A phase 2 study of neoadjuvant PARP inhibition followed by radical prostatectomy (RP) in patients with unfavorable intermediate-risk or high-risk prostate cancer with <i>BRCA1/2</i> gene alterations (NePtune).

Abstract

TPS430 Background: Patients with localized high-risk prostate cancer face an elevated risk of recurrence after radical prostatectomy (RP). Approximately 6% of these patients carry germline mutations in DNA repair pathways, most commonly involving BRCA1/2 genes. These mutations are linked to more aggressive disease, a higher likelihood of distant metastasis, and worse survival outcomes compared to those without them. Olaparib, a PARP inhibitor, has improved overall survival in metastatic castration-resistant prostate cancer with BRCA1/2 germline or somatic mutations. Additionally, olaparib has shown efficacy as adjuvant therapy in improving invasive disease-free survival in patients with germline BRCA1/2 mutations and HER2-negative breast cancer. Multimodal treatment strategies for high-risk localized prostate cancer patients with BRCA1/2 mutations, whether germline or somatic, may improve clinical outcomes. Methods: We initiated a multicenter, phase 2, single-arm study to evaluate neoadjuvant olaparib combined with an LHRH agonist for 6 months, followed by radical prostatectomy (RP). Eligible patients include those with a Gleason score ≥4+3=7, PSA &gt;20 ng/mL, or T3 disease (determined by DRE or prostate MRI) with lymph nodes &lt;20 mm. Patients with intraductal carcinoma are eligible regardless of Gleason score, PSA level, or T stage. All participants must have germline or somatic BRCA1/2 pathogenic or likely pathogenic alterations identified through standard of care molecular profiling. Eligible patients will receive olaparib 300 mg orally twice daily along with an LHRH agonist for 6 months before undergoing RP. The primary endpoint is the rate of pathologic complete response (pCR) or minimal residual disease (MRD, defined as tumor ≤5 mm) as assessed by central pathology review. Secondary endpoints include PSA response, surgical staging at RP, positive margin rate, time to testosterone recovery, and safety. Exploratory endpoints include quality of life assessments, the proportion of downstaging observed on multiparametric MRI (mpMRI), correlation of mpMRI findings with pathologic response, and tissue-based molecular predictors of response and resistance. Sample size was calculated using a Binomial Exact test to evaluate the null hypothesis of a pCR/MRD rate ≤10% at a one-sided 5% significance level. Assuming an observed rate of ≥32.5% in this study, to conclude that the pCR/MRD rate is above 10% with 90% power, a total of 30 patients will be enrolled. At least 7 responses are needed to reject the null hypothesis. This trial is enrolling through the Hoosier Cancer Research Network, with active sites at the University of California San Diego, University of Pennsylvania, Johns Hopkins Hospital, Memorial Sloan Kettering Cancer Center, Columbia University, and the University of Buffalo. Clinical trial information: NCT05498272 .