Exploring Pembrolizumab Plus Olaparib in BRCA-Mutated Metastatic Pancreatic Cancer

In this interview with Pharmacy Times at the 2026 American Society of Clinical Oncology Annual Meeting, Vincent Chung, MD, medical oncologist, City of Hope, discusses his abstract “Randomized phase II trial of olaparib and pembrolizumab vs olaparib alone as maintenance therapy in metastatic pancreatic cancer patients with germline BRCA1 or BRCA2 (gBRCA1/2) mutations: SWOG S2001 (NCT04548752).” Although the addition of pembrolizumab (Keytruda; Merck) to olaparib (Lynparza; AstraZeneca Pharmaceuticals LP) did not significantly improve progression-free survival and the study closed early for futility, Chung noted that correlative blood and tissue analyses may help identify patient subsets that could still benefit from the combination. He explained that the strategy was based on the biologic rationale that PARP inhibition may enhance immunotherapy response by increasing PD-L1 expression, activating the STING pathway, and promoting greater cytotoxic T-cell infiltration.

Pharmacy Times: Although the addition of pembrolizumab to olaparib did not significantly improve progression-free survival, were there any patient subsets or clinical signals that you believe warrant further investigation in future studies?

Vincent Chung, MD: In terms of this particular study, we did have a very high bar set for this clinical trial. We were looking to improve progression-free survival from 7 to 11.7 months, and we did not meet the statistical end point of improving progression-free survival, so the trial was closed early for futility.

In terms of the rationale behind why we did this, we know that with genomic instability, there is increased potential response to immunotherapy, and we have seen across different tumor types that these genomically unstable tumors do respond to immunotherapy. That was the rationale behind PARP inhibition in combination with the immune checkpoint inhibitor.

There were, of course, responses seen within our clinical trial. The question, and you raise a good point, is which subsets may benefit. That is where the blood, as well as the tissue that we collected, will be analyzed further to try to identify those subsets.

Pharmacy Times: The study highlights the growing interest in combining PARP inhibition with immunotherapy in pancreatic cancer. Mechanistically, what makes this strategy appealing, and why has translating that biology into meaningful clinical benefit remained challenging?

Chung: Yes, so the POLO trial [NCT02184195] established olaparib as a maintenance therapy for pancreatic cancer with germline BRCA1 and BRCA2 mutations. What we saw in the POLO trial was that it did improve progression-free survival; however, overall survival was not improved. That underscores the need to strengthen and deepen the response that we see because, although this is a very exciting time in pancreatic cancer, these therapies unfortunately are not curing the cancer at this time. They are basically slowing down the growth of the cancer.

Looking at strategies to deepen those responses was the rationale for why we did this study. In terms of the mechanism behind why this may actually work, we have seen in preclinical data that PARP inhibitors increase expression of PD-L1. It also activates the STING pathway and increases cytotoxic T-cell infiltration. We have also seen in other tumor types that the combination does have synergistic activity, and that is the mechanism behind why we chose that combination.

Pharmacy Times: From a practical treatment perspective, how should clinicians weigh the potential benefits of adding pembrolizumab against the added immune-related toxicities reported in the trial, particularly in a maintenance setting where quality of life is important?

Chung: In terms of right now, we do not have data to support giving the combination, so more studies need to be done in larger clinical trials to prove that it is effective before patients actually [use] this approach.

There are more immune-related adverse events associated with the combination. We saw that approximately 15% of patients had at least a grade 3 adverse event, and although they are manageable, including hypothyroidism, hyperthyroidism, and adrenal insufficiency, they are still significant [adverse] effects. We definitely want to make sure future clinical trials validate this combination before it is actually used.

Pharmacy Times: As biomarker-driven treatment strategies continue to evolve in pancreatic cancer, how important is multidisciplinary collaboration—including oncologists, pharmacists, and genetic counselors—in optimizing care for patients with BRCA1/2 mutations?

Chung: I think that is a broader question because cancer care and cancer cure are complex, and it really requires a multidisciplinary team approach. If you look at the NCCN [National Comprehensive Cancer Network] guidelines, they consistently emphasize that patients should have a multidisciplinary team approach to care because it may involve not only medical oncology but also surgery, radiation oncology, and gastroenterology. Ultimately, it is a team approach aimed at achieving the best outcomes.