Cabazitaxel versus enzalutamide/abiraterone in CARD eligible mCRPC patients with or without germline HRR defects.

Abstract

5554 Background: The CARD trial proved that in mCPRC patients (pts), previously treated with docetaxel and an androgen-receptor signaling inhibitor (ARSi), cabazitaxel (CBZ) significantly improves progression-free (PFS) and Overall Survival (OS) compared with the alternative ARSi. Concurrently, the PROFOUND study showed the superiority of olaparib vs. ARSi in pts with similar prior treatment history and genetic alterations in Homologus Recombination DNA repair related genes (HRR). Methods: PROREPAIR-B (NCT03075735) is a prospective study which aimed to demonstrate the prognostic role of germline deleterious mutations in (g)HRR genes and the benefit of first (1L), second (2L) and subsequent therapy lines for mCRPC. Outcomes with 1-2L have been previously reported. Here we evaluated radiographic (r)-PFS, clinical (c)-PFS, and OS in PROREPAIR-B pts who meet CARD study eligibility criteria and who received CBZ and/or ARSi. Survival analysis were performed using Kaplan Meier method and Cox regression models. Results: 95 out of 419 mCRPC pts included in PROREPAIR-B meet CARD eligibility criteria and received CBZ (n=60) or ARSi (n=35) including 14 gHRR carriers, 8/6 treated with CBZ/ARSi, respectively. Visceral metastases were more frequent among pts treated with CBZ (p=0.01). ECOG 2, M1 at diagnosis, Abiraterone as 1st ARSi and prior radiographic PD (all p<0.05) were more frequent in our pts than in the CARD study. Overall, CBZ was superior to ARSi in terms of rPFS (median 6.0 vs. 3.7 months (m), p=0.03), cPFS (median 4.4 vs. 3.4 m, p=0.01) and PSA50 responses (39% vs. 17%, p=0.027). Differences in OS were not observed, although approximately 60% of patients in ARSi had crossed to CBZ at the time of the analyses. Results of subgroups analyses were similar to those reported by CARD. In this series, gHRR carriers had a significant worse prognosis (OS HR 1.9; rPFS HR 2.4; cPFS HR 2.6) than non-carriers. In gHRR carriers CBZ was not superior to ARSi in terms of rPFS (2.5 vs. 3.0 m, p=0.8), cPFS (2.5 vs. 2.4 m, p=0.8) and OS (4.5 vs. 3.7, p=0.8). Cox MVA models adjusted for unbalances and CARD grouping factors confirmed a significant interaction between treatment and gHRR status for rPFS and cPFS, suggesting that the benefit of CBZ was not observed in gHRR. Conclusions: Our results confirm the benefit of CBZ treatment over a second ARSi (either abiraterone or enzalutamide) in unselected mCRPC population. However, the outcomes in gHRR carriers are poor with either CBZ or ARSi supporting the need of novel therapies in this setting. Clinical trial information: NCT03075735 .

Implications of DNA damage repair alterations for the management of prostate cancer

“…A post hoc analysis of the PROREPAIR-B study showed that the outcomes of patients with germline HHR mutations were worse than those of noncarriers following treatment with cabazitaxel [30]. Aldea et al [31] analysed the response to cabazitaxel in mCRPC patients with germline or somatic DDR defects and found no difference in response rates in patients with and without such alterations.…”