Background: Based on the concept of synthetic lethality combining platinum agents and PIs should benefit patients (pts) with BRCA-associated MBC. We report mature outcomes with vel alone, or with carb. Methods: Pts with germline BRCA-associated MBC, ECOG performance status of ≤ 2, without prior PI treatment were included. In phase I the maximum tolerated dose (MTD) of carb (AUC of 5) IV every 21 days, and vel 150 mg BID were defined. In phase II, pts received vel 400 mg BID and upon progression, carb and vel at the MTD. Results: Between 6/2010 and 4/2014, 72 evaluable pts (28 in phase I, 44 in phase II) with BRCA1 (34 patients) or BRCA2 (37 patients) mutations (1 pt had both) and with MBC were enrolled. The median age was 44-years (range; 28-68); 49% of pts had hormone receptor + MBC. Pts received a median of 1 (0 – 5) prior chemo-regimen for MBC. Response rate (RR) for the 28 pts in phase I was 50% [CR rate 18%] and 2 pts remain in CR at 43+ and 34+ cycles, both are on vel maintenance, alone; median progression-free survival (PFS) was 8.5 mos (95% CI 7.3-10.1), and median TTF was 8.3 mos (6.9-9.5). For 44 phase II pts treated with vel, the median PFS was 5.2 months (4.0-6.4) and including their cross-over carb/vel treatment the cumulative TTF was 6.7 months (4.6-8.5); 13/44 (30%) responded to vel; 2 pts are still on vel (1 with a PR at 14 cycles, 1 with a CR at 25 cycles); 1 pt converted to PR after cross-over to carb/vel. OS was 18.8 months (95% CI 15.0-26.3) for the 28 pts treated with the combination of carbo/vel, and 12.6 months (95% CI 11.7-NR) for the 44 pts treated with vel followed by carbo/vel (p < 0.1). In phase I, dose delay or adjustment was needed in 1/3of the pts treated at the MTD within the first 3 cycles due to cytopenias. In phase II, 8/44 (18%) required dose adjustment on single agent vel, and 5 pts required dose adjustment after cross-over to carb/vel. Conclusions: The trend for longer TTF with the carb/vel combination first vs. vel followed by carb/vel, combined with the improved time OS suggest that carb/vel followed by vel maintenance deserves further testing in a randomized prospective trial. Clinical trial information: NCT01149083