Updated results from the phase II BRCAAway trial showed that first-line treatment with abiraterone and prednisone plus olaparib resulted in a median overall survival of more than 5 years in patients with metastatic castration-resistant prostate cancer harboring BRCA1/2 and/or ATM alterations.¹ Presenting at the 2026 ASCO Genitourinary (GU) Cancers Symposium, Maha H. A. Hussain, MD, FACP, FASCO, of Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, described the outcome as “remarkable.”

Maha H. A. Hussain, MD, FACP, FASCO

Yüksel Ürün, MD

Median overall survival was 68 months (95% CI = 38 months to not reached [NR]) with the combination, compared with 28 months (95% CI = 13 months–NR) with abiraterone plus prednisone and 37 months (95% CI = 26 months–NR) with olaparib. The hazard ratio for overall survival was 0.39 (95% CI = 0.16–0.93) for abiraterone/prednisone plus olaparib vs abiraterone/prednisone alone and 0.51 (95% CI = 0.22–1.18) for the combination vs olaparib alone. Crossover between single-agent arms was permitted at disease progression.

Dr. Hussain noted that the combination “showed the longest [overall] survival—median [over] 5 years—compared with either agent alone or sequentially.” Updated progression-free survival data were also presented. With a small number of patients crossing over, she said, the front-line combination showed improved progression-free survival compared with sequential therapy.

On X, genitourinary cancer expert Yüksel Ürün, MD, Professor of Medicine, Ankara University School of Medicine, Turkey, wrote: “[The] front-line combination mattered. Sequential therapy did not catch up. [It’s a phase II study]—but a clear signal. Test early. Treat early.”

Study Rationale and Design

BRCAAway was conceived in 2016, before clinical trial data were available for combining androgen receptor pathway and PARP inhibition in this clinical context. Preclinical evidence suggested that PARP1 inhibition may synergize with androgen receptor pathway blockade, providing the biologic rationale for dual targeting, Dr. Hussain said.

The biomarker-preselected, randomized, open-label, multicenter phase II trial enrolled first-line patients with metastatic castration-resistant prostate cancer who had not received prior PARP inhibitors, androgen receptor inhibitors, or chemotherapy for their disease. Eligible patients underwent tumor next-generation sequencing and germline testing.

A total of 165 eligible patients were registered across 15 sites and underwent testing. Sixty-one were found to have qualifying BRCA1/2 or ATM alterations and were randomly assigned in a 1:1:1 ratio to:

• Arm I (n = 19): Abiraterone (1,000 mg once daily) and prednisone (5 mg twice daily)
• Arm II (n = 21): Olaparib (300 mg twice daily)
• Arm III (n = 21): Abiraterone and prednisone plus olaparib.
• Crossover at disease progression was permitted for patients receiving single-agent therapy.

Seventeen patients with other homologous recombination repair mutations were assigned to an exploratory arm (IV) of olaparib monotherapy followed by abiraterone and prednisone at disease progression.

Among randomized patients, BRCA2 alterations were the most common (68% in Arm I; 90% in Arm II; and 71% in Arm III). “Interestingly,” Dr. Hussain noted, a higher proportion of the combination arm had visceral metastases (33%) compared with the abiraterone (11%) and olaparib (14%) monotherapy arms; a similar proportion (29%) was observed in the exploratory arm.

The primary endpoint was radiographic progression–free survival. Secondary endpoints included measurable disease response rate, prostate-specific antigen (PSA) response rate, and toxicity, as well as overall survival.

Previously reported results from BRCAAway demonstrated that first-line treatment with the combination of abiraterone and olaparib significantly improved progression-free survival compared with either agent alone or sequential therapy in patients with BRCA1/2 or ATM alterations.² The current presentation reports updated progression-free survival data as well as overall survival outcomes.

Overall Survival in Detail

Dr. Hussain presented overall survival outcomes, summarized in Table 1, describing the results in the combination and exploratory arms as “remarkable.” She added that with the combination, a couple of her own patients have been in remission for nearly 4.5 years.

