Frontline Abiraterone/Olaparib Doubles PFS in Biomarker-Selected mCRPC

In patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA1/2 or ATM alterations, the triplet combination of abiraterone acetate (Zytiga)/prednisone plus olaparib (Lynparza) was well tolerated and led to better response rates, progression-free survival (PFS), and overall survival (OS) compared with either agent used alone or sequentially, according to results from the phase 2 BRCAAway trial (NCT03012321). Findings were presented at the 2026 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium in San Francisco, California.¹

A total of 165 eligible patients were registered for the trial, with 61 patients confirmed to have qualifying DNA repair mutations and subsequently randomized. Patients were randomly assigned to 3 arms. Arm 1 (n = 19) received 1000 mg abiraterone and 5 mg prednisone, arm 2 (n = 21) received 300 mg olaparib, and arm 3 (n = 21) received abiraterone/prednisone plus olaparib. In addition, patients with mutations other than BRCA1/2 or ATM were assigned to a fourth arm (n = 17) and received olaparib alone; this arm was exploratory in nature. Crossover was permitted for patients in arms 1 and 2.

The objective response rate (ORR) in arm 1 was 22%, in arm 2 the ORR was 9.5%, and in arm 3, the ORR was 33%, reported lead author Maha H.A. Hussain, MBChB. Hussain is the Genevieve Teuton Professor of Medicine, Division of Hematology-Oncology, Department of Medicine, and deputy director and leader of the GU Oncology Program at the Robert H. Lurie Comprehensive Cancer Center of the Northwestern University Feinberg School of Medicine.

Prostate-specific antigen (PSA) responses for arms 1 and 2 were modest but patients in arm 3 demonstrated a PSA response of 95%.

“Interestingly, for patients in arm 3, the undetectable PSA rate was 38%,” Hussain said. This rate was 17% in arm 1 and 14% in arm 2.

PFS in arm 1 was 8.6 months (range, 2.9-17), 14 months (range, 8.4-20) in arm 2, and 39 months (range, 22-not reached) in arm 3. The hazard ratio for arm 3 vs arm 1 was 0.33 (95% CI, 0.15-0.72) and 0.37 (95% CI, 0.17-0.84) for arm 3 vs arm 2. In arm 4 (n = 17), median PFS was 5 months (range, 2-11).

At progression, 8 of 19 patients crossed over from abiraterone/prednisone to olaparib (n = 8) and 8 of 21 patients crossed over from olaparib to abiraterone/prednisone (n = 8). Response rates for patients who crossed over to olaparib was 38%; for those who crossed over to abiraterone, the response was 25%.

The OS in arm 3 was 68 months (range, 38-not reached) compared with 28 months (range, 13-not reached) in arm 1, and 37 months (range, 26-not reached) in arm 2. The hazard ratio for arm 3 vs arm 1 was 0.39 (95% CI, 0.16-0.93) and 0.51 (95% CI, 0.22-1.8) for arm 3 vs arm 2. For arm 4, median OS was 39 months (range, 21-49).

Study Schema and Methodology

The BRCAAway trial was designed to evaluate the synergistic potential of co-targeting PARP1 and the androgen receptor (AR) in a population with high unmet needs. The primary end point was PFS, and secondary end points included ORR, PSA response rates, and safety.

Patient Characteristics

The median ages across the arms were 63 years (range, 60–69), 68 years (range, 66–72), 69 years (range, 62–74), and 70 years (range, 63–78), respectively.

“The triplet combination arm had the most patients with visceral disease [at 33%], followed by 29% in arm 4,” Hussain noted. The genetic profile breakdown of the study population was dominated by BRCA2 alterations at 68%, 90%, and 71%, respectively.

At baseline, the disease burden was representative of a typical mCRPC population. Bone metastases were present in 84% of the abiraterone group, 62% of the olaparib group, and 76% of the combination group.

Safety and Adverse Events

The combination of olaparib and abiraterone was generally well tolerated with a safety profile consistent with the known effects of each agent. “There were very few grade 3 events in both single-agent arms and the combination arm. In arm 4, there was 1 case of grade 3 and 1 case of grade 4,” Hussain said. “Some of these patients were on treatment for years and it is remarkable that the treatment was tolerated for that long,” she added.

The triplet regimen was approved by the FDA in 2023 for patients with deleterious or suspected deleterious BRCA-mutated mCRPC based on efficacy results from the PROpel trial (NCT03732820).²

“The combination of abiraterone/prednisone plus olaparib showed the longest survival, with a median greater than 5 years, compared with either agent alone or sequentially,” Hussain concluded.

DISCLOSURES: Dr Hussain reports receiving honoraria from Academic CME; AstraZeneca; AstraZeneca; Bayer; Bayer; Bayer; Clinical Care Options; Great Debates and Updates; Medscape; Novartis; Research to Practice; Targeted Oncology. She has served in a consulting or advisory role for Abbvie; AstraZeneca; Bayer; Bayer; BMS; Convergent Therapeutics; GlaxoSmithKline; GlaxoSmithKline; J&J; Novartis; Tango Therapeutics. She has received research funding from Arvinas (Inst); AstraZeneca (Inst); Bayer (Inst); Genentech (Inst); PCCTC (Inst); Pfizer (Inst). She has received travel, accommodation, and expense reimbursement from Bayer.

REFERENCES

1. Hussain MH, Kocherginsky M, Pailler CJ, et al. Overall survival from the phase 2 trial of abiraterone + olaparib in first-line metastatic castration-resistant prostate cancer (mCRPC) with DNA repair defects (BRCAAway). J Clin Onc. 2026;44(suppl 7):16. doi: 10.1200.JCO.2026.44.7_suppl.16

2. FDA approves olaparib with abiraterone and prednisone (or prednisolone) for BRCA-mutated metastatic castration-resistant prostate cancer. FDA news release. May 31, 2023. Accessed February 26, 2026. https://tinyurl.com/57c8tfes