Domenica Lorusso, MD, PhD

Invited discussant of the DUO-E trial, Domenica Lorusso, MD, PhD, commented: “Looking at the data, it’s clear to me that we are entering a new era of clinical research” in endometrial cancer. Patient populations are becoming molecularly refined, which will pave the way for more highly personalized therapies, she added. Dr. Lorusso is Head of the Clinical Research Development Unit of the Fondazione Policlinico A Gemelli IRCCS in Rome and Professor of Obstetrics and Gynecology at Humanitas University, Milan.

Noting that immunotherapy plus chemotherapy has become the new standard of care for patients with advanced mismatch repair–deficient (dMMR) tumors, she added: “In the MMR-proficient [pMMR] population, the results [from this approach] are still positive, but the magnitude of benefit is completely different, suggesting we can do better for these patients.” Since homologous repair gene mutations occur in up to 35% of endometrial cancers, one approach may be to combine PARP inhibitors with immunotherapy—there is strong biologic rationale and some clinical support for this approach, Dr. Lorusso indicated.

Nuances in Outcomes by Subgroups of Patients

Although DUO-E showed improved progression-free survival in the overall population, nuances in outcomes according to subgroups may later dictate how durvalumab and olaparib are incorporated with chemotherapy. As Dr. Lorusso observed, the benefit in the dMMR subgroup was essentially the same in both experimental arms—almost a 60% reduction—which suggests the addition of olaparib may not be necessary for these patients. “That’s not surprising,” she commented, “because the bar of immunotherapy plus chemotherapy in this population is so high it is very difficult to move forward.”

Dr. Lorusso continued: “However, in the pMMR population, we see a clear additional benefit in the full treatment arm…. This is a very heterogeneous population, so my suggestion is to try to better understand who these patients are. What is the molecular profile of patients with pMMR tumors who seem to gain benefit?”

In terms of other biomarkers, she noted the homologous repair–mutant subset derived a robust benefit (hazard ratio [HR] = 0.30), as did the PD-L1–positive subset (HR = 0.42) by treatment with both durvalumab and olaparib. In contrast, benefit was lacking in the PD-L1–negative subset (HR = 0.80). Because the study lacked power to formally compare the two experimental arms, the added benefit of olaparib to durvalumab, unfortunately, remains an unanswered question, Dr. Lorusso noted.

Although effective, chemotherapy plus durvalumab followed by durvalumab plus olaparib is not “priceless,” she observed, pointing to the increase in grade 3 to 4 adverse events. “This is a slightly different picture than we see in ovarian cancer, but not surprising if you consider the endometrial cancer population is more fragile,” Dr. Lorusso said. “It suggests we have to pay more attention when we propose this combination to our patients.”

DISCLOSURE: Dr. Lorusso reported personal financial relationships with GSK, AstraZeneca, MSD, Clovis Oncology, PharmaMar, Immunogen, Genmab, Seagen, Oncoinvest, Corcept, Sutro, and Novartis.