Abstract CT261: Phase II trial of nivolumab in combination with talazoparib in patients with unresectable or metastatic melanoma and mutations in BRCA or BRCA-ness
Authors: Isaacs James , Sussman Tamara A. , Kennedy Lucy B. , Arbesman Joshua , Gastman Brian , Zhou Millennia , Zabor Emily , Diaz-Montero Claudia , Ko Jennifer , Funchain Pauline 
Published: April 2024

Abstract
Novel therapies are needed for anti-PD-1 refractory metastatic melanoma. Few therapies rationally target biologically selected subpopulations of melanoma. In the Cleveland Clinic Familial Melanoma Registry, a high rate of germline mutations in proteins that regulate DNA repair were seen. PARP inhibitors can lead to synthetic lethality and clinical benefit in patients with BRCA mutations or mutations associated with DNA damage repair (“BRCAness phenotype”). Additionally, preclinical models have shown that PARP inhibitors lead to STING activation, raising the hypothesis that combination therapy with anti-PD-1 could augment immune responses. We conducted a phase II trial evaluating the combination of the PARP inhibitor talazoparib with nivolumab in patients with metastatic melanoma harboring germline or somatic DNA repair mutations. We enrolled a cohort of patients with multiple melanoma subtypes including cutaneous melanoma (3), melanoma arising from a blue nevus (2) and uveal melanoma (2). Mutant DNA repair genes included BAP1 (4), BRCA2 (1), ATM (1), ATR (1) and ARID2 (1), 3 of which were germline. The patient population had highly refractory disease with 6 of 7 patients having progression after ipilimumab + nivolumab (5 of these were primary progression). The 7th patient had a recurrence after adjuvant nivolumab. Of the 7 patients enrolled, all progressed within 6 months (using RECIST and iRECIST criteria).The toxicity profile was consistent with known profile of PARP inhibitors (anemia). Although patient enrollment was limited, this study suggests that in heavily pretreated patients selected for DNA repair mutations the combination of PARP inhibitors and anti-PD-1 has no effect on RECIST-based tumor response. Additional studies are needed. Possible alternative selection strategies include evaluating for genomic evidence of homologous recombination repair deficiency (HRD) or targeting specific mutations (BRCA).

TABLE 1: NAND Patient Characteristics and Treatment Outcome Age Subtype of Melanoma Gene Alteration Somatic or Germline TMB BRAF Status Prior Therapy Status of Prior IO response Clinical Trial Response 76 Cutaneous ATM Germline N/A WT Nivolumab Progression after Adjuvant Progression 32 Cutaneous ATR Somatic 4.2 V600E Ipilimumab + Nivolumab Primary Progression Progression 75 Uveal BRCA2 and BAP1 Germline 1.3 WT Ipilimumab + Nivolumab Primary Progression Progression 45 Cutaneous/Blue Nevus BAP1 Somatic 0.0 WT Ipilimumab + Nivolumab Primary Progression Progression 51 Cutaneous/Blue Nevus BAP1 Germline 1.6 WT Ipilimumab + Nivolumab Primary Progression Progression 69 Uveal BAP1 Somatic 1.6 WT Pembrolizumab Primary Progression Progression 61 Cutaneous ARID2 Somatic 17.9 WT Ipilimumab + Nivolumab Secondary Resistance Progression
Citation Format: James Isaacs, Tamara A. Sussman, Lucy B. Kennedy, Joshua Arbesman, Brian Gastman, Millennia Zhou, Emily Zabor, Claudia Diaz-Montero, Jennifer Ko, Pauline Funchain. Phase II trial of nivolumab in combination with talazoparib in patients with unresectable or metastatic melanoma and mutations in BRCA or BRCA-ness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT261.