Frontline Durvalumab/Chemo, Then Maintenance Durvalumab ± Olaparib, Improves ORR in Endometrial Cancer

Els Van Nieuwenhuysen, MD

Frontline treatment with the combination of durvalumab (Imfinzi), carboplatin, and paclitaxel, followed by maintenance durvalumab with or without olaparib (Lynparza), led to improved objective response rates (ORR), durations of response (DOR), and time to treatment discontinuation (TDT) vs chemotherapy alone, followed by maintenance placebo, in patients with stage III/IV or recurrent endometrial cancer, according to updated findings from the phase 3 DUO-E trial (NCT04269200).¹

Findings presented at the 2024 ESMO Gynecological Cancers Congress also showed that the experimental regimen improved ORR, DOR, and TDT in patients with mismatch repair–deficient (dMMR) disease. DOR and TDT were improved in the population of patients with mismatch repair–proficient (pMMR) disease.

In the intention-to-treat (ITT) population, evaluable patients treated with durvalumab plus chemotherapy, followed by durvalumab alone as maintenance therapy (CP+D arm; n = 202), achieved an ORR of 61.9%, including complete response (CR) and partial response (PR) rates of 12.9% and 49.0%, respectively. Conversely, the ORR was 55.1% in patients treated with chemotherapy alone, followed by placebo maintenance (CP arm; n = 198; odds ratio [OR], 1.32; 95% CI, 0.89-1.98). Patients in the CP arm had CR and PR rates of 9.6% and 45.5%, respectively. Patients treated with durvalumab plus chemotherapy, followed by durvalumab plus olaparib as maintenance (CP+D+O arm; n = 184) experienced an ORR of 63.6% (OR vs the CP arm, 1.44; 95% CI, 0.95-2.18) with a CR rate of 16.3% and a PR rate of 47.3%.

The median time to response was 2.1 months (interquartile range [IQR], 2.0-2.3) in all 3 arms. The median DOR was 13.1 months (IQR, 6.0–not reached [NR]) in the CP+D arm, 21.3 months (IQR, 8.1-29.9) in the CP+D+O arm, and 7.7 months (IQR, 5.1-13.5) in the CP arm. The 18-month DOR rates were 46.6%, 55.7%, and 14.8%, respectively. The respective 24-month DOR rates were 38.0%, 47.1%, and 14.8%.

“DUO-E results support the addition of durvalumab to platinum-based chemotherapy as a new treatment option for patients with endometrial cancer, with the greatest benefit for dMMR disease. Adding [maintenance] olaparib has a further benefit for the pMMR subpopulation,” lead study author Els Van Nieuwenhuysen, MD, a gynecologist/oncologist at UZ Leuven in Belgium, said in a presentation of the data.

Prior data from DUO-E showed that the study met its primary end point of progression-free survival (PFS) in the ITT population for the CP+D arm vs the CP arm, as well as the CP+D+O arm vs the CP arm.² The median PFS was 10.2 months (95% CI, 9.7-14.7) in the CP+D arm (n = 238) vs 9.6 months (95% CI, 9.0-9.9) in the CP arm (n = 241; HR, 0.71; 95% CI, 0.57-0.89; P = .003). The median PFS was 15.1 months (95% CI, 12.6-20.7) in the CP+D+O arm (n = 239; HR vs the CP arm, 0.55; 95% CI, 0.43-0.69; P < .0001).

The randomized, placebo-controlled, double-blind study enrolled patients with newly diagnosed FIGO stage III/IV or recurrent endometrial cancer.¹ Patients with newly diagnosed stage III disease needed to have measurable disease. All patients were required to have a known MMR status, be naive to first-line systemic treatment for advanced disease, and be naive to PARP inhibitors and immune-mediated therapy. Prior adjuvant chemotherapy was allowed if at least 12 months had passed since last treatment to relapse. The study included patients with all histologies other than sarcomas.

The study included 718 patients who were randomly assigned 1:1:1 to receive carboplatin at area under the curve of 5 or 6 mg/mL/min plus paclitaxel at 175 mg/m2 twice daily every 3 weeks followed by maintenance placebo (CP arm); the same chemotherapy regimen plus intravenous (IV) durvalumab at 1120 mg every 3 weeks, followed by maintenance durvalumab at 1500 mg every 4 weeks (CP+D arm); or chemotherapy plus IV durvalumab every 3 weeks, followed by maintenance durvalumab every 4 weeks plus oral olaparib at 300 mg twice daily (CP+D+O arm). The chemotherapy phase lasted for 6 cycles, and patients were only allowed to receive maintenance therapy if they were free from disease progression. Treatment continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met.

Stratification factors included MMR status (dMMR vs pMMR), disease status (recurrent vs newly diagnosed), and geographic region (Asia vs non-Asia).

Along with the primary end point of investigator-assessed PFS per RECIST 1.1 criteria, secondary end points included overall survival, ORR, DOR, TDT, and safety. Exploratory end points included a post-hoc analysis of ORR, DOR, and TDT based on MMR status.

The median age was 64 years (range, 31-85) in the CP arm, 64 years (range, 22-84) in the CP+D arm, and 63 years (range, 27-86) in the CP+D+O arm. The majority of patients in all 3 arms were White (CP, 59.3%; CP+D, 57.1%; CP+D+O, 55.6%), had an ECOG performance status of 0 (64.7%; 65.5%; 69.5%), had recurrent disease (52.3%; 52.5%; 52.3%), had endometroid histology (57.7%; 59.2%; 63.6%), had pMMR disease (79.7%; 80.7%; 79.9%), did not harbor homologous recombination repair mutations (54.8%; 58.0%; 59.0%), had positive PD-L1 expression (67.6%; 71.4%; 62.8%), did not receive prior chemotherapy (78.8%; 78.6%; 77.4%), and underwent prior surgery (83.8%; 86.1%; 86.6%).

