Intraductal carcinoma of the prostate as a predictor of efficacy of olaparib combined with novel hormone therapy in metastatic castration-resistant prostate cancer.

Abstract

e17063 Background: Intraductal carcinoma of the prostate (IDC-P) is a clinicopathological entity of prostate cancer characterized by increased homologous recombination repair deficiency (HRD). This study aimed to evaluate the predictive value of IDC-P for the efficacy of olaparib combined with novel hormonal therapy (NHT) in metastatic castration-resistant prostate cancer (mCRPC) after progression on NHT. Methods: A total of 64 consecutive patients treated with olaparib plus NHT after NHT progression were analyzed, including 33 IDC-P and 31 prostate adenocarcinoma (PAC) cases. Main outcomes included progression-free survival (PFS) and treatment change-free survival (TFS). Prostate-specific antigen (PSA) response, overall survival and adverse events were also evaluated. Additionally, paired blood and tissue samples from 187 PCa patients were analyzed to assess HRD scores. Results: After a median follow-up of 35.0 months, patients with IDC-P showed significantly longer PFS and TFS than those with PAC (PFS: 6.2 vs. 3.0 months, p < 0.01; TFS: 10.0 vs. 6.3 months, p < 0.01). Among BRCA1/2 mutated patients, IDC-P was associated with improved PFS and TFS (PFS: 9.8 vs. 3.0 months, p < 0.01; TFS: 11.3 vs. 10.2 months, p = 0.04). Multivariate analysis confirmed IDC-P as a predictor of better PFS and TFS after adjusting for BRCA1/2 mutation status. Additionally, IDC-P showed higher HRD scores than PAC in both BRCA1/2 mutated and non-mutated cohorts, potentially explaining its favorable response to olaparib plus NHT. Conclusions: IDC-P may serve as a predictor for the efficacy of PARPi-based therapy in mCRPC. Further large-scale and prospective validation is warranted Baseline characteristics of the mCRPC patients receiving olaparib plus NHT progression after NHT. Variable Overall,N = 64 1 PAC,N = 31 1 IDC-P,N = 33 1 p-value 2 Age (yrs, median (range)) 70 (62, 75) 71 (68, 77) 69 (61, 74) 0.07 Baseline PSA 0.7 <50 ng/ml 15 (23%) 8 (26%) 7 (21%) ≥50 ng/ml 49 (77%) 23 (74%) 26 (79%) ISUP >0.9 3 3 (4.7%) 2 (6.5%) 1 (3.0%) 4 11 (17%) 5 (16%) 6 (18%) 5 50 (78%) 24 (77%) 26 (79%) Metastatic burden 0.02 <5 20 (31%) 14 (45%) 6 (18%) ≥5 44 (69%) 17 (55%) 27 (82%) Visceral metastasis 9 (14%) 4 (13%) 5 (15%) >0.9 Progression-free interval of first-line NHT 10 (6, 14) 9 (6, 20) 10 (6, 13) 0.7 Pre-olaparib PSA 0.08 <50 ng/ml 34 (53%) 13 (42%) 21 (64%) ≥50 ng/ml 30 (47%) 18 (58%) 12 (36%) Number of treatment lines post-olaparib 0.8 0 34 (53%) 15 (48%) 19 (58%) 1 16 (25%) 9 (29%) 7 (21%) 2 10 (16%) 5 (16%) 5 (15%) 3 3 (4.7%) 1 (3.2%) 2 (6.1%) 4 1 (1.6%) 1 (3.2%) 0 (0%) BRCA mutation 31 (48%) 13 (42%) 18 (55%) 0.3 PSA: prostate specific antigen; ISUP: International Society of Urological Pathology; NHT: novel hormone therapy; IDC-P: intraductal carcinoma of the prostate; PAC: prostate adenocarcinoma.