The androgen receptor axis is a validated target for the treatment of castration-resistant prostate cancer. Several perturbations in this pathway are postulated to lead to androgen-independent growth, including androgen receptor mutation and amplification as well as the autocrine production of testosterone.
Two drugs targeting this pathway in castration-resistant prostate cancer—abiraterone acetate (Zytiga) and enzalutamide (Xtandi)—are approved for use in patients who have already received chemotherapy. Mechanistically, abiraterone exerts antitumor activity by inhibition of the 17,20-lyase pathway, crucial to testosterone synthesis. Enzalutamide binds to the androgen receptor and prevents its translocation into the nucleus. Abiraterone is also approved for patients in the prechemotherapy setting based on results of the Cougar 302 trial.1
Two Key Studies
The PREVAIL trial, reported by Beer and colleagues in The New England Journal of Medicine and reviewed in this issue of The ASCO Post, compared enzalutamide to placebo in 1,717 men with metastatic castration-resistant prostate cancer who had not received prior chemotherapy.2 The trial was terminated early after a planned interim analysis at 540 deaths found a statistically significant therapeutic benefit in men treated with enzalutamide, with a 29% reduction in risk of death being observed in the enzalutamide group (hazard ratio = 0.71, 95% confidence interval = 0.60–0.84, P < .001).
There are important differences between the PREVAIL and Cougar 302 trials. In contrast to Cougar 302, patients in PREVAIL were permitted to have visceral metastases at entry, and these were present in 12% of patients. PREVAIL used a placebo control arm, whereas COUGAR 302 used oral prednisone at 5 mg twice daily as its control treatment.
Androgen Receptor Targeting
The PREVAIL trial raises several important questions regarding the initial management of castration-resistant prostate cancer. The challenge in patient management and future clinical trials will be how to best sequence and combine enzalutamide and abiraterone, particularly in light of the fact that we have alternatives for asymptomatic patients (sipuleucel-T [Provenge]) and symptomatic patients (docetaxel and radium-223 [Xofigo]) that have efficacy in the in the initial treatment setting.
The patient’s clinical characteristics alone are not sufficient for drug selection. Critical to this task will be a better understanding of the mechanisms of resistance and response to androgen receptor–targeted therapy. Several potential resistance mechanisms and targets have already been identified.
A recent presentation at ASCO by Antonarkis et al demonstrated that the presence of androgen receptor splice variant 7 (AR-V7) in circulating tumor cells is associated with primary and acquired resistance to both enzalutamide and abiraterone in castration-resistant prostate cancer patients.3 Although this marker does not help us in the choice between abiraterone or enzalutamide, identification of AR-V7 in patients initially treated with enzalutamide or abiraterone could potentially dissuade sequential use of the agents. Moreover, those patients who develop the mutation while on treatment with abiraterone or enzalutamide may not be appropriate to be crossed over to the other drug.
Role of Testosterone
Steroid synthetic pathways also may yield important information for drug sequencing. 3β-hydroxysteroid dehydrogenase type 1 (3βHSD1) is crucial to the conversion of dehydroepiandrosterone (DHEA) into dihydrotestosterone (DHT). A mutation in 3βHSD1 has been identified in a subset of human castration-resistant prostate cancer tumors that prevents degradation of this enzyme, and the increased levels of 3βHSD1 have been shown to confer resistance to abiraterone in a mouse model. It has been demonstrated that upregulation of testosterone occurs in the bone marrow of castration-resistant prostate cancer patients treated with enzalutamide, thus making abiraterone a reasonable drug to consider in these patients since it lowers testosterone.
The practical use of this test is limited by the necessity of performing sequential bone marrow biopsies. Moreover, this resistance pathway points toward the use of androgen receptor–targeted therapy in combination with inhibitors of steroidogenesis. This may come at the expense of increased fatigue; the combination of enzalutamide, abiraterone, and prednisone was associated with a 73% rate of grade 1 to 3 fatigue in a phase I trial compared with 36% and 40% in the PREVAIL and Cougar 302 trials, respectively. The Alliance is currently accruing patients to a randomized trial of enzalutamide combined with abiraterone vs enzalutamide in the prechemotherapy castration-resistant prostate cancer setting.
Another important question is whether enzalutamide or abiraterone renders subsequent therapies less effective. Retrospective data suggest that patients treated with abiraterone have lower progression-free survival and overall survival than reported in patients treated with docetaxel in the TAX 327 as well as the SWOG 99-16 trial. This may in part be due to the fact that docetaxel also targets the androgen receptor axis by preventing its translocation into the nucleus. No such sequential data have been generated with enzalutamide followed by docetaxel.
Conclusions
In conclusion, the PREVAIL trial represents a major advance in the treatment of castration-resistant prostate cancer. In contrast to 2004, when docetaxel was the only agent demonstrating a survival benefit in castration-resistant prostate cancer, we now have five agents that we can use. A panel of markers appears to be emerging that characterizes the androgen receptor pathway; our task is to design rational clinical trials that take into account the biology of the disease. This will have important implications not only for patient care, but for health-care costs. ■
Disclosure: Dr. Petrylak is a consultant to Johnson & Johnson and Astellas, and he receives research support from Astellas.
References
1. Ryan CJ, Smith MR, de Bono JS, et al: Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 368:138-148, 2013.
2. Beer TM, Armstrong AJ, Rathkopf DE, et al: Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. June 1, 2014 (early release online).
3. Antonarakis ES, Lu C, Wang H, et al: Androgen receptor splice variant AR-V7, and resistance to enzalutamide and abiraterone in men with metastatic castration resistant prostate cancer. 2014 ASCO Annual Meeting. Abstract 5001. Presented June 1, 2014.
Dr. Petrylak is Director, Genitourinary Oncology Research Program, and Co-Director, Signal Transduction Program, Yale Comprehensive Cancer Center, Yale School of Medicine, New Haven, Connecticut.
