Deleterious germline/somatic homologous recombination-repair mutations (HRRm) are present in ~25% of metastatic castration resistant prostate cancer (mCRPC) patients. Preclinically, PARP-Inhibition demonstrated synergism with ARP-targeted therapy. This trial evaluated efficacy of ARP-Inhibitor versus PARP-Inhibitor versus combination as first-line therapy in mCRPC patients with HRRm.
BRCAAway is a biomarker pre-selected, randomized, phase-2 trial. Patients with BRCA1/2 and/or ATM alterations were randomized 1:1:1 to Arm1: Abiraterone (1000mg)/prednisone (Abi/pred) (5mg), Arm2: Olaparib (Ola) (300mg), or Arm3: Abiraterone/prednisone + Olaparib (Abi/pred+Ola). Single-agent arms could cross over at progression. Exploratory Arm4 patients with other HRRm received Olaparib alone. The primary endpoint was progression-free survival (PFS), and secondary endpoints were objective response, PSA response, and safety.
61/165 eligible patients had BRCA1/2 or ATM mutations: Median age: 67 (IQR 62-73) years. Mutations: BRCA1 n=3, BRCA2 n=46, ATM n=11, multiple n= 1; 33 germline, 28 somatic. Median PFS (95% CI): Abi/pred, 8.6 months (m) (2.9, 17), Ola, 14 m (8.4, 20), Abi/pred+Ola, 39 m (22, NR). There were no G4/5 AEs. 8/19 on Abi/pred crossed over to Ola, and 8/21 vice versa: Median PFS (95% CI) from crossover: Ola-after-Abi/pred, 8.3 m (5.5, 15); Abi/pred-after-Ola, 7.2 m (2.8, NR). Median PFS (95% CI) from randomization: Ola-after-Abi/pred, 16 m (7.8, 25), Abi/pred-after-Ola, 16 m (11, NR). 17/165 patients with other HRRm received olaparib: Median PFS (95% CI): 5.5 m (2, 11).
In mCRPC patients with BRCA1/2 or ATM HRRm, abiraterone/prednisone + olaparib was well tolerated and demonstrated longer PFS versus either agent alone or sequentially.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2024 Aug 08 [Epub ahead of print]
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 Shevrin, Travis Gerke, Arul M Chinnaiyan, Emmanuel S Antonarakis
Northwestern University Feinberg School of Medicine, Chicago, IL, United States., Northwestern University Feinberg School of Medicine, Chicago, Il, United States., Huntsman Cancer Institute, Salt lake City, UT, United States., Indiana University School of Medicine, Indianapolis, IN, United States., Moffitt Cancer Center, Tampa, Florida, United States., Johns Hopkins University, Baltimore, MD, United States., Washington University in St. Louis, St Louis, MO, United States., University of Michigan-Ann Arbor, Ann Arbor, MI, United States., University of Chicago, Chicago, IL, United States., Weill Cornell Medicine, New York, NY, United States., University of North Carolina at Chapel Hill, Chapel Hill, NC, United States., University of Virginia, Charlottesvile, VA, United States., Rutgers, The State University of New Jersey, New Brunswick, NJ, United States., University of California, Los Angeles, Los Angeles, CA, United States., NorthShore University HealthSystem, Evanston, IL, United States., Prostate Cancer Clinical Trials Consortium, United States., University of Minnesota, Minneapolis, United States.