Final results of a pilot study of docetaxel and carboplatin for treatment of patients with mCRPC containing biallelic inactivation of genes in the homologous recombination DNA repair pathway.

person Ruben Raychaudhuri Fred Hutchinson Cancer Center, Seattle, WA info_outline Ruben Raychaudhuri, Makayla DeJong, Evan Y. Yu, Roman Gulati, Matthew Rettig, Peter Nelson, Colin C. Pritchard, Robert Bruce Montgomery, Heather H. Cheng

Authors person Ruben Raychaudhuri Fred Hutchinson Cancer Center, Seattle, WA info_outline Ruben Raychaudhuri, Makayla DeJong, Evan Y. Yu, Roman Gulati, Matthew Rettig, Peter Nelson, Colin C. Pritchard, Robert Bruce Montgomery, Heather H. Cheng Organizations Fred Hutchinson Cancer Center, Seattle, WA, University of Washington, Seattle, WA, UCLA's Jonsson Comprehensive Cancer Center, West Los Angeles VA Medical Center, Los Angeles, CA, Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA Abstract Disclosures Research Funding Other Foundation Prostate Cancer Foundation and the Institute for Prostate Cancer Research, U.S. National Institutes of Health Background: Inactivating mutations in genes important in homologous recombination DNA repair (HRD) are present in the tumors of ~25% of patients with metastatic castration resistant prostate cancer (mCRPC). These alterations are associated with more aggressive disease but may also predict vulnerability to DNA damaging agents. We previously reported promising interim results from a single arm, Phase 1/2 trial studying the combination of the DNA damaging agent carboplatin with docetaxel for patients with mCRPC containing HRD mutations. Here we report final results after completing accrual and two additional years of follow up. Methods: We assessed response to the combination of docetaxel 60mg/m 2 and carboplatin AUC 5 IV q21 days in patients with mCRPC whose tumors had evidence of biallelic inactivation of genes involved in HRD and who had progressed on any prior treatment, including docetaxel and/or PARP inhibitor (PARPi). The primary endpoint was the proportion of patients who achieved ≥50% PSA decline from baseline (PSA 50 ). With H0 of PSA 50 of 26%, 14 patients provided 80% power to conclude H1 of PSA 50 of 60% based on Simon's 2-stage design with 1-sided α = 5%. The secondary endpoints included PSA 30 , response duration, progression-free survival (PFS), and overall survival (OS). Results: The trial opened in Jan 2016 and completed in Sep 2021. A total of 16 patients were treated on study, including 6 who had previously received PARPi and 5 who had received docetaxel. 11/16 patients (69%) achieved PSA 50 . 7/9 patients (78%) with biallelic inactivation of BRCA2 (7), BRCA1 (1), or PALB2 (1) achieved PSA 50 . Other biallelic inactivated HRD-related genes were ATM (1), CHD1 (1), CDK12 (3), MRE11A (1), and NBN (1). Of these patients, 4/7 (57%) achieved PSA 50 . Notably, 3/6 patients (50%) previously treated with PARPi therapy achieved PSA 50 . The median PFS was 8.4 months, and the median OS was 2 years. 6/16 patients (38%) had grade 3 AEs, most commonly thrombocytopenia (25%) and anemia (13%). One patient (6%) had a grade 4 AE (thrombocytopenia). Conclusions: The addition of carboplatin to docetaxel significantly improved response rates in patients with mCRPC with biallelic inactivation in genes involved in the HRD pathway. Responses were also seen in patients who had previously received PARPi. The combination was relatively safe and well-tolerated. The encouraging activity and favorable toxicity profile observed here merits further investigation. Additional work is ongoing to further refine biomarkers predictive of treatment response and resistance. Clinical trial information: NCT02598895.

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