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.

5082 Background: Approximately 10% - 15% of patients with metastatic hormone sensitive prostate cancer (mHSPC) harbor loss-of-function mutations in homologous recombination repair (HRR) genes. Although olaparib plus abiraterone and prednisone has significantly prolonged overall survival in metastatic castration resistant prostate cancer patients, there is a lack of evidence regarding the efficacy and safety of this combination therapy in patient with mHSPC. Here, we report the interim analysis results of PROact study, the first phase Ⅱ trial to evaluate the effects of olaparib plus abiraterone and prednisone in mHSPC patients with HRR gene mutation. Methods: This was a single center, single arm, phase Ⅱ trial ( NCT05167175 ) conducted in male patients with mHSPC who had at least one HRR gene mutation ( BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD 51C, RAD51Dand RAD54L) as determined by tissue-NGS. Patients were administered olaparib 300 mg BID plus abiraterone 1000 mg QD and prednisone 5 mg QD. Previous treatment with new hormonal agent (NHA) was not allowed. The primary endpoint was 1-year radiographic progression-free survival (rPFS) rate per PCWG3-modified RECIST 1.1 by investigator assessment. The secondary endpoint included prostate-specific antigen (PSA) response rate, objective response rate (ORR), and adverse events. Results: Between May 19, 2022 and Dec 8, 2023, a total of 30 patients were enrolled and administered combination therapy. All the patients had de novo mHSPC, and the median age was 68 (range 49-85), with a median PSA of 166 ng/mL at baseline. A total of 7 HRR mutations were identified, included BRCA2 (n=11), CDK12 (n=8), ATM(n=6), PALB2 (n=2), CHEK2 (n=2), RAD51B (n=2) and RAD51D (n=1). As of Jan 29, 2024, the median follow-up was 7.1 months. In the 30 patients who had PSA response evaluated, PSA50 response rate achieved 100% (30/30), and the PSA90 response rate was 96.7%(29/30). In the 12 patients who had RECIST assessment, the objective response rate was 91.7% (11/12). Two achieved complete response, nine obtained partial response, and one had stable disease. The treatment was well tolerated, with 7(23.3%) patients experienced ≥grade 3 treatment-related adverse events (TRAEs). Common TRAE was anemia. Conclusions: This was the first trial to show efficacy and an acceptable safety profile of olaparib plus abiraterone and prednisone in mHSPC patients with HRR mutation. Data of primary endpoint of 1-year rPFS will be reported in the due time. Clinical trial information: NCT05167175 .