A phase II study combining pembrolizumab and olaparib in metastatic pancreatic adenocarcinoma patients with high tumour mutation burden

Research Question

Does treatment with pembrolizumab plus olaparib improve outcomes for patients with metastatic pancreatic adenocarcinoma (mPDA) and high tumour mutation burden (TMB)? Background

Outcomes for patients with mPDA are extremely poor, despite optimal anticancer therapy. Recent breakthroughs with modern immunotherapy reported for many cancer types have not been replicated in mPDA, which is a disease generally characterised by an immunosuppressive microenvironment and low TMB. However, not all PDAs are the same.

In a small minority of PDAs, defective DNA damage repair mechanisms exist which generate very high TMB and these patients have the potential to benefit from immunotherapy. Some 2% of PDA patients could be eligible to access the immune checkpoint inhibitor (CPI), pembrolizumab, which was recently approved in the USA to treat cancers with the highest mutation rates caused by defects in DNA mismatch repair genes.

However, currently there is no European access to pembrolizumab for this indication. Furthermore, even for the most immunoresponsive cancers, only the minority of treated patients benefit from CPIs, so more effective combination strategies are needed. Pembrolizumab blocks the programmed death-1 receptor on T lymphocytes which unleashes their ability to seek out and kill cancer cells.

Emerging evidence suggest that drugs like olaparib, traditionally thought of as DNA repair targeted agents, can enhance response to CPIs. Aims

We aim to conduct a single arm prospective trial evaluating pembrolizumab plus olaparib in patients with mPDA and high TMB. The primary outcome is objective response rate (ORR); secondary outcomes are safety, duration of response and progression-free survival; exploratory outcomes are overall survival and additional response biomarkers.

Methods

Patients with high TMB mPDA will be identified via national research and other molecular screening platforms. Eligible patients will be invited to consent to receive treatment as either first or second line therapy for their disease. The regimen is pembrolizumab 200mg IV every 3 weeks plus olaparib 300mg orally twice a day, for as long as there is benefit, but maximum 2-years.

Patients continuing beyond 27 weeks can switch to pembrolizumab 400mg IV 6 weekly. Patients will be scanned every 9 weeks for 27 weeks, then and every 12 weeks for the second year, or until disease progression. Thereafter, they will be followed for survival.

We will collect blood samples before starting treatment, at 9 weeks, then at 1-year or on disease progression, whichever is sooner. We will use pre-treatment tumour samples to explore molecular and immune markers of response We will recruit 20 evaluable patients to assess ORR, with early stopping rules.

Timelines for delivery Study set up complete: month 9 First patient first visit: month 12 Stage 1 interim assessment: month 30 Stage 2 interim assessment: month 40 Stage 3 final ORR assessment: month 54 Final report, close out: month 60 Anticipated impact and dissemination

This signal-seeking trial will offer the first robust evidence of immunotherapy being an effective treatment strategy for a biomarker-stratified cohort of mPDA patients. A positive outcome will justify an international registration trial. The findings will be presented at conferences, published and shared with patients, carers, advocacy groups and commissioners