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).

Author(s): Maha H. A. Hussain1; Masha Kocherginsky1; Neeraj Agarwal2; Nabil Adra3; Jingsong Zhang4; Channing Judith Paller5; Joel Picus6; Zachery R Reichert7; Russell Zelig Szmulewitz8; Scott T. Tagawa9; Timothy Kuzel10; Latifa Bazzi11; Stephanie Daignault-Newton12; Young E. Whang13; Robert Dreicer14; Ryan D. Stephenson15; Matthew Rettig16; Daniel Shevrin17; Arul Chinnaiyan18; Emmanuel S. Antonarakis19
Maem Hussein MD

Dr. Maen Hussein's Thoughts

We know that combination PARP and antiandrogen is better than antiandrogen alone. I have wondered if we need antiancrogen on those patients. This shows that, YES, we do. The combination also was better than PARP inhibitor monotherapy in those patients carrying HRRm.


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.


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.


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%.


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.

Author Affiliations

1Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL; 2Huntsman Cancer Institute at the University of Utah, Salt Lake City, UT; 3Indiana University Simon Comprehensive Cancer Center, Indianapolis, IN; 4H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; 5The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; 6Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO; 7University of Michigan Medical School, Ann Arbor, MI; 8University of Chicago Medical Center, Chicago, IL; 9Division of Hematology & Medical Oncology, Weill Cornell Medicine, NewYork-Presbyterian Hospital, New York, NY; 10Rush University Medical Center, Chicago, IL; 11Northwestern University, Chicago, IL; 12University of Michigan, Ann Arbor, MI; 13University of North Carolina, Chapel Hill, NC; 14University of Virginia School of Medicine, Charlottesville, VA; 15Rutgers Cancer Institute of New Jersey, New Brunswick, NJ; 16Department of Medical Oncology, University of California, Los Angeles, Los Angeles, CA; 17NorthShore University Health System, Evanston Hospital Kellogg Cancer Center, Evanston, IL; 18University of Michigan Medical Center, Ann Arbor, MI; 19Department of Medicine, University of Minnesota, Masonic Cancer Center, Minneapolis, MN

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