BRCAAway: A randomized phase 2 trial of abiraterone, olaparib, or abiraterone + olaparib in patients with metastatic castration-resistant prostate cancer (mCRPC) bearing homologous recombination-repair mutations (HRRm).
Maha Hussain, Masha Kocherginsky, Neeraj Agarwal, Nabil Adra, Jingsong Zhang, Channing J. Paller, Joel Picus, Zachery R. Reichert, Russell Z. Szmulewitz, Scott T. Tagawa, Timothy M. Kuzel, Latifa A. Bazzi, Stephanie Daignault‐Newton, Young E. Whang, Robert Dreicer, Ryan D. Stephenson, Matthew B. Rettig, Daniel H. Shevrin, Arul M. Chinnaiyan, Emmanuel S. Antonarakis
Abstract
19 Background: Deleterious germline or somatic HRRm are present in about 20% of mCRPC patients (pts). Preclinically, PARP-inhibition demonstrated synergism with AR-targeted therapy. BRCAAway is a biomarker pre-selected, multicenter, randomized, phase-2 trial which evaluated efficacy of AR-inhibitor (i) vs PARPi vs combination in first-line mCRPC pts with germline and/or somatic mutations in BRCA1/2 or ATM. Methods: Eligibility required front-line mCRPC with no prior exposure to PARPi, ARi, or chemotherapy for mCRPC, and washout of antiandrogen, radiation, and other investigational agents. Eligible pts underwent tumor next-generation sequencing (NGS)/germline testing; pts with inactivating BRCA1/2 and/or ATM alterations were randomized 1:1:1 to Arm I abiraterone (1000 mg qd) + prednisone (5mg bid), Arm II olaparib (300 mg bid), or Arm III olaparib + abiraterone/prednisone. Primary endpoint was progression free survival (PFS) as per RECIST 1.1, PCWG3, clinical assessment, or death. Secondary endpoints included measurable disease response rate (RR), PSA RR, and toxicity. Arm I and II pts could cross over at progression. Results: 165 eligible pts were registered and underwent NGS/germline testing; 61 pts with HRRm were randomized to Arms I-III. Median age: 67 years (range 42-85); 55 White, 6 Black; prior Docetaxel 26% for mHSPC, Darolutamide/Enzalutamide 3.3% for nmCRPC; disease sites: bone n=44, viscera n=12, lymph node n=31, other n=3; median baseline PSA: 14 ng/ml (range 0.15-4,037 ng/ml). HRRm status: BRCA1 n=3, BRCA2 n=46, ATM n=11, multiple n=1 (33 germline, 28 somatic). Median (range) time from randomization to last encounter in pts still alive n=56: 16 (0.8-60), 15 (4.1-36), and 23 (2.9-56) months (m) in Arms I, II and III, respectively. 51 pts had treatment-related AEs; most common Grade 3: fatigue n=3, anemia n=2, and ALT increases n=2. OS is not mature enough with 3 deaths in Arm I and 2 in Arm II. Efficacy results for Arms I-III are presented in the table. At progression 8/19 pts crossed over from abiraterone to olaparib and 8/21 pts vice versa. Median (95% CI) PFS from crossover to: olaparib 8.3 m (5.5, 15), abiraterone 7.2 m (2.8, NR). Median (95% CI) PFS from randomization: olaparib 16 m (7.8-25) and abiraterone 16 m (11-28). RR to crossover treatment: olaparib 38% and abiraterone 25%. PSA RR to crossover treatment: olaparib 50% and abiraterone 63%. Conclusions: In mCRPC pts with BRCA1/2 or ATM alterations, abiraterone/prednisone + olaparib was well tolerated and resulted in a longer PFS vs either agent alone or sequentially. Clinical trial information: NCT03012321 . [Table: see text]