LODESTAR: A single arm phase II study of rucaparib in solid tumors with pathogenic germline or somatic variants in homologous recombination repair genes

Abstract

Purpose: To explore PARP inhibitor (PARPi) utility across solid tumors and identify biomarkers that predict sensitivity.

Patients and Methods: This single-arm phase II study assessed rucaparib monotherapy in patients with solid tumors and pathogenic variants (PVs) in BRCA1, BRCA2, PALB2, RAD51C, RAD51D (Cohort A) or BARD1, BRIP1, FANCA, NBN, RAD51B (Cohort B). The primary endpoint was ORR in Cohort A. Secondary endpoints included DCR, PFS, OS and safety. A scar-based HRD signature (HRDsig) and platinum sensitivity status were explored post-hoc.

Results: Fifty-one patients in Cohort A and 12 in Cohort B were evaluable for efficacy. ORR of cohort A was 18% (95% CI 10-30%). A significantly higher ORR was observed with HRDsig+ tumors compared to HRDsig- tumors (32%, 95% CI 15-54, vs. 0%, 95% CI 0-14%, p < 0.01). In the entire study population: DCR of 65% (95% CI 53-76%), mPFS of 5.5 mo (95% CI 3.68-7.82), and mOS of 12.1 mo (95% CI 10.6 – inf). PFS and hazard of death from any cause was significantly better for platinum sensitive tumors (mPFS: 7.8 mo vs. 3.5 mo, p = 0.02; hazard ratio 0.11 (0.02 – 0.55)). Tumor histology was not independently predictive of outcome. Tumors with PVs in Cohort A genes were more likely to be HRDsig+ than tumors with PVs in Cohort B genes. Analysis of a large commercial database showed that in non-canonical tumors with BRCA PVs, 30.2% were HRDsig+.

Conclusion: Rucaparib has activity in HRDsig+ solid tumors with PVs in HRR genes, regardless of histology. Platinum sensitivity correlated with improved outcomes.

Nicholas J. Seewald

Assistant Professor of Biostatistics

Assistant Professor of Biostatistics at the University of Pennsyvlania Perelman School of Medicine