Editor's Note: Studies have found that metastatic hormone-sensitive prostate cancer (mHSPC) patients with homologous recombination repair (HRR) gene mutations progress to metastatic castration-resistant prostate cancer (mCRPC) more quickly, significantly affecting overall survival. Previous research has shown that the combination of olaparib with abiraterone and prednisone significantly improves survival in mCRPC patients. At this year's ASCO Annual Meeting, a study from Professor Hongqian Guo's team at Nanjing Drum Tower Hospital analyzed this combined treatment strategy for mHSPC patients with HRR mutations for the first time. "Oncology Frontier" invited Professor Junlong Zhuang from Nanjing Drum Tower Hospital to share the findings on-site.Study Overview
Abstract No: 5082
PROact: A prospective phase II study to evaluate olaparib plus abiraterone and prednisone combination therapy in patients with metastatic hormone-sensitive prostate cancer with HRR gene mutation
Background: Approximately 10%-15% of mHSPC patients have functional loss mutations in HRR genes. Although olaparib combined with abiraterone and prednisone significantly extends overall survival in mCRPC patients, evidence is lacking for its efficacy and safety in mHSPC patients. This study reports the interim analysis of the PROact study, the first phase II trial to evaluate the efficacy of olaparib combined with abiraterone and prednisone in mHSPC patients with HRR gene mutations.
Methods: This single-center, single-arm, phase II trial (NCT05167175) enrolled male mHSPC patients with at least one HRR gene mutation (BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L), confirmed by tissue NGS sequencing. Patients received olaparib 300 mg BID combined with abiraterone 1000 mg QD and prednisone 5 mg QD. They had not previously used new hormonal agents (NHAs). The primary endpoint was the 1-year radiographic progression-free survival (rPFS) rate assessed by investigators using PCWG3-modified RECIST 1.1. Secondary endpoints included prostate-specific antigen (PSA) response rate, objective response rate (ORR), and adverse events.
Results: From May 19, 2022, to December 8, 2023, 30 patients were enrolled and received combined therapy. All patients had primary mHSPC, with a median age of 68 years (range 49-85 years) and a median baseline PSA of 166 ng/mL. Seven HRR mutations were identified: BRCA2 (n=11), CDK12 (n=8), ATM (n=6), PALB2 (n=2), CHEK2 (n=2), RAD51B (n=2), and RAD51D (n=1). As of April 30, 2024, with a median follow-up of 9.5 months, the PSA50 response rate was 100% (30/30), and the PSA90 response rate was 96.7% (29/30). Among 13 patients evaluated by RECIST, the ORR was 92.3% (12/13), with 2 complete responses and 10 partial responses. The treatment was well tolerated, with 7 patients (23.3%) experiencing ≥3 grade treatment-related adverse events (TRAEs), most commonly anemia.
Conclusion: This is the first clinical trial to evaluate and confirm the efficacy and acceptable safety of olaparib combined with abiraterone and prednisone in mHSPC patients with HRR mutations. The primary endpoint of 1-year rPFS will be reported in subsequent analyses.
Expert Commentary
It is a pleasure to share our research at ASCO, featuring the PROact study led by Professor Hongqian Guo from Nanjing Drum Tower Hospital. This single-arm, single-center, phase II study aims to evaluate the efficacy and safety of the olaparib, abiraterone, and prednisone combination in mHSPC patients with HRR gene mutations. While current data suggest significant benefits of olaparib in mCRPC patients with HRR mutations, the benefits for mHSPC remain unclear. Our team designed this exploratory study with a small sample size to address this question.
The study enrolled mHSPC patients without prior use of new hormonal agents, all carrying at least one HRR gene mutation. From May 2022 to December 2023, 30 patients were enrolled with a median age of 68 years and a median PSA of 166 ng/mL. Seven types of HRR mutations were identified. With a median follow-up of 9.5 months, PSA50 and PSA90 response rates were 100% and 96.7%, respectively. Among the 13 patients evaluated by RECIST, 92.3% achieved partial or complete response. The incidence of grade 3 or higher AEs was only 23%, lower than in the PROfound study, with anemia being the main adverse event.
This study has two significant implications. Firstly, it aligns with current treatment trends advocating for early intensive therapy, moving drugs from later to earlier lines of treatment. Given the high prevalence and severity of HRR mutations in mHSPC patients in China, exploring combination therapy for this population is crucial. Secondly, the study emphasizes the importance of early genetic testing. Guidelines recommend genetic testing for all metastatic prostate cancer patients, but further development of testing methods is needed to improve personalized treatment strategies.
