Data from BrUOG360: A Phase Ib/II Study of Copanlisib in Combination with Rucaparib in Patients with Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Abstract

<div>AbstractPurpose:<p>Metastatic castration-resistant prostate cancer with homologous recombination (HR) deficiency (HRD) is sensitive to PARP inhibitors (PARPi). PI3K inhibitors (PI3Ki) sensitize to PARPi by disrupting HR in preclinical models. This phase Ib/II study investigated copanlisib (Copa; pan–class I PI3Ki) and rucaparib (R).</p>Patients and Methods:<p>Eligible patients had metastatic castration-resistant prostate cancer treated with ≥1 androgen receptor inhibitor and taxanes. Phase I followed a standard 3 + 3 dose-escalation design (rucaparib 400–600 mg orally twice a day; Copa 45–60 mg i.v. on days 1, 8, and 15). Primary goal of phase I was to establish MTD and the recommended phase II dose. The primary endpoint of phase II was PSA50 response rate.</p>Results:<p>Thirteen patients enrolled had a median age of 64 (55–78) years and PSA was 11.7 ng/mL (0.018–2,101). Seven patients received taxanes, and one patient received PARPi. Eight patients had HRD+ tumors [<i>BRCA2</i> (four), <i>BRCA1</i> (one), <i>RAD51C</i> (one), <i>CDK12</i> (one), and <i>FANCA</i> (one)] and three had <i>PTEN</i> loss. There were two dose-limiting toxicities in dose level 1 (rucaparib 400 mg twice a day; Copa 45 mg on days 1, 8, and 15): grade 3 rash and aspartate aminotransferase/alanine aminotransferase elevation. Treatment-related adverse events ≥ grade 2 included leukopenia (54%), anemia (38%), rash (30%), fatigue (23%), and neutropenia (23%). Six patients were treated at dose level –1 without dose-limiting toxicities, which was established as the recommended phase II dose (rucaparib 400 mg twice a day + Copa 45 mg on day 1/15). Among patients with HRD+, one had confirmed partial response and three had stable disease by RECIST, including one patient treated with prior PARPi, and three patients had PSA50 responses (23%).</p>Conclusions:<p>Copa/R had an acceptable safety profile with a signal of efficacy supporting future studies of PARPi with PI3Ki.</p>Significance:<p>Gene alterations in the PI3K and HR pathways are common in prostate cancer. Based on preclinical studies, the inhibition of PI3K disrupts HR, and PARP blockade induces AKT activation, supporting the combination of PI3Ki and PARPi. Herein, we investigated the safety and preliminary efficacy of the PI3Ki copanlisib and the PARPi rucaparib in patients with or without alterations in HR repair pathway genes.</p></div>

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