New research findings have highlighted the importance of personalized treatment approaches with the monoclonal antibody durvalumab based on mismatch repair (MMR) status in newly diagnosed patients with advanced or recurrent endometrial cancer, according to data presented during the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer.¹ Results of the phase III DUO-E study showed significant improvement in progression-free survival for all patients who received durvalumab plus chemotherapy, followed by durvalumab or durvalumab plus olaparib, compared with chemotherapy alone as well as consistent improvements for other measures of activity.

Of note, a subpopulation analysis also showed clear benefits to distinct treatment regimens. For patients with tumors deficient in MMR (dMMR), the addition of durvalumab to standard chemotherapy resulted in clinically meaningful improvements in overall survival and other secondary endpoints, such as time to first subsequent therapy, progression-free survival 2 (ie, second disease progression or death), and time to second subsequent treatment. In the proficient MMR (pMMR) subpopulation, the triplet combination of durvalumab, olaparib, and chemotherapy demonstrated greater benefits in overall survival and other secondary endpoints compared with chemotherapy alone.

Jean-François Baurain, MD, PhD

“These results support potential new treatment options in endometrial cancer: chemotherapy plus durvalumab followed by durvalumab for dMMR disease and chemotherapy plus durvalumab followed by durvalumab plus olaparib for the pMMR subpopulation,” said lead study author Jean-François Baurain, MD, PhD, Professor, University Catholic of Louvain, and Chief Resident, University Saint-Luc, Brussels.

As Dr. Baurain reported, immunotherapy and chemotherapy combinations have shown activity in endometrial cancer, particularly in dMMR disease.^2,3 Adding a PARP inhibitor to immunotherapy in the maintenance setting has also demonstrated the potential to promote antitumor immunity and improve outcomes.^4,5

Study Methods

The phase III DUO-E trial examined the effects of adding the immunotherapy durvalumab and the targeted therapy olaparib to standard chemotherapy in patients with endometrial cancer. The study included patients with both dMMR and pMMR tumors, which accounted for 20% and 80% of the intention-to-treat population, respectively.

A total of 718 patients were randomly assigned to one of three treatment arms: (1) standard chemotherapy followed by maintenance with placebo; (2) chemotherapy plus durvalumab followed by durvalumab maintenance; and (3) chemotherapy plus durvalumab followed by maintenance with durvalumab plus olaparib.

Previously reported data from the DUO-E study showed a statistically significant and clinically meaningful improvement in progression-free survival for patients with advanced or recurrent endometrial cancer receiving durvalumab plus carboplatin/paclitaxel followed by maintenance durvalumab with or without olaparib.⁶

Improved Survival in MMR Subpopulations

At the SGO meeting, Dr. Baurain presented new findings on overall survival and other secondary endpoints in the intention-to-treat population and subpopulations based on MMR status.

In the dMMR subpopulation, the addition of durvalumab to chemotherapy resulted in a clinically meaningful improvement in overall survival, with a more than 20% increase at 18 months and a flattening of the survival curve. This benefit was observed across other secondary endpoints, including the time to first subsequent therapy, progression-free survival 2, and time to second subsequent treatment, with hazard ratios consistently below 1.

For the pMMR subpopulation, the addition of olaparib to the combination of durvalumab and chemotherapy demonstrated a greater benefit in overall survival, with a 7% increase at 18 months and a hazard ratio of 0.69. This benefit was further enhanced for other secondary endpoints. When comparing the triplet regimen of durvalumab, olaparib, and chemotherapy with chemotherapy alone, the hazard ratios were 0.56, 0.68, and 0.68 for the time to first subsequent therapy, progression-free survival 2, and time to second subsequent treatment, respectively.

Of note, both treatment regimens were reported to be well tolerated, with manageable toxicity profiles and low rates of treatment discontinuation from adverse events. No new safety signals were observed, according to Dr. Baurain, and the toxicity profiles were consistent with those seen with single-agent therapy. Of note, there were no cases of myelodysplastic syndrome or acute myeloid leukemia.

Neutropenia was the most common severe side effect (grade 3 or higher), occurring in 23%, 22%, and 27% of people in the respective study arms.

