KEY TAKEAWAYS
- The phase 2 trial aimed to assess the superior ORR of olaparib, pembrolizumab, and carboplatin in RM-HNSCC compared to the standard 5-FU.
- The primary endpoint was to determine ORR.
- Researchers observed favorable outcomes supporting the primary hypothesis in managing RM-HNSCC patients; further investigation is ongoing.
Jessica Ley and his team aimed to focus on the common occurrence of the homologous recombination deficiency (HRD) phenotype in head and neck squamous-cell carcinoma (HNSCC), attributed to genetic mutations, promoter hypermethylation of DNA repair genes, and PTEN alterations.
Pre-clinical models reveal HRD’s role in sensitizing tumors to PARP inhibition, with additive antitumor effects in combination with platinum agents. PARP inhibitors activate the STING pathway and upregulate PD-L1 expression, demonstrating synergistic antitumor activity when combined with PD-1 inhibitors.
Olaparib, a highly selective PARP inhibitor, has shown safety in combination with pembrolizumab and carboplatin. The primary hypothesis posited that first-line treatment with olaparib, pembrolizumab, and carboplatin would result in a higher objective response rate (ORR) compared to historical reports of 5-fluorouracil (5-FU), pembrolizumab, and a platinum agent.
They performed an inclusive analysis on untreated recurrent or metastatic (RM) HNSCC patients with suitable performance status and organ function. The treatment regimen consisted of up to six 21-day cycles of olaparib (200 mg bid orally days 1-10), pembrolizumab (200 mg IV day 1), and carboplatin (AUC 5 IV day 1). Subsequently, patients received up to twenty-nine 21-day cycles of olaparib (300 mg bid orally days 1-21) and pembrolizumab (200 mg day 1) or until discontinuation criteria were met. The primary endpoint, objective response, was evaluated by an independent radiologist using iRECIST criteria.
Utilizing a Simon optimal two-stage design, researchers tested the null hypothesis(H0:ORR<36%) against the alternative hypothesis (H1: ORR=62%) with a type I error rate of 10% and 90% power. The initial stage involved accruing up to 13 patients, with an additional 16 patients if >6 responses occurred. The rejection of H0 required observing >14 responses in these 29 patients. An interim analysis after the first stage assessed olaparib delivery during cycles 1 and 2, aiming for 100% delivery in ≥ 80% of patients.
About 29 enrolled patients in the trial exhibited key characteristics such as a median age of 65 years (range 38-83), a tobacco history of 54%, and primary site distribution of (oropharynx 50%, oral cavity 36%, and larynx 14%). HPV status was (positive in 46% and negative in 54%), while PD-L1 CPS status distribution was (0: 4%, 1-19: 29%, >20: 64%, and unknown: 3%). Of the enrolled patients, 28 were evaluable for response. Tumor response was observed in 14 patients, with 13 confirmations on subsequent imaging. Best tumor response included complete response (CR) in 3 patients, partial response (PR) in 11, stable disease (SD) in 10, and progressive disease (PD) in 4. The overall response rate (ORR) was 50.0% (95%CI 30.7-69.4%). Olaparib delivery during cycles 1 and 2 achieved 100% for all patients in the first stage of the trial. Notably, no unexpected safety concerns were reported.
The study concluded that the primary hypothesis was met, affirming the efficacy of the investigated treatment combination. This success suggests the need for further studies to explore and validate the potential of this therapeutic approach.
The study is sponsored by Washington University School of Medicine
Clinical Trial: https://clinicaltrials.gov/study/NCT04643379
Source: https://astro.confex.com/astro/hncs2024/meetingapp.cgi/Paper/59764
Ley J, Liu J, Adkins D, et al. (2024). “Olaparib, a poly (ADP-ribose) polymerase (PARP) Inhibitor, in Combination with Pembrolizumab and Carboplatin as First-Line Treatment of Recurrent or Metastatic Head and Neck Squamous-Cell Carcinoma (RM-HNSCC): A Single-Arm, Phase 2 Trial.” MHNCS 2024 (Poster Screen 4).
