PARPi effectiveness after CDK4/6i in BRCA1- and BRCA2-associated HR+/HER2- advanced breast cancer: Results from the multicenter real-world PAMBRACA study

Background: Poly(adenosine diphosphate–ribose) polymerase inhibitors (PARPi) are the paramount of personalized therapy for BRCA1 and BRCA2 pathogenic/likely pathogenic variant (P/LPV) carriers with hormone receptor-positive (HR+)/HER2-negative (HER2-) advanced breast cancer (aBC). Nevertheless, data on the efficacy of PARPi following cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) are limited. Methods: The PAMBRACA study is a multicenter, hospital-based, retrospective-prospective cohort study enrolling BRCA1 and BRCA2-P/LPV carriers with HR+/HER2- aBC treated with ET+CDK4/6i and/or PARPi. In this analysis, the real-world Progression-Free Survivals (rwPFS) of ET+CDK4/6i and subsequent lines were evaluated through Kaplan-Meier method and compared with the log-rank test. Median follow-up was calculated using the reverse Kaplan-Meier method. Multivariate Cox regression model was used to adjust the association between treatment regimens and rwPFS for clinically relevant variables. Results: We included12 BRCA1 and 57 BRCA2-P/LPV carriers who were diagnosed with HR+/HER2- aBC between January 1998 and December 2023 in six Italian Institutions. All the patients (pt) received CDK4/6i+ET for aBC (85.5% as first line, 7.2% as second line, 7.3% as third or subsequent line). At CDK4/6i starting, median age was 45 years (range 28-80); 52.2% of pts had visceral metastases and 17.4% had de novo aBC. Median follow-up was 39.5 months (mo). Among pts treated with CDK4/6i as first or second line, median rwPFS was 15.1 mo (95%CI 11.8-18.5) and 3.1 mo (95%CI 2.1-NA), respectively. Among the 49 patients who progressed to first or second-line CDK4/6i, 17 (34.7%) received a PARPi as first line post-CDK4/6i, 12 (24.5%) a monochemotherapy (monoCT), 8 (16.3%) an ET (+/- everolimus), 8 (16.3%) a polychemotherapy (polyCT) and 4 (8.2%) died without receiving a subsequent line. No significant differences in clinicopathological characteristics were observed among the treatment groups, except for the number of metastatic sites (<3 vs > 3), which was higher for pts receiving mono/polyCT (p = 0.053). PARPi treatment was associated with significantly higher median rwPFS (13 mo vs 4.5 mo for monoCT vs 3 mo for ET vs 6 mo for polyCT, p < 0.001), also after adjusting for the number of metastatic sites [for PARPi vs other lines, adjusted hazard ratio (aHR) 0.20, 95%CI 0.09-0.49, p < 0.001]. 17 pts received PARPi as later treatment lines, which were independently associated with lower median rwPFS vs PARPi as first post-CDK4/6i line (6 vs 13 mo, aHR 2.81, 95%CI 1.15-6.90, p = 0.024). Conclusions: AfterCDK4/6i+ET, PARPi were independently associated with longer rwPFS compared to other systemic therapies in BRCA1 and BRCA2-P/LPV carriers with HR+/HER2- aBC. Earlier PARPi use after CDK4/6i was associated with greater clinical benefit.