Other Efficacy Outcomes

Objective response rates were “decent, but not huge” in the single-agent arms, Dr. Hussain reported: 22% with abiraterone/prednisone; at 33%, the rate was “much higher” with the combination. PSA responses occurred in 61%, 67%, and 95% of Arms I, II, and III, respectively; she noted that 38% of the combination arm achieved undetectable PSA.

In her discussion of progression-free survival, Dr. Hussain described the single agents as “give and take—but not similar exactly,” with olaparib demonstrating a longer median than abiraterone and prednisone (14 months [95% CI = 8.4–20 months] vs 8.6 months [95% CI = 2.9–17 months]). “But when you look at the combination arm,” she added, “it was actually over 3 years” (39 months [95% CI = 22 months–NR]). The hazard ratio was 0.33 (95% CI = 0.15–0.72) for the combination vs abiraterone and prednisone and 0.37 (95% CI = 0.17–0.84) vs olaparib.

At disease progression, eight patients crossed over from abiraterone and prednisone to olaparib, and an equal number crossed from olaparib to abiraterone and prednisone. Response rates after crossover were 38% and 25%, respectively.

This analysis represents the first report of progression-free survival data from the exploratory arm. In that cohort, median progression-free survival was 5 months (95% CI = 2–11 months). “Some patients had a long response, but the majority had shorter responses,” Dr. Hussain added.

Safety

“Overall, the treatment was very well tolerated,” Dr. Hussain stated. She continued that there were few grade 3 adverse events in the randomized arms, and no toxicities of a higher grade were observed. In the exploratory arm, one grade 3 and one grade 4 event were reported.

She pointed out that some patients were treated for years, stating, “It is remarkable that it [was] tolerated for that long.”

She concluded, “In patients with metastatic castration-resistant prostate cancer and BRCA1/2 or ATM alterations, abiraterone and prednisone plus olaparib was well tolerated and resulted in better response rates, progression-free survival, and overall survival, and also PSA responses, compared with olaparib or abiraterone, despite allowing crossover.”

In 2023, the U.S. Food and Drug Administration approved abiraterone and prednisone plus olaparib for first-line treatment of metastatic castration-resistant prostate cancer with BRCA1/2 alterations. Additional PARP inhibitor and androgen receptor–targeted combinations—talazoparib plus enzalutamide and niraparib plus abiraterone and prednisone—have also received regulatory approval. 

DISCLOSURE: The study was funded by AstraZeneca and Merck Sharp & Dohme. Dr. Hussain has received honoraria from AcademicCME, AstraZeneca, Bayer, Clinical Care Options, Great Debates & Updates, Medscape, Novartis, Research To Practice, and Targeted Oncology; has served as a consultant or advisor for AbbVie, AstraZeneca, Bayer, BMS, Convergent Therapeutics, GlaxoSmithKline, Johnson & Johnson, Novartis, and Tango Therapeutics; has received institutional research funding from Arvinas, AstraZeneca, Bayer, Genentech, PCCTC, and Pfizer; has received reimbursement for travel expenses from Bayer; and holds patents, royalties, or other intellectual property related to dual MET and VEGF inhibition for the treatment of castration-resistant prostate cancer with osteoblastic bone metastases, as well as tissue imaging. Dr. Ürün reported no conflicts of interest.

REFERENCES

1. Hussain MH, Kocherginsky M, Paller CJ, et al: Overall survival from the phase 2 trial of abiraterone, olaparib, or abiraterone + olaparib in first-line metastatic castration-resistant prostate cancer with DNA repair defects (BRCAAway). 2026 ASCO GU Cancers Symposium. Abstract 16. Presented February 26, 2026.

2. Hussain M, Kocherginsky M, Agarwal N, et al: Abiraterone, olaparib, or abiraterone + olaparib in first-line metastatic castration-resistant prostate cancer with DNA repair defects (BRCAAway). Clin Cancer Res 30:4318-4328, 2024.

Prioritizing Upfront Combination in BRCA1/2- and ATM-Mutated Metastatic Castration-Resistant Prostate Cancer

Yüksel Ürün, MD, Professor of Medicine, Ankara University School of Medicine, Turkey, commented on updated results from the phase II BRCAAway trial in an interview with The ASCO Post.

