A phase II clinical trial evaluating the combination of niraparib and dostarlimab in patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) was terminated early after failing to meet its primary efficacy endpoint. The single-arm, open-label study achieved only 20% clinical benefit, falling short of the target 50% threshold required for continuation.
Trial Design and Patient Population
The study employed Simon's two-step minimax design, initially planning to enroll 14 patients in the first stage. However, only 10 patients were enrolled before early termination. The patient population consisted primarily of White males with a median age of 62.5 years, representing a challenging treatment scenario as nine patients had previously failed anti-PD-1/PD-L1 therapy.
Patients received niraparib and dostarlimab until disease progression or unacceptable toxicity occurred. The primary endpoint focused on overall response rate and clinical benefit as assessed by RECIST version 1.1 criteria.
Limited Efficacy Results
The combination therapy demonstrated modest activity with a best overall response rate of 10% and clinical benefit rate of 20%, consisting of one partial response and one stable disease. At a median follow-up of 10.13 months, the median progression-free survival reached 3.8 months, while median overall survival was 10.1 months.
One patient presented with particularly notable biomarkers, including a PD-L1 combined positive score greater than 20, high tumor mutational burden, a BRCA1 rearrangement, and an ATRX splice site mutation, suggesting potential for biomarker-driven patient selection.
Safety Profile
The most common grade 3 or higher treatment-related adverse events were thrombocytopenia and hypertension. The safety profile appeared manageable, with no unexpected toxicities reported from the combination approach.
Scientific Rationale and Future Directions
The study was based on the understanding that DNA pathway repair mutations in HNSCC are associated with higher tumor mutational burden rates and immune checkpoint inhibitor response. PARP inhibitors induce single-strand DNA breaks and demonstrate efficacy in cancers with DNA repair defects through synthetic lethality mechanisms.
Additionally, PARP inhibitors inhibit glycogen synthase kinase-3β activity, leading to upregulated PD-L1 expression, which can be counteracted by PD-1 inhibitors. This biological rationale supported combining niraparib with dostarlimab, an anti-PD-L1 antibody.
Despite the trial's early termination for futility, researchers noted that activity may be improved with biomarker-driven treatment selection in carefully chosen patients. The poor prognosis of patients with R/M HNSCC who progress on PD-1 inhibitors underscores the continued need for novel therapeutic approaches in this challenging patient population.
