Overall Survival Results From the POLO Trial: A Phase III Study of Active Maintenance Olaparib Versus Placebo for Germline BRCA-Mutated Metastatic Pancreatic Cancer

Author(s): Hedy L. Kindler, MD¹;Pascal Hammel, MD, PhD²;Michele Reni, MD³;Eric Van Cutsem, MD, PhD⁴;Teresa Macarulla, MD, PhD⁵;Michael J. Hall, MD⁶;Joon Oh Park, MD, PhD⁷;Daniel Hochhauser, MD, PhD⁸;Dirk Arnold, MD, PhD⁹;Do-Youn Oh, MD, PhD¹⁰;Anke Reinacher-Schick, MD, PhD¹¹;Giampaolo Tortora, MD, PhD¹²;Hana Algül, MD, PhD, MPH¹³;Eileen M. O’Reilly, MD¹⁴;Sonal Bordia, MD¹⁵;David McGuinness, MSc¹⁶;Karen Cui, MD, PhD¹⁷;Gershon Y. Locker, MD¹⁷;and Talia Golan, MD¹⁸

Source: DOI: 10.1200/JCO.21.01604 Journal of Clinical Oncology 40, no. 34 (December 01, 2022) 3929-3939.

Dr. Maen Hussein's Thoughts

Another maintenance trial, NO statistically significant OS benefit but prolonged time to second-line chemotherapy. HR was favored Olaparib.

PURPOSE

The phase III POLO study demonstrated significant progression-free survival (PFS) benefit for active olaparib maintenance therapy versus placebo for patients with metastatic pancreatic adenocarcinoma and a germline BRCA mutation. Here, we report the final analysis of overall survival (OS) and other secondary end points.

PATIENTS AND METHODS

Patients with a deleterious or suspected deleterious germline BRCA mutation whose disease had not progressed after ≥ 16 weeks of first-line platinum-based chemotherapy were randomly assigned 3:2 to active maintenance olaparib (300 mg twice daily) or placebo. The primary end point was PFS; secondary end points included OS, time to second disease progression or death, time to first and second subsequent cancer therapies or death, time to discontinuation of study treatment or death, and safety and tolerability.

RESULTS

In total, 154 patients were randomly assigned (olaparib, n = 92; placebo, n = 62). No statistically significant OS benefit was observed (median 19.0 v 19.2 months; hazard ratio [HR], 0.83; 95% CI, 0.56 to 1.22; P = .3487). Kaplan-Meier OS curves separated at approximately 24 months, and the estimated 3-year survival after random assignment was 33.9% versus 17.8%, respectively. Median time to first subsequent cancer therapy or death (HR, 0.44; 95% CI, 0.30 to 0.66; P < .0001), time to second subsequent cancer therapy or death (HR, 0.61; 95% CI, 0.42 to 0.89; P = .0111), and time to discontinuation of study treatment or death (HR, 0.43; 95% CI, 0.29 to 0.63; P < .0001) significantly favored olaparib. The HR for second disease progression or death favored olaparib without reaching statistical significance (HR, 0.66; 95% CI, 0.43 to 1.02; P = .0613). Olaparib was well tolerated with no new safety signals.

CONCLUSION

Although no statistically significant OS benefit was observed, the HR numerically favored olaparib, which also conferred clinically meaningful benefits including increased time off chemotherapy and long-term survival in a subset of patients.

Author Affiliations

¹The University of Chicago, Chicago, IL ²Paul Brousse Hospital (AP-HP), University Paris-Saclay, Villejuif, France ³IRCCS Ospedale, San Raffaele Scientific Institute, Vita e Salute University, Milan, Italy ⁴University Hospitals Gasthuisberg and KU Leuven, Leuven, Belgium ⁵Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology, Barcelona, Spain ⁶Fox Chase Cancer Center, Philadelphia, PA ⁷Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea ⁸University College London Cancer Institute, London, United Kingdom ⁹Asklepios Tumorzentrum Hamburg AK Altona, Hamburg, Germany ¹⁰Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea ¹¹St Josef-Hospital, Ruhr University Bochum, Bochum, Germany ¹²Fondazione Policlinico A Gemelli IRCCS and Università Cattolica del Sacro Cuore, Rome, Italy ¹³Klinikum rechts der Isar, Comprehensive Cancer Center Munich TUM, Technische Universität München, Munich, Germany ¹⁴Memorial Sloan Kettering Cancer Center, New York, NY ¹⁵Merck & Co Inc, Kenilworth, NJ ¹⁶AstraZeneca, Cambridge, United Kingdom ¹⁷AstraZeneca, Gaithersburg, MD ¹⁸The Oncology Institute, Sheba Medical Center at Tel-Hashomer, Tel Aviv University, Tel Aviv, Israel

Addition of Metastasis-Directed Therapy to Systemic Therapy for Oligometastatic Pancreatic Ductal Adenocarcinoma (EXTEND): A Multicenter, Randomized Phase II Trial

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Safety and Efficacy of CT041 in Patients With Refractory Metastatic Pancreatic Cancer: A Pooled Analysis of Two Early-Phase Trials

CAR-T agent for refractory met-pancreas showing a median duration of response of 9.5 months. These treatments are far from widely available, but the proof of principle is nice to see in a disease that otherwise has not had responses to immunotherapy. Hopefully more agents to come.

Nimotuzumab Plus Gemcitabine for K-Ras Wild-Type Locally Advanced or Metastatic Pancreatic Cancer

Asian study of nimotuzumab (humanized EGFR-inhibitor) + gemcitabine (gem) vs. gem alone. The overall survival (OS) was 10.9 vs. 8.5 months in favor of the combination arm. While the OS difference is small, recall that the OS in the NALIRIFOX and FOLFIRINOX studies are similar. The safety profile of nimotuzumab + gemcitabine is superior to a triplet or double cytotoxic chemotherapy combination regimen. This drug is currently not available in the USA but is approved for nasopharyngeal carcinoma in China.

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You may have enrolled a patient in this trial, but it seems we may have a new first line regimen. Surprisingly toxicity simar in both arms, but there was improvement in PFS and OS (17% reduction in death) although it wasn’t statistically significant in OS.
More diarrhea with nalirifox, but more neutropenia with gem abraxane.

Adjuvant nab-Paclitaxel + Gemcitabine in Resected Pancreatic Ductal Adenocarcinoma: Results From a Randomized, Open-Label, Phase III Trial

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