Durvalumab/Chemo Maintenance Followed by Olaparib Confers PFS Advantage in Endometrial Cancer

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Durvalumab plus first-line chemotherapy, followed by maintenance treatment with durvalumab plus olaparib, emerges as a potentially effective combination for patients with limited treatment options.

Shannon N. Westin

Shannon N. Westin

Patients with newly diagnosed advanced or recurrent endometrial cancer derived significant progression-free survival (PFS) improvements with the addition of durvalumab (Imfinzi) to first-line chemotherapy, followed by maintenance treatment with durvalumab plus olaparib (Lynparza), according to data from the phase 3 DUO-E/GOG-3041/ENGOT-EN10 trial (NCT04269200) presented at the 2023 ESMO Congress.1-3

In particular, PFS benefit with durvalumab was greatest in mismatch repair–deficient (dMMR) patients, while adding olaparib to durvalumab maintenance therapy improved PFS in those who were mismatch repair–proficient (pMMR) and those positive for PD-L1.

“DUO-E is the first phase 3 study to demonstrate that durvalumab plus olaparib confers PFS benefit and provides new treatment options for patients with advanced or recurrent endometrial cancer,” Shannon N. Westin, MD, MPH, FACOG, Department of Gynecologic Oncology and Reproductive Medicine, Division of Surgery, The University of Texas MD Anderson Cancer Center, said during a presentation of the data.

At the meeting, Westin presented the primary analysis of PFS and the first preplanned interim analysis of overall survival (OS).

Patients were followed at a median of 16.4 months (range, 0.2-32.9) in the placebo arm, 17.1 months (range, 0.2-33.0) in the durvalumab monotherapy arm, and 17.5 months (range, 0.2-33.4) in the durvalumab plus olaparib arm.

In the intent-to-treat population, treatment with durvalumab (median PFS, 10.2 months [95% CI, 9.7-14.7]; HR, 0.71; 95% CI, 0.57-0.89; P = .003) and durvalumab plus olaparib (median PFS, 15.1 months [95% CI, 12.6-20.7]; HR, 0.55; 0.43-0.69; P < .0001) induced statistically significant improved PFS, compared with the control arm (median PFS, 9.6 months; 95% CI, 9.0-9.9). Compared with durvalumab monotherapy, the combination maintenance therapy reduced the risk for disease progression by 22% (HR, 0.78; 95% CI. 0.61-0.99).

Further, Westin highlighted that the 18-month PFS rates across the control, durvalumab, and durvalumab plus olaparib arms were 21.7%, 37.8%, and 46.3%, respectively, demonstrating a more than doubling rate between the control and combination maintenance arms.

In the subgroup analysis, all hazard rate-point estimates favored the durvalumab arm, compared with the control arm. “As expected, we see smaller hazard ratios with the mismatch repair-deficient subgroup as opposed to the mismatch repair-proficient subgroup, and patients with PD-L1 positive [status] as opposed to negative disease,” Westin said, adding that durvalumab plus olaparib was also favored over placebo. “We generally see smaller hazard ratios than we saw for durvalumab vs control, except for the mismatch repair-deficient group. And this was most apparent for patients that had [homologous recombination repair mutation (HRRm)].”

In a prespecified exploratory analysis of PFS by MMR status, both treatment with durvalumab monotherapy and durvalumab plus olaparib was superior to placebo in the dMMR arm (18-month PFS, 67.9% vs 62.7% vs 43.4%, respectively; median PFS, NR [95% CI, NR-NR] vs 31.8 months [95% CI, 12.4-NR] vs 7.0 months [95% CI, 6.7-14.8]) and pMMR arm (18-month PFS, 44.4% vs 42.0% vs 20.0%; median PFS, 9.9 months [95% CI, 9.4-12.5] vs 15.0 months [95% CI, 12.4-18.0] vs 9.7 months [95% CI, 9.2-10.1]).

Similarly, in a pre-specified exploratory analysis of PFS by PD-L1 status, both treatment with durvalumab monotherapy and durvalumab plus olaparib was superior to placebo in the positive (18-month PFS, 40.2% vs 54.9% vs 38.6%, respectively; median PFS, 11.3 months vs 20.8 months vs 9.5 months) and negative groups (18-month PFS, 31.1% vs 30.4% vs 22.7%; median PFS, 9.7 months vs 10.1 months vs 9.9 months).

In an interim analysis of OS, median OS was not reached with durvalumab monotherapy (95% CI, NR-NR) and durvalumab plus olaparib (95% CI, NR-NR), compared with 25.9 months (95% CI, 23.9-NR) with placebo (durvalumab vs control, HR, 0.77 [95% CI, 0.56-1.07]; durvalumab plus olaparib vs control, HR, 0.59 [95% CI, 0.42-0.83]). “Interim OS data showed a positive trend in both experimental arms,” Westin said.

