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Galeterone for the Treatment of Castration- Resistant Prostate Cancer Bruce Montgomery1, Mario A

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Galeterone for the Treatment of Castration- Resistant Prostate Cancer Bruce Montgomery1, Mario A Published OnlineFirst November 2, 2015; DOI: 10.1158/1078-0432.CCR-15-1432 Cancer Therapy: Clinical Clinical Cancer Research Androgen Receptor Modulation Optimized for Response (ARMOR) Phase I and II Studies: Galeterone for the Treatment of Castration- Resistant Prostate Cancer Bruce Montgomery1, Mario A. Eisenberger2, Matthew B. Rettig3, Franklin Chu4, Roberto Pili5, Joseph J. Stephenson6, Nicholas J. Vogelzang7, Alan J. Koletsky8, Luke T. Nordquist9, William J. Edenfield10, Khalid Mamlouk11, Karen J. Ferrante11, and Mary-Ellen Taplin12 Abstract Purpose: Galeterone is a selective, multitargeted agent that Results: In ARMOR1, across all doses, 49.0% (24/49) achieved a inhibits CYP17, antagonizes the androgen receptor (AR), and 30% decline in prostate-specific antigen (PSA; PSA30) and reduces AR expression in prostate cancer cells by causing an 22.4% (11/49) demonstrated a 50% PSA decline (PSA50). In increase in AR protein degradation. These open-label phase I ARMOR2 part 1, across all doses, PSA30 was 64.0% (16/25) and and II studies [Androgen Receptor Modulation Optimized PSA50 was 48.0% (12/25). In the 2,550-mg dose cohort, PSA30 for Response-1 (ARMOR1) and ARMOR2 part 1] evaluated was 72.7% (8/11) and PSA50 was 54.5% (6/11). Galeterone was the efficacy and safety of galeterone in patients with treat- well tolerated; the most common adverse events were fatigue, ment-naive nonmetastatic or metastatic castration-resistant increased liver enzymes, gastrointestinal events, and pruritus. Most prostate cancer (CRPC) and established a dose for further were mild or moderate in severity and required no action and there study. were no apparent mineralocorticoid excess (AME) events. Experimental Design: In ARMOR1, 49 patients received Conclusions: The efficacy and safety from ARMOR1 and increasing doses (650–2,600 mg) of galeterone in capsule ARMOR2 part 1 and the pharmacokinetic results support the formulation; 28 patients in ARMOR2 part 1 received increasing galeterone tablet dose of 2,550 mg/d for further study. Galeterone doses (1,700–3,400 mg) of galeterone in tablet formulation for was well tolerated and demonstrated pharmacodynamic changes 12 weeks. Patients were evaluated biweekly for safety and consistent with its selective, multifunctional AR signaling inhibi- efficacy, and pharmacokinetic parameters were assessed. tion. Clin Cancer Res; 22(6); 1356–63. Ó2015 AACR. Introduction common cancer-related mortality in men in the United States (1). The development of a new generation of therapies targeting the Despite recent advances in the treatment of castration-resistant androgen axis has been based on an expanded understanding of prostate cancer (CRPC), prostate cancer remains the second most the molecular mechanisms of CRPC. It is now understood that in the clinical setting of castrate levels of serum testosterone, prostate tumors adapt by upregulating tissue androgens and androgen 1University of Washington, Seattle,Washington. 2Sidney Kimmel Com- prehensive Cancer Center at Johns Hopkins University, James Bucha- receptors (AR) to maintain proliferation. Tumor androgen levels nan Brady Urological Institute, Baltimore, Maryland. 3UCLA Jonsson remain sufficiently elevated to stimulate ARs as a result of tumor Comprehensive Cancer Center, Los Angeles, California. 4San Berna- de novo 5 conversion of circulating adrenal androgens and androgen dino Urological Associates, San Bernadino, California. Indiana – University School of Medicine, Indianapolis, Indiana. 6Institute for synthesis (2 5). In addition, prostate cancer adapts to androgen- Translational Oncology Research, Greenville, South Carolina. 7Com- deprivation therapy by AR gene amplification, upregulation of AR prehensive Cancer Centers of Nevada and U.S. Oncology Research, transcripts, or protein expression (6, 7). Thus, inhibition of the Las Vegas, Nevada. 8Lynn Cancer Institute, Boca Raton, Florida. 9Urol- ogy Cancer Center and GU Research Network, Omaha, Nebraska. synthesis of nongonadal androgens and blockade of AR remain 10Greenville Hospital System and University Medical Center, Green- key targets in CRPC therapy. 11 ville, South Carolina. Tokai Pharmaceuticals, Cambridge, Massachu- Abiraterone and enzalutamide have improved outcomes for setts. 