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5052 Background: Genes involved in homologous recombination DNA repair (HR) are inactivated in ~25% of patients with metastatic castration-resistant prostate cancer (mCRPC). Inactivation of HR has been associated with sensitivity to DNA damage by platinum chemotherapy and PARP inhibitors (PARPi). While both drug classes have shown efficacy, resistance and/or cumulative dose-limiting toxicities are inevitably observed. Here, we report results from a single-center phase 2 study investigating whether induction chemotherapy (IC) with docetaxel and carboplatin followed by maintenance PARPi would provide prolonged disease control. Methods: Patients with mCRPC tumors harboring a pathogenic alteration in an HR gene, who had received prior taxane and/or androgen receptor pathway inhibitor (ARPI), but not prior PARPi were eligible. Patients received IC with 4 cycles of docetaxel 60mg/m 2 with carboplatin AUC 5 IV q21 days, followed by the PARPi rucaparib 600mg BID continuously as maintenance therapy until disease progression or unacceptable toxicity. The primary endpoint was clinical/radiographic progression free survival (PFS) compared to a historical control of 9.1 months with PARPi alone without prior platinum. 20 patients provided ~90% power to determine whether this treatment lowered risk of progression with a hazard ratio of 0.5 (implying PFS of 18.2 months), based on a 1-sided 1-sample log-rank test. Secondary endpoints included PSA 50 response rate, safety, and overall survival. Post-hoc subgroup analysis was performed for the BRCA complex group (alterations in BRCA1, BRCA2, and PALB2) and for those refractory to IC. Results: 18 patients were enrolled between 2018 and 2021. Under-enrollment occurred due to loss of manufacturer support for rucaparib prior to study completion. 11/18 (61%) of patients had ≥2 prior ARPI, and 9/18 (50%) had previously received docetaxel. HR genes included on study were ATM (7), BRCA1 (3), BRCA2 (8), PALB2 (1), FANCA (1) and CHD1/ SPOP (1) with three tumors harboring two alterations. Clinical outcomes for the overall cohort and key sub-groups are reported in the table. 6/18 (33%) patients experienced grade ≥3 adverse events, including one patient with grade 4 thrombocytopenia. Conclusions: IC followed by maintenance rucaparib did not significantly increase PFS in patients with HR alterations compared to historical control. Results were more encouraging in the BRCA complex group. IC refractory patients were not rescued by subsequent PARPi, suggesting overlapping mechanisms of resistance when platinum is used prior to PARPi. Clinical trial information: NCT03442556 . Table: see text
Raychaudhuri et al. (Sat,) studied this question.