First-line treatment with the PARP inhibitor olaparib plus the androgen biosynthesis inhibitor abiraterone acetate and the steroid prednisone improved progression-free survival and response rates compared with either treatment alone (ie, olaparib or abiraterone plus prednisone) in patients with BRCA1/2- or ATM–altered metastatic castration-resistant prostate cancer. These findings from the relatively small phase II BRCAAway trial were presented at the 2024 ASCO Genitourinary Cancers Symposium.¹

Median progression-free survival was 39 months with olaparib plus abiraterone and prednisone (arm 3) vs 8.4 months in arm 1 (abiraterone plus prednisone) and 14 months in arm 2 (olaparib alone). The rates of objective response showed a similar effect: 33% in arm 3, 22% in arm 1, and 9.5% in arm 2. The prostate-specific antigen (PSA) response rates in arms 3, 1, and 2, respectively, were 95%, 61%, and 67%; the rates of undetectable PSA levels were 33%, 17%, and 14%, respectively.

“This is a small randomized study, but the separation of [progression-free survival] curves is impressive, favoring the combination,” stated lead author Maha Hussain, MD, FASCO, FACP, of the Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago. “The combination of abiraterone/prednisone plus olaparib [in this preselected patient population] was well tolerated and achieved better progression-free survival than either drug alone or sequentially.”

Maha Hussain, MD, FASCO, FACP

In May 2023, the U.S. Food and Drug Administration approved the combination of olaparib plus abiraterone and prednisone for first-line treatment of patients with castration-resistant disease and BRCA1/2 alterations.²

“When we designed the trial, olaparib was not approved for patients with germline or somatic mutations, which affects about 20% of patients with castration-resistant prostate cancer. PARP has been shown to interact with androgen signaling, and the hypothesis of our study was that targeting both pathways in a biomarker-preselected group of patients would result in more benefit,” Dr. Hussain explained.

Study Details and Results

In this open-label study, 165 eligible patients with metastatic castration-resistant prostate cancer were screened, and 61 patients were selected who had BRCA1/2 or ATM alterations; these genetic findings were identified by next-generation sequencing and germline testing. Patients were randomly assigned 1:1:1 to one of three treatment arms: arm 1 received abiraterone and prednisone (n = 19); arm 2 received 300 mg of olaparib (n = 21); and arm 3 received 300 mg of olaparib plus abiraterone and prednisone (n = 21). Crossover was allowed from arms 1 and 2 at disease progression, with eight patients crossing over from abiraterone plus prednisone to olaparib and eight, from olaparib to abiraterone.

The median progression-free survival was 8.3 months in patients who crossed over to olaparib and 7.2 months with crossover to abiraterone. Additionally, the median progression-free survival from randomization was 16.0 months in both crossover cohorts. The objective response and PSA response rates with crossover treatment were 38% and 25% and 50% and 63%, respectively.

“Looking at declines from baseline [PSA levels] to the lowest PSA [level], the combination arm did better than the single-agent arm,” Dr. Hussain noted.

Among the total study population, grade 3 adverse effects occurred in 19% of arm 3, 21% of arm 1, and 14% of arm 2. Common grade 3 adverse events included anemia and fatigue.

In patients with metastatic castration-resistant prostate cancer and BRCA1/2 or ATM alterations, Abiraterone/prednisone plus olaparib was well tolerated and resulted in better progression-free survival and response rates vs olaparib or abiraterone/prednisone. Although the number of patients who crossed over was small, the front-line combination yielded better progression-free survival compared to sequential therapy. n

DISCLOSURE: Dr. Hussain has received honoraria from Academic CME, AstraZeneca, Bayer, Clinical Care Options LLC, Great Debates and Updates in GU Oncology, Medscape Zero, Merck, Novartis, RTP, and Targeted Oncology; has had a consulting or advisory role with AstraZeneca, Bayer, Convergent Therapeutics, GSK, Janssen, Merck, Novartis, Pfizer, Tango Therapeutics, and Tempus; has received research funding from Arvinas, AstraZeneca, Bayer, Genentech, PCCTC, and Pfizer; has received travel expenses from Bayer; and holds several patents (issued or pending) related to systems and methods for tissue imaging and treatment of castration-resistant prostate cancer and osteoblastic bone metastases.

REFERENCES

1. Hussain MHA, Kocherginsky M, Agarwal N, et al: BRCAAway. 2024 ASCO Genitourinary Cancers Symposium. Abstract 19. Presented January 25, 2024.

2. U.S. Food and Drug Administration: FDA approves olaparib with abiraterone and prednisone (or prednisolone) for BRCA-mutated metastatic castration-resistant prostate cancer. May 31, 2023. Available at https://bit.ly/3C2UVzg. Accessed February 14, 2024.