Closing Thoughts

According to Dr. Baurain, further research is needed to validate these results and to explore the long-term efficacy and safety of these combination regimens. However, the DUO-E trial has provided compelling evidence for the use of immunotherapy and targeted therapy in conjunction with chemotherapy.

“The DUO-E trial results suggest the combination of durvalumab and chemotherapy may be a promising new treatment option for patients with dMMR endometrial cancer, and the triplet regimen of durvalumab, olaparib, and chemotherapy could offer improved outcomes for those with pMMR disease,” Dr. Baurain concluded. 

DISCLOSURE: Dr. Baurain reported financial relationships with AstraZeneca, Bristol Myers Squibb, GSK, Immunocore, Merck, MSD, Novartis, Pfizer, Pierre-Fabre, Regeneron, Sanofi, and Sun Pharma.

REFERENCES

1. Baurain JF, Chon HS, Thomes-Pepin J, et al: Durvalumab + carboplatin/paclitaxel followed by durvalumab ± olaparib as a first-line treatment for endometrial cancer: overall survival and additional secondary efficacy endpoints by mismatch repair status in the DUO-E/GOG-3041/ENGOT-EN10 trial. Society of Gynecologic Oncology 2024 Annual Meeting on Women’s Cancer. Scientific Plenary V. Presented March 18, 2024.

2. Mirza MR, Chase DM, Slomovitz BM, et al: Dostarlimab for primary advanced or recurrent endometrial cancer. N Engl J Med 388:2145-2158, 2023.

3. Eskander RN, Sill MW, Beffa L, et al: Pembrolizumab plus chemotherapy in advanced endometrial cancer. N Engl J Med 388:2159-2170, 2023.

4. Stewart RA, Pilié PG, Yap TA: Development of PARP and immune-checkpoint inhibitor combinations. Cancer Res 78:6717-6725, 2018.

5. Wanderley CWS, Correa TS, Scaranti M, et al: Targeting PARP1 to enhance anticancer checkpoint immunotherapy response: Rationale and clinical implications. Front Immunol 13:816642, 2022.

6. Westin SN, Moore K, Chon HS, et al: Durvalumab plus carboplatin/paclitaxel followed by maintenance durvalumab with or without olaparib as first-line treatment for advanced endometrial cancer: The phase III DUO-E trial. J Clin Oncol 42:283-299, 2024.

EXPERT POINT OF VIEW

Discussant of the DUO-E trial, Robert L. Coleman, MD, FACOG, FACS, a gynecologic oncologist at Texas Oncology, Houston; Special Advisor, GOG-Partners; and Chief Medical Officer, Vaniam Group, Georgetown, Texas, emphasized several key takeaways.

“The first very important takeaway is that if you were a responder, you are much more likely to have been on the experimental arm (32% and 44%, respectively),” said Dr. -Coleman. “This effect is primarily driven in the dMMR [mismatch repair–deficient] category with immunotherapy, but we don’t know what part adds to that potential pop in the pMMR [mismatch repair–proficient] tumors, although we see consistently there is potential benefit.”

Robert L. Coleman, MD, FACOG, FACS

According to Dr. Coleman, however, because the sample sizes are small, it is difficult to “tease out directly” who should receive PARP inhibition.

In addition, although the secondary endpoints, including the time to first subsequent therapy, progression-free survival 2, and time to second subsequent treatment, seem to be related to each other, “what happens in between [the first and second disease progressions and subsequent treatment] can confound this kind of analysis.”

Dr. Coleman continued: “When you see a patient who comes in with disease progression, do you start that day with the next line of therapy, or do you wait for the patient to become symptomatic or wait for some other feature? Ultimately, we would like to know the efficacy of the next line of therapy with a previous exposure, and that’s what we call the second progression-free survival.” 

DISCLOSURE: Dr. Coleman reported financial relationships with Clovis Oncology, Genentech/Roche, AstraZeneca, Genmab/Seagen (Pfizer), Pharma&, GSK, AbbVie, Zentalis Pharmaceuticals, Merck, Alkermes, ImmunoGen (AbbVie), and Karyopharm.