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Clinical Trial
. 2025 Jun 1;5(6):939-944.
doi: 10.1158/2767-9764.CRC-25-0192.

Phase II Study Evaluating the Efficacy of Niraparib and Dostarlimab (TSR-042) in Patients with Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma

Olga Zamulko  1 , Vidhya Karivedu  2 , Muhammad Kashif Riaz  3 , Ilaina Monroe  4 , Audrey Romano  4 , Rachel Mulanda  4 , Nicky Kurtzweil  4 , Allie Forsythe  4 , Casey L Allen  4 , Nusrat Harun  5 , Jianmin Pan  6   7   8 , Shesh Rai  6   7   8 , Dalia El-Gamal  1 , Trisha M Wise-Draper  1
Affiliations
Clinical Trial

Phase II Study Evaluating the Efficacy of Niraparib and Dostarlimab (TSR-042) in Patients with Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma

Olga Zamulko et al. Cancer Res Commun. .

Abstract

Purpose: Recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) portends a poor prognosis. DNA pathway repair mutations in HNSCC are associated with higher tumor mutational burden rates and immune checkpoint inhibitor response. PARP inhibitors (PARPi) induce ssDNA breaks and are efficacious in cancers with DNA repair defects. Thus, we designed a single-arm, open-label, phase II clinical trial to evaluate the combination of niraparib and dostarlimab in patients with R/M HNSCC.

Patients and methods: Patients with R/M HNSCC were treated with niraparib and dostarlimab until disease progression or unacceptable toxicity. The primary endpoint was the overall response rate and clinical benefit assessed by RECIST version 1.1. Using Simon's two-step minimax design, 14 patients were planned to enroll in the first stage with a goal of overall clinical benefit of 50%.

Results: Ten patients were enrolled. The majority were White males with a median age of 62.5. One patient had a PD-L1 combined positive score >20, a high tumor mutational burden, a BRCA1 rearrangement, and an ATRX splice site mutation. Nine patients previously failed anti-PD-1/PD-L1 therapy. The best overall response rate was 10%, with a 20% clinical benefit (1 partial response, 1 stable disease). The trial was terminated early for futility as the goal clinical benefit could not be reached. At a median follow-up of 10.13 months, the median progression-free survival was 3.8 months, and the median overall survival was 10.1 months. The most common grade 3 or higher treatment-related adverse events were thrombocytopenia and hypertension.

Conclusions: The combination of niraparib and dostarlimab did not achieve the primary endpoint of clinical benefit, but activity may be improved with biomarker-driven treatment and selected patients.

Significance: Patients with R/M HNSCC that progress on PD-1 inhibitors have poor prognoses. PARPis cause ssDNA breaks that accumulate in cells with mutations in DNA damage repair pathways, leading to synthetic lethality. However, PARPi also inhibits glycogen synthase kinase-3β activity, leading to upregulated PD-L1, which is abrogated by PD-1 inhibitors. In this study, we combine niraparib (PARPi) with dostarlimab (anti-PD-L1) to evaluate clinical benefit in patients with R/M HNSCC.

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Conflict of interest statement

O. Zamulko reports grants from GSK during the conduct of the study as well as other from Pfizer outside the submitted work. V. Karivedu reports a patent number 20240148725 pending. D. El-Gamal reports grants from AbbVie, the Nebraska Department of Health & Human Services Cancer and Smoking Disease Research Program, the Great Plains IDeA-CTR Network, and the American Cancer Society (ACS-IRG) and nonfinancial support from Opna Bio LLC outside the submitted work. T.M. Wise-Draper reports grants from GSK during the conduct of the study as well as grants and personal fees from Merck & Co; grants from Bristol Myers Squibb, Janssen, and AstraZeneca/MedImmune; and personal fees from EMD Serono, Adaptimmune, Replimune, Need Inc, High Enroll, and Caris Life Sciences outside the submitted work. No disclosures were reported by the other authors.

Figures

Figure 1
Figure 1
Grade 3 or higher treatment-related AEs. Thrombocytopenia and hypertension were the most common. One grade 4 event of thrombocytopenia occurred. There were no grade 5 treatment-related AEs.
Figure 2
Figure 2
Kaplan–Meier survival curves. A, Median PFS was 3.8 months. B, Median OS was 10.1 months.
See this image and copyright information in PMC

References

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