LODESTAR: A Single-Arm Phase II Study of Rucaparib in Solid Tumors With Pathogenic Germline or Somatic Variants in Homologous Recombination Repair Genes.

Abstract

To explore poly (ADP-ribose) polymerase inhibitor utility across solid tumors and identify biomarkers that predict sensitivity. This single-arm phase II study assessed rucaparib monotherapy in patients with solid tumors and pathogenic variants (PVs) in <i>BRCA1</i>, <i>BRCA2</i>, <i>PALB2</i>, <i>RAD51C</i>, and <i>RAD51D</i> (cohort A) or <i>BARD1</i>, <i>BRIP1</i>, <i>FANCA</i>, <i>NBN</i>, and <i>RAD51B</i> (cohort B). The primary end point was overall response rate (ORR) in cohort A. Secondary end points included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. A scar-based homologous recombination deficiency signature (HRDsig) and platinum sensitivity status were explored post hoc. Fifty-one patients in cohort A and 12 in cohort B were evaluable for efficacy. ORR of cohort A was 18% (95% CI, 10 to 30). A significantly higher ORR was observed with HRDsig+ tumors compared with HRDsig- tumors (32%; 95% CI, 15 to 54 <i>v</i> 0%; 95% CI, 0 to 14; <i>P</i> < .01). In the entire study population, DCR was 65% (95% CI, 53 to 76), median PFS (mPFS) 5.5 months (95% CI, 3.68 to 7.82), and median OS 12.1 months (95% CI, 10.6 to inferred). PFS and hazard of death from any cause was significantly better for platinum-sensitive tumors (mPFS: 7.8 months <i>v</i> 3.5 months; <i>P</i> = .02; hazard ratio, 0.11 [95% CI, 0.02 to 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 noncanonical tumors with <i>BRCA</i> PVs, 30.2% were HRDsig+. Rucaparib has activity in HRDsig+ solid tumors with PVs in homologous recombination repair genes, regardless of histology. Platinum sensitivity correlated with improved outcomes.