Abstract
Purpose: Deleterious germline/somatic homologous recombination repair mutations (HRRm) are present in ∼25% of patients with metastatic castration-resistant prostate cancer (mCRPC). Preclinically, poly(ADP-ribose) polymerase (PARP) inhibition demonstrated synergism with androgen receptor pathway (ARP)-targeted therapy. This trial evaluated the efficacy of ARP inhibitor versus PARP inhibitor versus their combination as firstline therapy in patients with mCRPC with HRRms. Patients and Methods: BRCAAway is a biomarker preselected, randomized, phase 2 trial. Patients with BRCA1/2 and/or ATM alterations were randomized 1:1:1 to Arm1: abiraterone (1,000 mg)/ prednisone (5 mg BID) (Abi/pred), Arm2: olaparib (300 mg BID) (Ola), or Arm3: abiraterone/prednisone + olaparib (Abi/pred + Ola). Single-agent arms could cross over at progression. Exploratory Arm4 patients with other HRRms received olaparib alone. The primary endpoint was progression-free survival (PFS), and secondary endpoints were objective response, PSA response, and safety. Results: Sixty-one of 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, and multiple n = 1; 33 germline and 28 somatic mutations. Median PFS [95% confidence interval (CI)]: Abi/pred, 8.6 months (m; 2.9, 17), Ola, 14 m (8.4, 20), and Abi/pred + Ola, 39 m [22, not reached (NR)]. There were no G4/5 adverse events; 8/19 patients on Abi/pred treatment 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) and 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) and Abi/pred-after-Ola, 16 m (11, NR). Seventeen of 165 patients with other HRRms received olaparib: median PFS (95% CI): 5.5 m (2, 11). Conclusions: In patients with mCRPC with BRCA1/2 or ATM HRRm, Abi/pred + Ola was well tolerated and demonstrated longer PFS versus either agent alone or sequentially.
Original language | English (US) |
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Pages (from-to) | 4318-4328 |
Number of pages | 11 |
Journal | Clinical Cancer Research |
Volume | 30 |
Issue number | 19 |
DOIs | |
State | Published - Oct 1 2024 |
Funding
This work was supported by AstraZeneca and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (to M. Hussain, M. Kocherginsky, N. Agarwal, N. Adra, J. Zhang, C.J. Paller, J. Picus, Z.R. Reichert, R.Z. Szmulewitz, S.T. Tagawa, T.M. Kuzel, L.A. Bazzi, S. Daignault-Newton, Y.E. Whang, R. Dreicer, R.D. Stephenson, M.B. Rettig, D. Shevrin, T. Gerke, A.M. Chinnaiyan, and E.S. Antonarakis). Northwestern University is the Sponsor and M. Hussain is the Principal Sponsor Investigator responsible for overall study execution and oversight. The funder, AstraZeneca, provided the investigational product, olaparib, and financial support for the study. The data were presented in part at the American Society of Clinical Oncology Annual Meeting, Chicago, IL, June 3 to 7, 2022. The final results were invited for oral presentation at the American Society of Clinical Oncology Genitourinary Cancers Symposium Meeting, San Francisco, CA, January 25, 2024.
ASJC Scopus subject areas
- General Medicine