detrimental effects of mineralocorticoid excess induced by abiraterone acetate, and thus does not require co-administration with steroids, which often complicates CRPC treatment. Similar to abiraterone acetate, which demonstrated a statistically significant improvement in radiographic progression free survival in an interim analysis, enzalutamide has also been studied in the CRPC chemotherapy naïve population, with data currently maturing.14 The FDA has not endorsed the use of either agent in the chemotherapy naïve population to date.

Future Development Currently enzalutamide is being evaluated in multiple earlier disease states in prostate cancer as well as in studies ongoing in patients with hormone refractory breast cancer. In patients with newly diagnosed localized prostate cancer, men will be randomized to enzalutamide alone or enzalutamide, leuprolide acetate, and dutasteride for 6 months prior to radical prostatectomy, with primary outcome of pathologic complete response rate (NCT01547299). A single arm phase II study of enzalutamide in men with normal serum testosterone levels who are candidates for castration for advanced prostate cancer has completed accrual, with primary endpoint of PSA progression (NCT01302041). In the castrate refractory setting, men with either PSA, bone or visceral progression will be randomized in a phase II study to receive bicalutamide or enzalutamide, with primary endpoint of progression free survival (STRIVE, NCT01664923). A similar ongoing Phase II TERRAIN trial enrolling only patients with radiographic progression is being conducted, predominantly in Europe. The Phase III PREVAIL trial is a randomized, double-blind, placebo-controlled study in men with CRPC who have failed antiandrogen treatment, prior to receiving chemotherapy. The study completed target accrual of 1680 patients in May 2012 and the primary endpoints is overall survival and radiographic progression-free survival. The ongoing Phase II study of the combination of enzalutamide and abiraterone acetate in CRPC patients with bone disease is supported by data which demonstrated increased bone marrow testosterone in enzalutamide treated patients, and increased nuclear AR expression in abiraterone treated patients, suggesting that these agents will work synergistically (NCT01650194).15 Finally, a Phase Ib study of enzalutamide in combination with docetaxel has completed enrollment, with final reporting of data pending (NCT01565928). 7

Enzalutamide is an exciting novel agent for prostate cancer and these ongoing trials will further define the appropriate use of enzalutamide in prostate cancer.

Table 1: Overall Survival Benefit in Recent CRPC Trials Agent Disease State Comparator Hazard Median (trial, year) Ratio Survials (months) Docetaxel/ Taxotere1 Chemo-naive Mitoxantrone 0.76 18.9 CRPC Prednisone 16.4

TAX327 2004 Radium-223/Alpharadin16 Bone Placebo + 0.695 14.0 metastases CRPC best standard of care 11.2

(ALSYMPCA 2011) Cabazitaxel/Jevtana13 Post-docetaxel Mitoxantrone 0.70 15.1 CRPC Prednisone 12.7

(TROPIC 2010) Sipuleucel-T / Provenge17 Chemo-naive Placebo 0.775 25.8 CRPC 21.7

(IMPACT 2010) Abiraterone/Zytiga5 Post-docetaxel Placebo Prednisone 0.65 14.8 CRPC 10.9

(COU-AA-301 2010) MDV-31009 Post-docetaxel Placebo 0.631 18.4 CRPC 13.6

(AFFIRM 2011)

Figure 1: Legend

Mechanisms of Action of Enzalutamide and Bicalutamide: 1. Enzalutamide inhibits AR–testosterone binding with higher affinity than bicalutamide; 2. Enzalutamide receptor inhibition blocks the activational change induced by AR–testosterone binding; 3.Enzalutamide inhibits AR–testosterone nuclear translocation and DNA transcription; 4.Enzalutamide lacks partial AR agonist activity that occurs with bicalutamide resistance.

1. Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004; 351:1502-12; PMID: 15470213; DOI: 10.1056/NEJMoa040720.

2. Berthold DR, Pond GR, Soban F, de Wit R, Eisenberger M, Tannock IF. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: Updated survival in the TAX 327 study. J Clin Oncol 2008; 26:242-5; PMID: 18182665 ; DOI: 10.1200/jco.2007.12.4008.

3. Knudsen KE, Penning TM. Partners in crime: Deregulation of AR activity and androgen synthesis in prostate cancer. Trends in Endocrinology & Metabolism 2010; 21:315-24; DOI: 10.1016/j.tem.2010.01.002.

