A phase 1 study of PARP inhibitor (niraparib) plus HSP90 inhibitor (pimitespib) in solid tumors: Dose-expansion results from the NiraPim (EPOC2102) study.

Abstract

3079 Background: Heat shock protein 90 (HSP90) inhibitors have shown potential in destabilizing homologous recombination repair (HRR) proteins, thereby inducing homologous recombination deficiency and enhancing PARP inhibitor efficacy. The NiraPim (EPOC2102) study is a phase 1 study to evaluate this combination therapy in humans, investigating the safety and efficacy of combining niraparib, a PARP inhibitor, with pimitespib, a novel HSP90 inhibitor, in patients with advanced solid tumors. Following establishing the recommended dose (RD) in the dose-escalation part, we present primary analysis results from the dose-expansion part. Methods: In the dose-expansion part, patients received pimitespib 80 mg (5-day on/2-day off) combined with niraparib 200 mg daily. Cohort A included patients with BRCA-associated cancers (breast, ovarian, prostate, and pancreatic) harboring BRCA pathogenic variants and immediately after progression to prior PARP inhibitors. Cohort B included patients with breast/pancreatic cancer without g BRCA, prostate cancer without t BRCA , and other solid tumors (excluding ovarian cancer) not previously treated with PARP inhibitors. Results: As of August 2024, 30 patients were enrolled: 14 in cohort A and 16 in cohort B. Cohort A included breast (n=6), ovarian (n=5), prostate (n=2), and pancreatic (n=1) cancers. Cohort B included breast (n=3), prostate (n=4), pancreatic (n=4), and other tumors (n=5). The median follow-up period was 6.0 months. The median treatment cycle was 2 (range 1–18). Treatment-related adverse events ≥Grade 3 occurred in 33.3%. Common adverse events (≥20.0%) included nausea (73.3%), diarrhea (40.0%), anorexia (23.3%), vomiting (20.0%), fatigue (20.0%), and decreased platelet count (20.0%). No treatment-related deaths occurred during the study period. The objective response rate was 10.0% (95% CI: 2.1, 26.5), with disease control rate of 36.7% (19.9, 56.1) and 3-month PFS of 27.7%. In cohort A, one patient with hormone receptor-positive breast cancer achieved partial response post-olaparib progression. In cohort B, two patients (leiomyosarcoma and urothelial carcinoma) with BRCA pathogenic variants achieved partial response, and one prostate cancer patient with CDK12 pathogenic variant maintained stable disease ≥3 months. Conclusions: The dose-expansion part demonstrated a manageable safety profile and potential efficacy at the recommended dose of niraparib plus pimitespib. Clinical benefit was observed in both BRCA-associated cancers resistant to PARP inhibitors and PARP inhibitor-naive non-BRCA associated cancers, supporting further investigation in biomarker-selected populations. Clinical trial information: jRCT2031220179 .