“In oncology, we face a fundamental dilemma regarding treatment sequencing: Is it better to initiate therapy with a potent combination or to utilize agents in a deliberate sequence? Both strategies offer distinct tradeoffs. While sequential therapy may preserve future options and minimize cumulative toxicity, the results of the BRCAAway trial provide a compelling, data-driven argument that for a specific molecular subset, the upfront combination is the superior path. Specifically, for patients with metastatic castration-resistant prostate cancer harboring BRCA1/2 or ATM alterations, the study addressed a critical clinical question: Is it more effective to lead with a single active agent and reserve the next for progression, or to hit both pathways simultaneously from the start?

The results from the randomized phase II BRCAAway study show that the combination of abiraterone and prednisone plus olaparib significantly improved progression-free survival and overall survival compared with either agent alone or in sequence in patients with metastatic castration-resistant prostate cancer harboring BRCA1/2 or ATM alterations. These findings support the shift toward biomarker-selected upfront combination therapy in the first-line setting.

The Overall Survival Benefit: A High-Magnitude Signal

Although the patient cohort was relatively small (n = 61 in the primary arms), the delta in survival is too significant to ignore. The median overall survival for the combination was 68 months, more than doubling the 28 months seen with abiraterone alone and nearly doubling the 37 months seen with olaparib alone.

The hazard ratio of 0.39 against the abiraterone arm suggests a 61% reduction in the risk of death. In a disease state where survival gains are often incremental, a 40-month improvement in median overall survival is a ‘strong’ signal. It suggests that in the presence of specific DNA repair defects, the synergy between androgen receptor–directed therapy and PARP inhibition is not just additive but transformative.

Upfront Combination vs Sequencing

The study included a unique exploratory arm (Arm IV) to test exactly this. Patients who experienced disease progression with abiraterone or olaparib monotherapy were allowed to cross over to the other agent.

The results were clear; the median overall survival for the sequential monotherapy group was only 39 months, significantly trailing the 68 months achieved by the upfront combination. These data suggest that starting with the combination prevents the early emergence of resistant clones that sequential therapy cannot effectively ‘salvage.’ For patients with BRCA or ATM mutations, the most effective therapy should be utilized when the tumor burden is likely at its most sensitive—at the start of metastatic castration-resistant prostate cancer treatment.

Toxicity and Tolerability: Balancing Intensity With Quality of Life

A primary concern with upfront combination therapy is the potential for increased cumulative toxicity compared with sequential monotherapy. However, in BRCAAway, the combination of abiraterone and olaparib was remarkably well tolerated, with a safety profile consistent with the known individual effects of each drug. Most adverse events were manageable, and the study reported no new or unexpected safety signals. This suggests that the biologic synergy of these two agents does not necessarily translate into synergistic toxicity. For the patient, this means the significant survival advantage does not come at the cost of a prohibitive decline in quality of life, further strengthening the argument for using both drugs early when the patient’s performance status is typically at its best.

Clinical Practice: What Should Change Today?

Genomic Testing is Non-Negotiable: You cannot offer this survival benefit if you do not know the patient›s mutational status. Germline and somatic testing for BRCA1/2 and ATM should be standard at the time of metastatic castration-resistant prostate cancer diagnosis.

Move Beyond ‘Saving’ Drugs: The fear of ‘running out of options’ is countered by the fact that sequential therapy resulted in much shorter lives in this study. The goal is to maximize the first-line response.

Confidence in Tolerability: The study confirmed that the combination of abiraterone and olaparib is well tolerated, meaning the survival gains do not come at a prohibitive cost to quality of life.

The BRCAAway trial reinforces that in the era of precision medicine, biology dictates the schedule. For the roughly 10% to 15% of patients with metastatic castration-resistant prostate cancer who have these specific mutations, the ‘sequence’ should start with a combination.” 

REFERENCE

1. Hussain MH, Kocherginsky M, Paller CJ, et al: Overall survival from the phase 2 trial of abiraterone, olaparib, or abiraterone + olaparib in first-line metastatic castration-resistant prostate cancer with DNA repair defects (BRCAAway). 2026 ASCO GU Cancers Symposium. Abstract 16. Presented February 26, 2026.

