PM01183, a trabectedin analogue that inhibits transactivated transcription and induces DNA double-strand breaks, displays remarkable clinical activity in germline BRCA (gBRCA)-related metastatic breast cancer (MBC). However, the mechanisms of primary and acquired resistance to PM01183 and their potential impact on the efficacy of other active agents, namely PARP inhibitors (PARPi) and platinum salts, are unknown. This knowledge may help to delineate the optimal therapeutic sequence to maximize the clinical benefit in the metastatic setting.
We assessed the antitumor activity of PM01183 (0.18mg/kg IV) and cisplatin (6mg/kg IV) q7dx5 in a panel of 10 gBRCA PDXs from PM01183-naïve patients (8 PARPi-resistant and 2 PARPi-sensitive), and one additional PDX implanted at PM01183 progression. Additionally, we performed exome sequencing analysis in baseline (pre-treatment, n = 5) and paired tumor biopsies (pre- and post-treatment, n = 5) from patients treated with PM01183.
PM01183 exhibited antitumor activity (partial response, complete response or stabilization) in 75% (6/8) of the PARPi-resistant PDXs. These results suggest that the mechanisms of resistance to PARPi do not confer resistance to PM01183. Exome sequencing of gBRCA PM01183-resistant tumors unveiled the presence or acquisition of genetic alterations that may disrupt the nucleotide excision repair (NER) pathway in 5 samples, which may impair sensitivity to PM01183. Conversely, these alterations confer sensitivity to cisplatin in vitro and in the clinic. Accordingly, the PDX model implanted at progression to PM01183 showed PM01183 resistance but cisplatin sensitivity. These results suggest that NER alterations potentially driving resistance to PM01183 do not compromise cisplatin efficacy.
Our results on cross-resistance in gBRCA MBC suggest that PM01183 is active in the context of PARPi resistance, and that PM01183 resistance will not interfere on platinum efficacy.
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Legal entity responsible for the study
C. Galmarini, P.M. Avilés: Empoyee at PharmaMar S.A. J. Balmaña: Non-commercial research agreement with PharmaMar S.A. All other authors have declared no conflicts of interest.