Additional data from the ITT population showed that the median TDT was 9.9 months (95% CI, 8.8-11.2) in the CP+D arm (n = 238) vs 8.8 months (95% CI, 7.6-9.7) in the CP arm (n = 241; HR, 0.74; 95% CI, 0.60-0.91). The median TDT was 15.1 months (95% CI, 12.5-18.6) in the CP+D+O arm (n = 239; HR vs the CP arm, 0.51; 95% CI, 0.41-0.63).

The post-hoc analysis of patients with dMMR disease showed that those treated in the CP+D arm (n = 30) achieved an ORR of 71.4%, including a CR rate of 28.6% and a PR rate of 42.9%, vs an ORR of 40.5% in the CP arm (n = 42; OR, 3.68; 95% CI, 1.51-9.39). The respective CR and PR rates in the CP arm were 9.5% and 31.0%. The ORR was 73.0% in the CP+D+O arm (n = 37; OR vs the CP arm, 3.97; 95% CI, 1.57-10.65), including CR and PR rates of 18.9% and 54.1%, respectively. The median time to response was 2.1 months in each arm, and the median DOR was NR (IQR, 22.0-NR) in the CP+D arm (n = 30), 29.9 months (IQR, 9.7-29.9) in the CP+D+O arm (n = 27), and 10.5 months (IQR, 4.5-NR) in the CP arm (n = 17). The respective 18-month DOR rates were 75.2%, 73.6%, and 48.2%. The 24-month DOR rates were 60.2%, 73.6%, and 48.2%, respectively.

In the dMMR population, the median TDT was 21.2 months (95% CI, 9.3-NR) in the CP+D arm (n = 46) vs 6.7 months (95% CI, 5.1-7.9) in the CP arm (n = 49; HR, 0.47; 95% CI, 0.27-0.79). The median TDT was 20.6 months (95% CI, 13.4-NR) in the CP+D+O arm (n = 48; HR vs the CP arm, 0.36; 95% CI, 0.21-0.62).

In the pMMR population, the ORR was 59.4% in the CP+D arm (n = 160) vs 59.0% in the CP arm (n = 156; OR, 1.02; 95% CI, 0.65-1.59). The ORR was 61.2% in the CP+D+O arm (n = 147; OR vs the CP arm, 1.10; 95% CI, 0.69-1.74). The respective CR and PR rates were 8.8% and 50.6% for the CP+D arm, 15.6% and 45.6% for the CP+D+O arm, and 9.6% and 49.4% for the CP arm.

The median time to response was 2.1 months in all 3 arms. The median DOR was 10.6 months (IQR, 5.6-NR) in the CP+D arm, 18.7 months (IQR, 8.0-NR) in the CP+D+O arm, and 7.6 months (IQR, 5.1-13.1) in the CP arm. The respective 18-month DOR rates were 37.4%, 50.0%, and 12.1%. The 24-month DOR rates were 32.4%, 37.8%, and 12.1%, respectively.

Patients in the pMMR population treated in the CP+D arm (n = 192) achieved a median TDT of 9.6 months (95% CI, 8.1-10.6) compared with 9.3 months (95% CI, 8.0-9.9) in the CP arm (n = 192; HR, 0.81; 95% CI, 0.65-1.02). The median TDT was 13.4 months (95% CI, 10.6-15.6) in the CP+D+O arm (n = 191; HR vs the CP arm, 0.54; 95% CI, 0.43-0.69).

Safety data showed that the most common adverse effects (AEs) in the CP+D arm were alopecia, anemia, fatigue, and asthenia; the most common in the CP+D+O arm were anemia, nausea, fatigue, and asthenia. No cases of acute myeloid leukemia or myelodysplastic syndrome were reported in any arms. In the CP+D+O arm, 3 patients (1.6%) experienced pure red cell aplasia; no instances of this AE occurred in the CP or CP+D arms. Autoimmune hemolytic anemia was reported in 1 patient (<1%) in the CP+D arm and 2 patients (<1%) in the CP+D+O arm, compared with none in the CP arm. All instances of pure red cell aplasia and autoimmune hemolytic anemia were grade 3, and none were fatal.

The rates of immune-mediated AEs were 8.6% in the CP arm, 28.1% in the CP+D arm, and 23.5% in the CP+D+O arm. AEs led to discontinuation of any study treatment in 18.6%, 20.9%, and 24.4% of patients, respectively.

Disclosures: Dr Van Nieuwenhuysen reported serving in a consulting or advisory role with Regeneron (institution), Oncoinvent (individual), and AstraZeneca (institution); receiving travel accommodations or expenses from Regeneron (institution); and receiving institutional research funding from AstraZeneca, Lilly, Merck, Seagen, Roche, Novartis, Regeneron, and Oncoinvent.

Reference

Van Nieuwenhuysen E, Chon HS, Pepin JT, et al. First-line durvalumab + carboplatin/paclitaxel followed by durvalumab ± olaparib for endometrial cancer (DUO-E): objective response rate, duration of response and time to treatment discontinuation or death by mismatch repair status. Presented at: 2024 ESMO Gynecological Cancers Congress; June 20-22, 2024; Florence, Italy. Abstract: 40MO.