Antitumor activity of trabectedin and lurbinectedin in germline BRCA2 carriers with metastatic breast cancer (MBC) as compared to BRCA1 carriers: Analysis of two phase II trials

574 Background: BRCA 1/2-associated breast cancer share homologous recombination deficiency, but also have independent and potentially actionable roles. Novel drugs with innovative mechanism of action, lacking cross-resistance with other used agents are needed for BRCA 1/2 MBC. Trabectedin (TR) and its analog, lurbinectedin (L), have shown to be active in BRCA 1/2 MBC. This study was sought to determine if there was a difference in activity of these agents between BRCA1 and 2 carriers. Methods: Safety and efficacy in MBC BRCA 1/2 were analyzed in 2 separate phase II trials of single agent TR and L. Results: 88 patients were evaluated: 34 with TR, 54 with L. Median age: 46 and 43, respectively. Median (range) prior chemotherapy lines: TR, 4 (1-10); L, 2 (0-5). Clinical responses were seen in the 2 trials (see table) and were higher in BRCA2 than in BRCA1 (33% vs 9% with TR and 61% vs 26% with L). Main adverse event was myelosuppression (grade 3-4 neutropenia / thrombocytopenia / febrile neutropenia: TR, 62.1%/24.3%/10.8% L, 66.7%/20.4%/20.4%). Non-hematological toxicity was mostly grade 1-2: fatigue, nausea/vomiting and high transaminases (grade 3/4 TR, 40.5%, L 18.5%). Conclusions: Remarkable activity of trabectedin and lurbinectedin as single agents was observed in BRCA 2 associated MBC. This finding warrants further investigation. One potential mechanistic rationale is the role of both lurbinectedin and BRCA 2 in transcription. Safety was acceptable and manageable in both studies. Clinical trial information: NCT01525589. [Table: see text]