Abstract C006: LODESTAR: A Single Arm Phase II Study of Rucaparib in Solid Tumors with Pathogenic Germline or Somatic Variants in Homologous Recombination Repair (HRR) Genes
Authors: Anbil Sriram , Seewald Nicholas J , Lin Kevin , Craib Marcia , Connor Christy , Giordano Heidi , McLachlan Karen , Kwan Tanya , Maloney Lara , Tukachinsky Hanna , Schrock Alexa , Wang Shuoguo , Sokol Ethan , Decker Brennan , Nathanson Katherine , Domchek Susan , Reiss Kim 
Published: September 2024

Abstract
Purpose: Poly (ADP-ribose) polymerase inhibitors (PARPi) have proven clinical utility in platinum-sensitive breast, ovary, pancreas, and prostate cancers with homologous recombination deficiency (HRD). We explored whether PARPi might be efficacious in other solid tumors and for a broader range of genomic variants. Patients and Methods: This single-arm phase II study assessed rucaparib monotherapy in patients with advanced, platinum-sensitive or -resistant 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 overall response rate (ORR) in cohort A. Secondary endpoints included disease control rate (DCR), progression free survival (PFS), overall survival (OS) and safety[SS3] [SA4] in the entire study population. Available tumors were analyzed for pre-specified exploratory objective of allele specific loss of heterozygosity (LOH). [SA7] HRD signature (HRDsig) and platinum sensitivity status were explored as biomarkers for rucaparib activity in post hoc exploratory analyses. The study was terminated early by the sponsor due to feasibility concerns. Results: Eighty-three patients were enrolled (Cohort A: 63; Cohort B: 20). Fifty-seven patients in Cohort A and 16 in Cohort B were evaluable for efficacy analysis. The[LM8] [SA9] ORR of cohort A was 16% (95% CI 9-27%) and DCR was 61% (95% CI 48-73%). LOH and HRDsig were available for 48% of Cohort A and 71% of Cohort B. Of 11 patients who had a response to treatment, 6 tumors were HRDsig+, 1 HRDsig-and 4 were unknown. The ORR and DCR were significantly greater in patients with HRDsig+ vs HRDsig-tumors (ORR: HRDsig+ 32% [95% CI 15-54%] vs HRDsig-3% [95% CI 0-15%], p &lt; 0.01; DCR: HRDsig+ 74% [95% CI 51-88%] vs HRDsig-38% [95% CI 24-55%], p = 0.02). mPFS was numerically longer for HRDsig+ vs HRDsig-: 7.0 mos (95% CI, 4.3 – inf), vs. 3.0 mos (95% CI 2.3-5.6), HR 0.57, p = 0.14. mPFS was greater for platinum sensitive vs resistant tumors (7.82 mos [95% CI 5.5-inf] vs. 2.9 mos [95% CI 1.8-inf], HR 0.28, p = 0.02); Neither tumor tissue of origin nor specific mutation was independently predictive of outcome. The HR for progression in tumors that were both HRDsig+ and platinum sensitive versus those that were HRDsig-and platinum resistant was 0.09 (95% CI 0.01-0.55, p = 0.047). The Rucaparib safety profile was consistent with prior studies. Conclusion: Rucaparib has activity across solid tumors with PVs in HRR genes, regardless of tissue of origin. Patients with platinum resistant or HRDsig-tumors had limited clinical benefit from rucaparib. The combined use of HRDsig and platinum sensitivity to predict sensitivity to PARPi is encouraging as a biomarker strategy and warrants prospective study.
Citation Format: Sriram Anbil, Nicholas J Seewald, Kevin Lin, Marcia Craib, Christy Connor, Heidi Giordano, Karen McLachlan, Tanya Kwan, Lara Maloney, Hanna Tukachinsky, Alexa Schrock, Shuoguo Wang, Ethan Sokol, Brennan Decker, Katherine Nathanson, Susan Domchek, Kim Reiss. LODESTAR: A Single Arm Phase II Study of Rucaparib in Solid Tumors with Pathogenic Germline or Somatic Variants in Homologous Recombination Repair (HRR) Genes [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C006.