Grade 3 or higher adverse events (AEs) were observed in 133 patients (56.4%) of the control arm, 129 (54.9%) in the durvalumab arm, and 160 (67.2%) in the durvalumab plus olaparib arm. Overall, AEs that led to treatment discontinuation occurred in 18.6%, 20.9%, and 24.4% of patients in the control, durvalumab, and durvalumab plus olaparib arms, respectively, whereas dose interruptions were seen in 50.0%, 54.5%, and 68.9% of patients. In the maintenance phase, discontinuation occurred in 4.1%, 6.0%, and 14.1%, respectively, while interruptions were seen in 21.9%, 28.4%, and 58.9%.

Any grade AEs occurring in 20% or more of patients included anemia, alopecia, fatigue and asthenia, nausea, neutropenia, constipation, diarrhea, thrombocytopenia, arthralgia, peripheral neuropathy, peripheral sensory neuropathy, vomiting, decreased appetite, leukopenia, and urinary tract infection.

“The safety profiles across treatment arms were generally consistent with the known profiles of each individual agent,” Westin added.

In the global, double-blind, placebo-controlled phase 3 trial, investigators randomized patients 1:1:1 to receive either of the following:

  • carboplatin/paclitaxel plus placebo every 3 weeks, followed by placebo maintenance therapy (control arm; n = 241)
  • carboplatin/paclitaxel plus durvalumab every 3 weeks, followed by maintenance therapy with 1500 mg durvalumab IV every 4 weeks plus placebo (durvalumab arm; n = 238)
  • carboplatin/paclitaxel plus durvalumab every 3 weeks, followed by maintenance therapy with 1500 mg durvalumab IV every 4 weeks plus 300 mg oral olaparib (durvalumab plus olaparib arm; n = 239).

Patients were treated until disease progression, unacceptable toxicity, or other discontinuation criteria were met. Of note, those without evidence of disease progression during the chemotherapy stage were transitioned to the maintenance phase.

Patients were eligible for the trial if they had newly diagnosed FIGO 2009 stage III/IV or recurrent endometrial cancer, known MMR status, were naïve to first-line systemic anticancer treatment for advanced disease, and were naïve to PARP inhibitors and immune-mediated therapy. In addition, adjuvant chemotherapy was allowed if patients were 12 months or more from their last treatment to relapse, and all histologies were allowed, except sarcomas.

Patients were stratified by MMR status, disease status, and geographic region. In the control, durvalumab monotherapy, and durvalumab plus olaparib arms, 80, 81, and 80 patients, respectively, had pMMR disease, compared with 20, 19, and 20 patients who had dMMR disease, while 68, 71, and 63 patients were PD-L1 positive, vs 31, 26, and 34 patients who were negative for PD-L1.

PFS for the durvalumab and durvalumab plus olaparib arms served as the primary end points. Key secondary end points included OS and safety, while PFS in the durvalumab plus olaparib arm vs durvalumab alone and subgroup analyses of PFS, including MMR, PD-L1, and HRRm status, were exploratory end points.

In total, 169 patients (70%) in the control arm, 183 patients (77%) in the durvalumab monotherapy arm, and 192 patients (80%) in the combination maintenance therapy arm started the maintenance phase of the trial. Further, 147 (61%), 159 (67%), and 170 (71%) patients in each arm were still ongoing in the study at a data cutoff date of April 12, 2023.

“The treatment options for most patients with advanced endometrial cancer are limited, especially for those with mismatch repair proficiency, and have not changed for many years,” Susan Galbraith, executive vice president of Oncology Research and Development at AstraZeneca, stated in a press release.3 “We are delighted that these DUO-E data show meaningful clinical improvements for patients when [durvalumab] and [olaparib] are combined or when [durvalumab] is added alone. We look forward to discussing these data with global regulatory authorities and bringing these important new treatment approaches to patients as soon as possible.”

References

  1. Westin SN, Moore KN, Chon HS, et al. Durvalumab (durva) plus carboplatin/paclitaxel (CP) followed by maintenance (mtx) durva ± olaparib (ola) as a first-line (1L) treatment for newly diagnosed advanced or recurrent endometrial cancer (EC): Results from the phase III DUO-E/GOG-3041/ENGOT-EN10 trial. Ann Onc. 2023;34(S2):S1277-S1278. doi:10.1016/j.annonc.2023.10.035
  2. 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. Published October 21, 2023. doi:10.1200/JCO.23.02132
  3. Imfinzi (durvalumab) plus Lynparza (olaparib) reduced the risk of disease progression or death by 45% vs. chemotherapy in advanced or recurrent endometrial cancer. News release. AstraZeneca. October 21, 2023. Accessed: October 21, 2023. https://www.astrazeneca-us.com/media/press-releases/2023/imfinz-durvalumab-plus-lynparza-olaparib-reduced-the-risk-of-disease-progression-or-death-by-45-vs-chemotherapy-in-advanced-or-recurrent-endometrial-cancer.html
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