ASCO 2019: Alliance A031201: A Phase III Trial of Enzalutamide Versus Enzalutamide, Abiraterone, and Prednisone for Metastatic Castration Resistant Prostate Cancer - Medical Oncologist Perspective

Chicago, IL (UroToday.com) Enzalutamide and abiraterone are second generation androgen antagonists both approved for metastatic castration resistance prostate cancer (mCRPC). Enzalutamide’s antiandrogen mechanism is through binding of the androgen receptor (AR), inhibiting nuclear translocation of AR and subsequent AR binding of DNA.1
Abiraterone’s mechanism of action is through CYP17A inhibition, thus preventing androgen biosynthesis. Both agents are well tolerated by most patients and at this time, we have no definitive evidence of which sequence of therapy is most appropriate for most patients. However, it is known that for the vast majority of patients who proceed on one of these therapies, they are most likely resistant to the other. For example, Yamada et al reported that the PSA50 rate of patients receiving abiraterone after enzalutamide was 7%.2 Additionally, while the majority of patients will have a confirmed PSA50 (50% decrease in PSA) with frontline enzalutamide before chemotherapy, the response is not durable, with a median progression-free survival of 11.2 months. Following second generation androgen antagonists, options include chemotherapy (cabazitaxel and docetaxel), radium-223, and sipuleucel-T, all of which have limited benefit and may not be appropriate for all patients. Thus, there is an unmet need in this space for patients with mCRPC.

In this study, enzalutamide is compared with the combination of enzalutamide and abiraterone with prednisone. Efstathiou et al have previously reported the clinical outcomes of patients treated with this combination – by targeting both the androgen receptor as well as androgen biosynthesis, the theory is that this may be more effective than targeting one pathway alone. The study by Eleni Efstathiou, MD, showed that this combination is safe and well tolerated for most patients, without significant drug-drug interactions. This study by Morris et al builds on that study by providing phase III randomized data comparing the combination vs enzalutamide alone.

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In this abstract, 1311 men with mCRPC were randomly assigned to either enzalutamide alone or enzalutamide plus abiraterone plus prednisone. Patients were stratified by prior chemotherapy as well as the Halabi prognostic risk factors.3 The primary endpoint of the study was overall survival (OS). In this study, 15.6% of patients were high risk, 35.3% intermediate, and 48.1% low risk.

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There was no significant difference in OS between the two groups (33.6 months vs and 32.7 months, two-sided p = 0.53). There was almost no difference in PSA decline either.

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The adverse event rate was double with abiraterone than enzalutamide alone. Most patients became off treatment because of radiographic progression.ASCO2019_notable_AEs.png
In terms of the adverse events, imbalances were seen with fatigue, atrial fibrillation, and hypertension in the combination arm. The median duration of treatment was 52 days in favor of enzalutamide alone.

This overall survival is similar to the OS seen in Cougar 302 (Abiraterone in Metastatic Prostate Cancer without Previous Chemotherapy)4 where the median OS in the abiraterone group was 34.7 months. There was no difference in this study between PSA50 either. Patients on the combination arm had 68.8% grade 3-5 adverse events compared to 55.6% with enzalutamide alone and 13% of patients in the combination arm withdrew.

One unique aspect of this study was the evaluation of rPFS as a surrogate for OS. This study found a very strong correlation between rPFS and OS and the relationship was seen as well in Cougar 302 and PREVAIL.

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The combination of abiraterone and enzalutamide for patients with mCRPC does not prolong survival compared with enzalutamide alone but does increase the toxicity of therapy. This combination approach should not be used for patients with mCRPC.

Presented by: Michael J. Morris, MD, Medical Oncologist, Clinical Director, Genitourinary Medical Oncology Service & Prostate Cancer Section Head, Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY

Written by: Jason Zhu, MD, Fellow, Division of Hematology and Oncology, Duke University Twitter: @TheRealJasonZhu at the 2019 ASCO Annual Meeting #ASCO19, May 31-June 4, 2019, Chicago, IL USA

References:
  1. Dhawan M, Ryan CJ. Utility of novel androgen receptor therapies in the real world: A nuanced approach. Urologic Oncology: Seminars and Original Investigations; 2016: Elsevier. p. 340-7.
  2. Yamada Y, Matsubara N, Tabata K-i, et al. Abiraterone acetate after progression with enzalutamide in chemotherapy-naive patients with metastatic castration-resistant prostate cancer: a multi-center retrospective analysis. BMC research notes 2016;9:471.
  3. Halabi S, Lin C-Y, Kelly WK, et al. Updated Prognostic Model for Predicting Overall Survival in First-Line Chemotherapy for Patients With Metastatic Castration-Resistant Prostate Cancer. Journal of Clinical Oncology 2014;32:671-7.
  4. Ryan CJ, Smith MR, Fizazi K, et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. The Lancet Oncology 2015;16:152-60.
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