Editor's Note: At a recent major oncology academic conference, Professor Maha Hussain from the Robert H. Lurie Comprehensive Cancer Center of Northwestern University in Chicago presented the latest efficacy and overall survival (OS) data from the BRCAaway trial (Abstract 16). This Phase II clinical trial thoroughly investigated the definitive efficacy and safety profile of abiraterone combined with olaparib versus either agent alone as a first-line treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) harboring DNA repair defects.01 Scientific Rationale and Study Design: A Biomarker-Driven Prospective Exploration
Preclinical data previously indicated a synergistic effect between poly (ADP-ribose) polymerase (PARP) inhibition and the androgen receptor (AR) pathway. Based on this, the BRCAaway study was designed as a biomarker-selected, randomized, open-label, multicenter Phase II clinical trial.
The study enrolled patients with mCRPC in the first-line setting who had not received prior AR inhibitors, PARP inhibitors, or chemotherapy for castration-resistant disease. All patients underwent somatic and germline tissue genomic testing. Patients harboring BRCA1, BRCA2, or ATM mutations were randomized 1:1:1 to three main treatment arms:
- Arm 1 (Control Group): Abiraterone + prednisone
- Arm 2 (Monotherapy Group): Olaparib monotherapy
- Arm 3 (Combination Group): Abiraterone + prednisone + olaparib
Additionally, patients with other homologous recombination repair (HRR) gene mutations were assigned to a single-arm cohort (Arm 4) receiving olaparib monotherapy. The study allowed patients in the monotherapy groups (Arm 1 and Arm 2) to cross over upon radiographic progression. The primary endpoint was radiographic progression-free survival (rPFS), and secondary endpoints included objective response rate (ORR), prostate-specific antigen (PSA) response rate, and overall survival (OS).
02 Baseline Characteristics and Long-Term Safety Profile: Well-Tolerated Combination Therapy
The trial screened and enrolled 61 eligible patients with BRCA1/2 or ATM mutations from 15 centers (randomized to Arms 1–3), while another 17 patients with other HRR mutations entered Arm 4. Regarding baseline characteristics, the combination therapy group (Arm 3) had a higher proportion of patients with visceral metastases, reaching nearly 30%; the overall enrolled population predominantly harbored BRCA2 mutations.
Safety data demonstrated that the first-line combination regimen was generally well-tolerated. Very few severe adverse events (Grade 3 or higher) occurred in both the monotherapy and combination arms (Arm 4 reported only one Grade 3 and one Grade 4 event). Prof. Hussain specifically noted that some patients have been on treatment for several years, further validating the safety and feasibility of this combination regimen for long-term therapy.
03 Deep Biochemical Response: Superior PSA Response Rate in the Combination Arm
In terms of efficacy evaluation, while the monotherapy arms showed certain objective and PSA responses, the abiraterone plus olaparib combination group (Arm 3) demonstrated a significantly superior deep response advantage.
Data showed that up to 95% of patients in the combination arm achieved a PSA response, and even more remarkably, 38% of these patients achieved a deep response, defined as an undetectable PSA level. This significant difference in the biochemical response dimension laid the foundation for subsequent survival prolongation.
04 Survival Data Breakthrough: First-Line Combination Far Exceeds Sequential Monotherapy
The core highlights of this report lie in the long-term follow-up data for rPFS and OS. Although the study allowed for crossover treatment post-progression, the survival advantage of adopting the combination regimen directly in the first line remained robust.
- rPFS Data: The median rPFS was 8.4 months for the abiraterone monotherapy arm, 14 months for the olaparib monotherapy arm, and an astounding 39 months (over 3 years) for the combination therapy arm.
- Crossover Efficacy: Data indicated that among patients crossing over from olaparib to abiraterone, 38% showed a response; whereas among those crossing over from abiraterone to olaparib, the response rate was only 25%.
- OS Data: The median OS was 28 months for the abiraterone monotherapy arm and 37 months for the olaparib monotherapy arm. Conversely, the median OS for the combination therapy arm was not reached, with follow-up exceeding 60 months (5 years). Prof. Hussain disclosed that several patients currently remain in long-term disease remission, with an actual on-study treatment duration exceeding 4.5 years.
05 Conclusion and Clinical Outlook
In conclusion, Prof. Hussain emphasized that for mCRPC patients harboring BRCA1/2 or ATM mutations, the first-line abiraterone combined with olaparib regimen not only exhibits a favorable safety profile but also demonstrates clear superiority across multiple dimensions, including response rate, rPFS, and OS. Although sequential monotherapy (with crossover) can yield certain benefits, adopting a dual-target combination regimen directly in the first line provides the most significant long-term survival benefit.
Coupled with the recent FDA approvals of several PARP inhibitors combined with novel endocrine therapies (such as olaparib + abiraterone, niraparib + abiraterone, and talazoparib + enzalutamide) for first-line mCRPC indications, the long-term follow-up results of the BRCAaway trial further consolidate the core position of precision screening via genomic testing combined with first-line targeted combination therapy in the clinical management of advanced prostate cancer, supported by high-level evidence-based medicine.
