This podcast will discuss the findings from a phase II trial of gemcitabine, cisplatin and PARP inhibitor therapy in germline BRCA/PALB2 mutant pancreatic cancer and discuss an optimal treatment strategy in this setting.

TRANSCRIPT

This JCO Podcast provides observations and commentary on the JCO article "A Randomized, Multi-Center, Phase II Trial of Gemcitabine, Cisplatin with or without Veliparib in Patients with Pancreas Adenocarcinoma and a Germline BRCA/ PALB2 Mutation" by O'Reilly et al. My name is Daniel Renouf, and I am a medical oncologist at the BC Cancer Vancouver Centre in Vancouver, Canada. My oncologic specialty is pancreatic cancer.

In this podcast, we will be discussing an important and evolving area that is changing our standard treatment strategies for pancreatic cancer. Progress has been slow for pancreatic adenocarcinoma, which is now the third leading cause of cancer-related death in North America and is projected to become the second leading cause of cancer-related death within the next decade. Modest gains in our treatments have been achieved with new chemotherapy combinations, including FOLFIRINOX and gemcitabine and nano-albumen bound-paclitaxel, yet still the majority of patients diagnosed with advanced disease will live for less than one year.

There is a critical need for improved treatment options as well as clinically relevant predictive markers to guide our therapeutic decision making. The first clinically important predictive marker in pancreatic cancer is germline BRCA/PALB2 mutation status, which is present in 5-9% of pancreatic adenocarcinomas. Multiple translational studies and case series have demonstrated distinct molecular features of these tumors, as well as unique clinical characteristics. Germline BRCA/PALB2 mutant pancreatic adenocarcinomas have been noted to be sensitive to platinum agents and be associated with a better prognosis. Despite this data, and a general acceptance within the community that platinum agents are the preferred therapies in this setting, there is minimal prospective trial data specifically assessing the activity of platinum combinations in germline BRCA/PALB2 mutant pancreatic adenocarcinoma.

At a plenary session at ASCO 2019 and its subsequent publication, the POLO trial assessed the role of maintenance therapy with a poly-ADP ribose polymerase (PARP) inhibitor (olaparib), compared to placebo, in patients with metastatic pancreatic adenocarcinoma and germline mutations in BRCA/PALB2 who had responded or had stable disease after initial therapy with FOLFIRINOX. This was a positive trial, demonstrating that maintenance olaparib significantly improved progression-free survival compared to placebo. There was no difference noted in overall survival, but this data was not yet mature. The role of combining a PARP inhibitor with platinum-based chemotherapy as upfront treatment in this patient population is yet to be defined. A previous Phase I trial of gemcitabine, cisplatin and the PARP inhibitor veliparib determined a recommended phase II dose for velipirib in this combination and demonstrated promising efficacy in germline BRCA-mutant pancreatic adenocarcinoma.

In the article that accompanies this podcast, Dr. O'Reilly and colleagues report on the results of a phase II prospective trial comparing gemcitabine and cisplatin versus gemcitabine, cisplatin and veliparib in patients with advanced pancreatic adenocarcinoma with germline aberrations in BRCA/PALB2. In the trial, patients with locally advanced or metastatic pancreatic cancer who had not received chemotherapy in the advanced setting, had a good performance status, and who harbored germline aberrations in BRCA/PALB2 were randomized.

A total of 50 patients were enrolled, and the results demonstrated good efficacy in both arms, with a response rate of 74.1% in the veliparib arm and 65.2% in the control arm. Median progression-free survival was 10.1 months and 9.7 in the veliparib and non-veliparib arms respectively, and median overall survival was 15.5 and 16.4 months. Of note, for the entire cohort, 2-year overall survival was notably high at 30.6%, and 3-year overall survival was 17.8%. Grade 3-4 toxicities, including neutropenia, thrombocytopenia, and anemia were greater in the veliparib arm.

The authors concluded that gemcitabine and cisplatin demonstrated significant activity in BRCA/PALB2 germline mutant pancreatic adenocarcinoma, and the addition of concurrent veliparib did not improve efficacy. Given this promising data, it was concluded that gemcitabine and cisplatin should be considered a standard treatment for BRCA/PALB2 germline mutant pancreatic adenocarcinoma.

This is an important trial, as it is one of the first to specifically assess platinum chemotherapy prospectively in this patient population and has important implications for treatment strategies for pancreatic cancer, the first of which is that testing for germline BRCA/PALB2 mutations should now be considered standard of care for all newly diagnosed pancreatic adenocarcinomas. Not only does this have important treatment implications for the patient; it also has strong relevance to the patients' family members, as it was found to also harbor a germline BRCA/PALB2 mutation. Screening and potential prevention strategies could be considered for other cancers, such as breast and ovarian.

Secondly, if a patient is found to have a germline BRCA/PALB2 mutation, the data from this trial in combination with the body of literature in this setting would suggest that first line therapy with a platinum agent should be considered. In this setting, one could consider either FOLFIRINOX or gemcitabine and cisplatin. The efficacy of gemcitabine and nano albumen bound-paclitaxel in this patient population is not clearly defined, but in the context of data from other disease sites also demonstrating increased sensitivity to platinum in this patient population, and given many patients with advanced pancreatic adenocarcinoma are often not well enough to received multiple lines of therapy, a first line platinum combination should be strongly considered. Thirdly, this trial demonstrates that there is no additional benefit from adding a PARP inhibitor to chemotherapy in this setting, but there is added toxicity, and thus this strategy should not be considered at this time.

Finally, given that toxicity from platinum-based chemotherapy is cumulative, the question of an optimal maintenance strategy remains. The POLO trial demonstrated that there is activity and a progression-free survival benefit when using olaparib as a maintenance post upfront platinum-based chemotherapy when compared to placebo, and therefore this represents one potential strategy. One criticism of the POLO trial is that many centers do not stop treatment and instead continue therapy without the platinum after an initial response. In patients responding to initial treatment with FOLFIRINOX, maintenance FOLFIRI is often considered. Data from a second line trial of FOLFIRI with or without veliparib presented as a poster discussion at ASCO 2019 by Dr. Chiorean and colleagues noted that BRCA/PALB2 mutant tumors also appear to have increased sensitivity to FOLFIRI. At this time, the optimal maintenance strategy after upfront platinum therapy is yet to be fully defined, and further research in this setting is needed. In addition, to what extent these strategies should be applied to patients with pancreatic adenocarcinomas that are germline BRCA/PALB2 wildtype but have other homologous recombination deficiency defects requires further investigation.

In summary, this is an exciting time in pancreatic adenocarcinoma as we now have a clinically important biomarker to guide treatment strategies. This important trial by Dr. O'Reilly and colleagues further solidifies the importance of BRCA/PALB2 germline testing in pancreatic adenocarcinoma and that first line platinum-based chemotherapy should be considered in these patients.

This concludes this JCO Podcast. Thank you for listening.

Optimizing Treatment Strategies for Germline BRCA/PALB2 Mutant Pancreatic Adenocarcinoma

Journal of Clinical Oncology (JCO) Podcast

Optimizing Treatment Strategies for Germline BRCA/PALB2 Mutant Pancreatic Adenocarcinoma