4. Barrie SE, Potter GA, Goddard PM, Haynes BP, Dowsett M, Jarman M. Pharmacology of novel steroidal inhibitors of cytochrome P450(17) alpha (17 alpha-hydroxylase/C17-20 lyase). J Steroid Biochem Mol Biol 1994; 50:267-73; PMID: 7918112.

5. de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011; 364:1995-2005; DOI: 10.1056/NEJMoa1014618.

6. Steinkamp MP, O'Mahony OA, Brogley M, Rehman H, LaPensee EW, Dhanasekaran S, et al. Treatment-dependent androgen receptor mutations in prostate cancer exploit multiple mechanisms to evade therapy. Cancer Research 2009; 69:4434-42; DOI: 10.1158/0008-5472.CAN-08-3605.

7. Scher HI, Beer TM, Higano CS, Anand A, Taplin M, Efstathiou E, et al. Antitumour activity of MDV3100 in castration-resistant prostate cancer: A phase 1–2 study. The Lancet 2010; 375:1437-46; DOI: 10.1016/S0140-6736(10)60172-9.

8. Higano CS, Beer TM, Taplin M, Efstathiou E, Anand A, Hirmand M, et al. Antitumor activity of MDV3100 in pre- and post-docetaxel advanced prostate cancer: Long-term follow-up of a phase I/II study. ASCO Meeting Abstracts 2011; 29:134.

9. Scher HI, Fizazi K, Saad F, Taplin M, Sternberg CN, Miller K, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012; 367:1187-97; DOI: 10.1056/NEJMoa1207506.

10. Rathkopf D, Liu G, Carducci MA, Eisenberger MA, Anand A, Morris MJ, et al. Phase I dose- escalation study of the novel antiandrogen BMS-641988 in patients with castration-resistant prostate cancer. Clinical Cancer Research 2011; 17:880-7; DOI: 10.1158/1078-0432.CCR-10-2955.

11. Foster WR, Car BD, Shi H, Levesque PC, Obermeier MT, Gan J, et al. Drug safety is a barrier to the discovery and development of new androgen receptor antagonists. Prostate 2011; 71:480-8; DOI: 10.1002/pros.21263.

12. Scher HI, Fiazi K, Saad F, Chi K, Taplin M, Sternberg CN, et al. Association of baseline corticosteroid with outcomes in a multivariate analysis of the phase 3 AFFIRM study of enzalutamide (ENZA), an androgen receptor signaling inhibitor (ARSI). Annals of Oncology 2012; 23:xi297.

13. de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels J, Kocak I, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: A randomised open-label trial. The Lancet 2010; 376:1147-54; DOI: DOI: 10.1016/S0140- 6736(10)61389-X.

14. Ryan CJ, Smith MR, De Bono JS, Molina A, Logothetis C, De Souza PL, et al. Interim analysis (IA) results of COU-AA-302, a randomized, phase III study of abiraterone acetate (AA) in chemotherapy- naive patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). ASCO Meeting Abstracts 2012; 30:LBA4518.

15. Efstathiou E, Titus MA, Tsavachidou D, Hoang A, Karlou M, Wen S, et al. MDV3100 effects on androgen receptor (AR) signaling and bone marrow testosterone concentration modulation: Apreliminary report. ASCO Meeting Abstracts 2011; 29:4501.

16. Parker C, Heinrich D, O'Sullivan JM, Fossa SD, Chodacki A, Demkow T, et al. Overall survival benefit and safety profile of radium-223 chloride, a first-in-class alpha-pharmaceutical: Results from a phase III randomized trial (ALSYMPCA) in patients with castration-resistant prostate cancer (CRPC) with bone metastases. ASCO Meeting Abstracts 2012; 30:8.

17. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010; 363:411-22; DOI: 10.1056/NEJMoa1001294.

Figure 1:

Androgen receptor (AR) Testosterone Enzalutamide

AR after conformational change due to Bicalutamide testosterone or bicalutamide binding

1. Enzalutamide inhibits 4. Enzalutamide lacks AR–testosterone binding partial AR agonist with higher affinity than activity that occurs bicalutamide with bicalutamide resistance 2. Enzalutamide receptor inhibition blocks the activational change induced by AR–testosterone 3. Enzalutamide inhibits binding AR–testosterone nuclear translocation and DNA transcription

Enzalutamide: a novel anti-androgen for patients with castrate resistant prostate cancer

Jeannie Hoffman-Censits and William K Kelly

Clin Cancer Res Published OnlineFirst January 8, 2013.

Updated version Access the most recent version of this article at: doi:10.1158/1078-0432.CCR-12-2910

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