A phase II trial of olaparib in combination with pembrolizumab in metastatic uveal melanoma.

Abstract

9553 Background: Metastatic uveal melanoma (mUM) has a poor prognosis with modest response to immune checkpoint blockade (ICB). Inactivating mutations in BRCA-1 associated protein 1 ( BAP1 ) are common in mUM leading to deficient homologous recombinant DNA repair and increasing reliance on alternate repair pathways, including poly[ADP-ribose] polymerase (PARP). We investigated if the PARP inhibitor olaparib could improve objective response to pembrolizumab (PEM) in mUM (NCT05524935). Methods: Key eligibility included mUM with measurable disease, ECOG 0-1, and adequate organ function. Prior liver directed therapy was allowed. Patients (pts) received PEM 200mg IV every 21 days plus oral olaparib 300mg BID till progression, toxicity, or completion of 2 years of treatment. In a Simon 2-stage optimal design, > 1 response by RECIST 1.1 in 12 evaluable patients would permit accrual to expand to 37 pts. Results: Twelve eligible mUM pts, 6 male and 6 female, median age 59 years (42, 84) were treated in stage 1 of this trial. Most pts (11/12; 92%) had both liver and extra-hepatic metastatic disease; 5 pts had elevated serum LDH at baseline. Seven pts (58%) were naïve to prior systemic therapy; 4 had prior liver directed therapy. There was no objective response observed; best response was stable disease (SD, n=5), remainder (n=7) with progression; disease-control rate was 42%. One patient continues treatment at 13 months with ongoing SD. Of 4 pts who received prior tebentafusp, three had SD lasting greater than 6 months. At median follow-up of 13 months, the median progression-free survival (PFS) was 3.6 months (95% CI: 2.2, 8.3), and median overall survival (OS) was 13.8 months (95% CI: 2.5, 24.3). Six-month PFS and OS were 0.42 (95% CI: 0.15, 0.67) and 0.83 (95% CI: 0.48, 0.96) respectively; one year OS was 0.73 (95% CI: 0.37, 0.91). Most common (≥ 25%) all grade treatment related adverse events (AEs) were fatigue, arthralgia, diarrhea, nausea/vomiting, dyspnea, anemia, abdominal pain, bloating, anorexia, muscle weakness, pruritus, rash, vitiligo, dyspnea, cough, hypertension, muscle weakness, ↑ AST, ↑ alkaline phosphatase, ↓ lymphocyte count, ↑ glucose, ↑ potassium and ↓ albumin. Grade 3 AEs were infrequent; nausea, anorexia, dehydration, hypotension, and muscle weakness (all n=1); there was no treatment related death. 5/12 (42%) pts required a dose reduction for olaparib. Conclusions: The addition of olaparib to pembrolizumab was well tolerated but did not result in any objective response in molecularly unselected mUM. Landmark survival results appear clinically meaningful and likely related to disease control with stable metastatic burden. Ongoing biomarker studies of tumor tissue (BAP1, PD-L1, PARP1, TIL) and blood may help discern which patients could benefit from this combination regimen. Optimal sequencing of ICB with tebentafusp in HLA-A*02:01+ mUM should be explored further. Supported by Merck, Inc. Clinical trial information: NCT05524935 .