12Dana-Farber Cancer Institute, Boston, Massachusetts. patients with metastatic CRPC (mCRPC). Although abiraterone Note: Supplementary data for this article are available at Clinical Cancer and enzalutamide have been shown to improve overall survival Research Online (http://clincancerres.aacrjournals.org/). (OS), these agents are not curative and not without safety and Corresponding Author: Mary-Ellen Taplin, Dana-Farber Cancer Institute, 450 tolerability issues (8–11). In addition, a significant proportion of Brookline Avenue, Boston, MA 02215. Phone: 617-632-3237; Fax: 617-632-2165; patients do not respond; and in those who do respond, therapy E-mail: [email protected] will eventually fail because of the development of resistance doi: 10.1158/1078-0432.CCR-15-1432 (9, 10, 12–14). A major component of resistance to second- Ó2015 American Association for Cancer Research. generation AR-targeting agents may be mediated by AR splice 1356 Clin Cancer Res; 22(6) March 15, 2016 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst November 2, 2015; DOI: 10.1158/1078-0432.CCR-15-1432 Galeterone for Metastatic Castration-Resistant Prostate Cancer study confirmed a significant food effect with the capsule formu- Translational Relevance lation that was used in ARMOR1 (Supplementary Data). The SDD Despite the recent advances in the understanding and tablet formulation was shown in a healthy volunteer study to not treatment of metastatic castration-resistant prostate cancer be affected by food, providing similar exposure (area under the (mCRPC), it remains a lethal disease. Androgen receptor (AR) concentration-time curve, AUC) in fed and fasted states (28). signaling remains a primary target of therapy, as the under- Results of this study also demonstrated equivalent serum con- standing of both the disease and mechanisms of resistance centrations using either 1,700 mg of the SDD tablet or 2,600 mg of expand. Galeterone, a selective, multitargeted agent, is distinct the capsule, which was the highest dose studied in ARMOR1. from other mCRPC therapies in that it combines the mechan- Thus, the dose-escalation portion of ARMOR2 was conducted to isms of current agents—CYP17 inhibition and AR antago- evaluate the safety and tolerability of escalating doses of the SDD nism—with the novel mechanism of increasing AR protein formulation and to determine the recommended dose for degradation. These first assessments of galeterone in mCRPC ARMOR2 part 2 and ARMOR3. identified a well-tolerated dose that resulted in clinically significant reductions in prostate-specific antigen, and dem- onstrate the potential of this agent. In vitro data and results of Patients and Methods these studies have informed future investigation of galeterone, Patients which will include AR-related biomarker analyses. Eligible men had histologically confirmed nonmetastatic (M0) or metastatic (M1) adenocarcinoma of the prostate, a life expec- tancy of >12 weeks, and progressive disease despite ongoing androgen-deprivation therapy. Patients were required to have progressive disease according to Prostate Cancer Clinical Trials variants, such as AR-V7, which are produced in tumor cells as a Working Group 1 [PCWG1] criteria (29) in ARMOR1, or PCWG2 result of aberrant RNA splicing of the wild-type AR transcript. The criteria (30) in ARMOR2 part 1, ongoing treatment with gonad- resultant truncated AR protein lacks the C-terminal domain to otropin-releasing hormone analogs or orchiectomy (serum tes- which androgen binds and is the primary site of action of tosterone <50 mg/dL), and an Eastern Cooperative Oncology nonsteroidal antiandrogens such as enzalutamide. Furthermore, Group (ECOG) performance status of 1. ARMOR1 excluded splice variants have been shown to be constitutively active tran- patients who had previously received chemotherapy, ketocona- scription factors, leading to the activation of androgen-responsive zole, abiraterone, or enzalutamide. ARMOR2 part 1 permitted the genes even at castrate levels of androgens (15, 16). Mutations in enrollment of abiraterone-refractory patients, provided it had the AR may also contribute to resistance in CRPC, and AR point been discontinued 4 weeks before enrollment and that the mutations allow activation of the receptor by nonphysiologic duration of therapy was 6 months before PSA progression or ligands (e.g., cortisol, progesterone, flutamide, bicalutamide; >6 weeks with documentation of an initial response followed by refs. 17, 18, 19). As a result, androgen-independent, but PSA progression. Previous ketoconazole treatment was permitted AR-dependent, tumor growth occurs, and tumors become resis- upon agreement between the investigator and the study sponsor. tant to therapeutic agents that alter androgen production (e.g., Patients with nonhepatic visceral metastases and/or tumor-asso- abiraterone) or antagonize binding to the AR (e.g., bicalutamide, ciated bone pain that required active pain management were enzalutamide). Recent data demonstrated that patients with excluded from ARMOR1. Patients with indeterminate lung detectable circulating tumor cells harboring AR-V7 had inferior nodules were eligible. Other exclusion criteria included any responses
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