DISCLOSURE: Dr. Ürün reported no conflicts of interest.

EXPERT POINT OF VIEW

The phase II BRCAAway trial has prompted further consideration in metastatic castration-resistant prostate cancer: What should clinicians do when a significant overall survival benefit is achieved?

Invited discussant Evan Y. Yu, MD, of Fred Hutch, Seattle, explained that such a result is difficult to achieve, but “when it occurs, I think [the treatment] should be the default, and we need to think very hard about how to incorporate it in our practice.” He cautioned, “we always have to think about efficacy balance with safety and quality of life, and we need individualized treatment for patients.”

Evan Y. Yu, MD

In BRCAAway, first-line abiraterone and prednisone plus olaparib yielded a median overall survival of 68 months in patients with BRCA1/2 or ATM alterations,¹ which Dr. Yu said was “very impressive.” Baseline characteristics—including performance status of 1, presence of visceral metastases, BRCA2 alterations, and prior docetaxel exposure—“aren’t exactly equal as you might see in a larger randomized study.” Further, the trial was not statistically powered for overall survival and did not mandate crossover, introducing the possibility of bias from self-selected crossover.

Is the magnitude of benefit surprising? “Maybe not for the BRCA1/2 population,” he said, pointing to corroborating overall survival benefits in PROpel and TALAPRO-2.^2,3 The biologic rationale for combining a PARP inhibitor with an androgen receptor pathway inhibitor, however, remains less definitive: “Maybe there is some rationale for additive or synergistic effects,” he noted—suggesting cautious interpretation.

Guideline context further complicates the picture: abiraterone plus olaparib is included in the NCCN Guidelines as a category 1 recommendation in the pre–androgen receptor pathway inhibitor setting, based on PROpel, but cannot be recommended for patients previously treated with such therapy.^2,4 Because PROpel and BRCAAway enrolled almost exclusively androgen receptor pathway inhibitor–naive patients, Dr. Yu described this as the study’s “biggest clinical limitation.”

He emphasized the need to individualize treatment by weighing toxicity, noting that PARP inhibitors are associated with anemia, fatigue, and GI adverse effects, which were observed in BRCAAway, primarily with the olaparib-containing regimens. Other risks, such as myelodysplastic syndrome and acute myeloid leukemia, he said, require long-term data from larger populations.

Ultimately, Dr. Yu posed the central clinical question: “Is combination androgen receptor pathway inhibition plus PARP inhibition for everybody with a pathogenic BRCA1/2 alteration? I would say no.” While BRCAAway “builds on a body of evidence for combination therapy and supports the opportunity to give a PARP inhibitor early if you think your patient population has really aggressive disease,” he emphasized that better studies of clinical and molecular features are needed to distinguish aggressive from indolent BRCA1/2-altered disease.

“Trials are not a perfect fit for our patients in the clinic, [but] they can provide a general guide…,” Dr. Yu concluded. The BRCAAway combination regimen is available, he said, but the decision to go “all in” or play the long game must remain individualized. 

DISCLOSURE: Dr. Yu has served as a consultant or advisor for Astellas Pharma, AstraZeneca, Bayer, Johnson & Johnson, Lantheus, Merck, Novartis, and Tolmar; and has received institutional research funding from Bayer, Blue Earth Diagnostics, Dendreon, Lantheus, Merck, Pfizer, and Tyra Biosciences.

REFERENCES

1. Hussain MH, et al: Overall survival from the phase 2 trial of abiraterone, olaparib, or abiraterone + olaparib in first-line metastatic castration-resistant prostate cancer with DNA repair defects. 2026 ASCO GU Cancers Symposium. Abstract 16. Presented February 26, 2026.

2. Saad F, et al: Olaparib plus abiraterone vs placebo plus abiraterone in metastatic castration-resistant prostate cancer. Lancet Oncol 24:1094-1108, 2023.

3. Agarwal N, et al: Talazoparib plus enzalutamide in men with metastatic castration-resistant prostate cancer. Lancet 406:447-460, 2025.

4. Spratt DE, et al: NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer. Version 5.2026. Available at www.nccn.org. Accessed March 4, 2026.