Durvalumab Plus Carboplatin and Paclitaxel Delivers One-Two Punch for Endometrial Cancer Treatment
Trial evaluates frequency of different biomarkers and distribution of histological subtypes.
Combining the chemotherapy drugs carboplatin and paclitaxel (CP) with the maintenance therapy agent durvalumab (with or without olaparib) has become a formidable tool in the treatment of endometrial cancer. The approach was recently credited with improved, progression-free survival (PFS), as outlined in the phase 3 DUO-E trial (NCT04269200).
The study, “Durvalumab plus carboplatin/paclitaxel followed by durvalumab with/without olaparib in endometrial cancer: biomarkers, histological heterogeneity, baseline circulating tumor DNA levels, and efficacy in the DUO-E mismatch repair proficient subpopulation,” revealed a statistically significant and clinically meaningful improvement in PFS compared to the use of CP alone. According to the study’s principal investigator Kathleen N. Moore, MD, the study taps an unmet need for new therapies for treating endometrial cancer, one of the most common cancers in female patients worldwide, with rising incidence and mortality. Approximately 70%–80% of these patients have mismatch repair proficient (pMMR) tumors, she said.
“Endometrial cancer is a highly heterogenous disease, characterized by multiple genomic drivers,” said Dr. Moore, a gynecologic oncologist with the University of Oklahoma Health Stephenson Cancer Center in Oklahoma City. “Our observations provide greater understanding into the frequency of different biomarkers and distribution of histological subtypes in the DUO-E pMMR subpopulation and demonstrate that high presence of baseline circulating tumor DNA (ctDNA) is consistent with higher tumor burden in the advanced disease setting.”
The DUO-E study, first published in 2023, was the first phase 3 trial to examine the combination of immunotherapy and poly (ADP-ribose) polymerase (PARP) inhibition in endometrial cancer. Patients with newly diagnosed stage 3 and 4 or recurrent endometrial cancer were randomized by CP alone, CP plus durvalumab followed by durvalumab, and CP plus durvalumab followed by durvalumab and Olaparib. In the pMMR subpopulation, researchers determined the histological subtype by observing the prevalence and overlap of biomarkers such as programmed cell death ligand 1 (PD-L1) status, homologous recombination repair (HRR), and BRCA1/BRCA2 mutation (BRCAm) status. Researchers also evaluated blood samples for ctDNA levels at baseline.
According to Dr. Moore, DUO-E met both dual primary endpoints, demonstrating a statistically significant and clinically meaningful PFS benefit with CP plus durvalumab followed by durvalumab with or without olaparib.
In pre-specified exploratory subgroup analyses of PFS by MMR status, durvalumab plus CP followed by durvalumab had the greatest benefit versus CP alone in the pMMR-deficient subpopulation, and the addition of olaparib maintenance further enhanced the PFS benefit seen with durvalumab plus CP followed by durvalumab in the pMMR subpopulation.
“This exploratory, post-hoc analysis of the DUO-E study showed that the pMMR subpopulation was highly heterogeneous, with frequent overlap of biomarkers and histology, including PD‑L1 positive, TP53 mutated (TP53m), and serous histology,” Dr. Moore said. “Among evaluable patients, 84% of patients in the biomarker subpopulation were positive for more than one biomarker. Adding olaparib maintenance further enhanced the PFS benefit for CP plus durvalumab followed by durvalumab versus CP alone across a range of biomarker and histological subgroups.”
The results, according to Dr. Moore, expand on their earlier findings by reporting rates of baseline ctDNA detection. Among evaluable patients, 79% had detectable ctDNA at baseline.
“Importantly, this study demonstrated that the addition of olaparib maintenance to durvalumab further enhanced PFS benefit in the pMMR subpopulation across a range of biomarker and histological subgroups, and in patients with detectable ctDNA at baseline,” she said.
Dr. Moore underscored the fact that the results highlight the potential of this combination therapy to become a new standard of care, particularly for patients with specific biomarker profiles and histological subtypes.
“There are two main points to take away from this study: The pMMR subpopulation in DUO-E was highly heterogenous, with a frequent overlap of biomarkers and histology, and a high prevalence of baseline ctDNA, she said. “And despite the heterogeneity within the pMMR subpopulation, adding olaparib maintenance further enhanced the PFS benefit for CP plus durvalumab followed by durvalumab versus CP alone across a range of biomarker and histological subgroups, and those with detectable ctDNA at baseline.”
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