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Purpose: Despite promising preclinical studies, toxicities have precluded combinations of chemotherapy and DNA damage response (DDR) inhibitors. We hypothesized that tumor-targeted chemotherapy delivery might enable clinical translation of such combinations. Patients and Methods: In a phase I trial, we combined sacituzumab govitecan, antibody–drug conjugate (ADC) that delivers topoisomerase-1 inhibitor SN-38 to tumors expressing Trop-2, with ataxia telangiectasia and Rad3-related (ATR) inhibitor berzosertib. Twelve patients were enrolled across three dose levels. Results: Treatment was well tolerated, with improved safety over conventional chemotherapy-based combinations, allowing escalation to the highest dose. No dose-limiting toxicities or clinically relevant ≥grade 4 adverse events occurred. Tumor regressions were observed in 2 patients with neuroendocrine prostate cancer, and a patient with small cell lung cancer transformed from EGFR-mutant non–small cell lung cancer. Conclusions: ADC-based delivery of cytotoxic payloads represents a new paradigm to increase efficacy of DDR inhibitors.

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Pharmacokinetic assessment

Trial protocol dose limiting toxicity criteria

Purpose:Despite promising preclinical studies, toxicities have precluded combinations of chemotherapy and DNA damage response (DDR) inhibitors. We hypothesized that tumor-targeted chemotherapy delivery might enable clinical translation of such combinations.Patients and Methods:In a phase I trial, we combined sacituzumab govitecan, antibody–drug conjugate (ADC) that delivers topoisomerase-1 inhibitor SN-38 to tumors expressing Trop-2, with ataxia telangiectasia and Rad3-related (ATR) inhibitor berzosertib. Twelve patients were enrolled across three dose levels.Results:Treatment was well tolerated, with improved safety over conventional chemotherapy-based combinations, allowing escalation to the highest dose. No dose-limiting toxicities or clinically relevant ≥grade 4 adverse events occurred. Tumor regressions were observed in 2 patients with neuroendocrine prostate cancer, and a patient with small cell lung cancer transformed from EGFR-mutant non–small cell lung cancer.Conclusions:ADC-based delivery of cytotoxic payloads represents a new paradigm to increase efficacy of DDR inhibitors.

Rif1 plays important roles in the repair of DNA double-strand breaks in multiple organisms. In mammals, RIF1 promotes non-homologous end joining and suppresses homologous recombination by interacting with 53BP1 to inhibit resection. In Saccharomyces cerevisiae, Rif1 directly binds DNA to inhibit resection and promote non-homologous end-joining. Yeast Rif1 can also facilitate long-range resection and promote single-strand annealing. Since it is not clear if Rif1 regulates resection-mediated pathway choice in other eukaryotes, we explored the role of Rif1 in double-strand break repair in Drosophila melanogaster. We found that rif1 mutants are not sensitive to ionizing radiation or hydroxyurea, demonstrating that it is not essential for the resolution of DNA damage in Drosophila. However, we show that rif1 null mutants are largely unable to repair a specific type of double-strand break that is induced upon the excision of a P-element transposon. Furthermore, assessment of repair pathway choice at I-SceI-induced breaks revealed Rif1 suppresses homologous recombination and promotes single-strand annealing. Collectively, our findings illustrate Drosophila Rif1 shares functions with both its yeast and mammalian counterparts and serves a unique role in repairing P-element-induced double-strand breaks.