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Ref Type Journal Article
PMID (40632975)
Authors Anbil S, Seewald NJ, Chiorean EG, Hussein M, Kasi PM, Laux DE, Schwartz GK, Shapiro GI, Lin KK, Craib M, Maloney L, McLachlan K, Tukachinsky H, Schrock AB, Wang S, Sokol ES, Decker B, Nathanson KL, Domchek SM, Reiss KA
Title LODESTAR: A Single-Arm Phase II Study of Rucaparib in Solid Tumors With Pathogenic Germline or Somatic Variants in Homologous Recombination Repair Genes.
Journal Vol Issue Date Pages Journal Short Title
JCO precision oncology 9 2025 Jul e2500090 JCO Precis Oncol
URL
Abstract Text 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 BRCA1, BRCA2, PALB2, RAD51C, and RAD51D (cohort A) or BARD1, BRIP1, FANCA, NBN, and RAD51B (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 v 0%; 95% CI, 0 to 14; P < .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 v 3.5 months; P = .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 BRCA 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PALB2 inact mut Advanced Solid Tumor sensitive Rucaparib Phase II Actionable In a Phase II trial (LODESTAR), Rubraca (rucaparib) treatment led to an overall response rate of 18% (9/51, 1 complete, 8 partial responses), a disease control rate of 63% (32/51), median progression-free survival of 5.52 months, and overall survival of 13.63 months in advanced solid tumor patients harboring pathogenic BRCA1 (n=17), BRCA2 (n=27) PALB2 (n=14), RAD51C (n=1), and RAD51D (n=2) mutations (PMID: 40632975; NCT04171700). 40632975