A triplet regimen consisting of the PARP (poly [ADP-ribose] polymerase) inhibitor olaparib, metronomic (the chronic administration of low, equally spaced doses of) cyclophosphamide, and metformin demonstrated activity in elderly, heavily pretreated patients with recurrent, advanced endometrial carcinoma, according to results from the ENDOLA trial, presented at the American Association for Cancer Research (AACR) Annual Meeting 2022.1 At 10 weeks, the triplet combination showed a non–disease progression rate of 61.5% in 14 evaluable patients. The overall response rate was 20.8%, and the disease control rate was 66.6%.
“In patients with recurrent endometrial cancer, there is a need for innovative approaches beyond first-line treatment,” said lead author Benoit You, MD, PhD, a medical oncologist at Lyon University Hospital (HCL, CITOHL), Lyon, France. “There was a very strong rational to create a less-toxic regimen with olaparib (a PARP inhibitor), metronomic cyclophosphamide (known to be an effective alkylating chemotherapy), and metformin (cited for its inhibition of the PI3K pathway and reduction of the circulation of IGF1).”
Benoit You, MD, PhD
Rowan Miller, MBBS, PhD
Invited discussant of the ENDOLA trial, Rowan Miller, MBBS, PhD, of University College London, was enthusiastic about the promise of this regimen. “The ENDOLA trial data support the use of PARP inhibitors in endometrial cancer. This triplet combination—olaparib, cyclophosphamide, and metformin—merits further evaluation,” Dr. Miller told listeners.
Median progression-free survival was 5.1 months for the evaluable cohort of patients, with progression-free survival of 7.5 months for patients with endometrioid carcinoma and 4.3 months for patients with serous carcinoma.
Dr. You pointed out that the current reference treatment of endometrial cancer consisting of pembrolizumab plus lenvatinib had a median progression-free survival of 7.2 months, including 7.6 months for endometrioid carcinoma and 5.7 months for serous carcinoma, as previously reported in the KEYNOTE-775 trial.2 “Notably, most of these patients were treated in the second-line setting and were younger [than those in the ENDOLA trial],” Dr. You added.
Dr. You explained the rationale for the design of this triplet regimen. “We thought the metronomic dosing of chemotherapy would be associated with antiangiogenic effects known to increase the effects of PARP inhibitors,” he said. “Moreover, inhibition of PI3K by metformin is thought to increase the activity of PARP inhibitors.”
From December 2016 to November 2019, the phase I/II ENDOLA trial enrolled 35 patients at six French centers; of these patients, 31 were evaluable. A total of 17 patients were included in the phase I part of the study, which assessed safety. The phase II part included 14 patients for efficacy assessment of the combination, as measured by the non–disease progression rate at 10 weeks.
As determined in phase I, the recommended phase II doses were olaparib at 300 mg twice daily, metronomic cyclophosphamide at 50 mg daily, and metformin at 1,500 mg daily.
Of the 31 patients in the study, 18 had endometrioid carcinoma, 11 had serous carcinoma, and 2 had carcinosarcoma. At baseline, the median patient age was 69, and 54.8% of patients had received four or more lines of previous therapy, with 29% of these treated with at least six lines of therapy. More than 90% had no prior radiotherapy or immunotherapy, and nine patients had previous endocrine therapy.
Among all 31 patients, most treatment-related adverse events were grade 1 or 2. The most common treatment-related adverse events included anemia (71%), asthenia/fatigue (61.3%), nausea (54.8%), lymphopenia (38.7%), diarrhea (32.3%), neutropenia (32.3%), and thrombocytopenia (29.0%). Grade 3 or 4 treatment-related adverse events included asthenia/fatigue (12.9%), lymphopenia (32.3%), neutropenia (16.1%), and thrombocytopenia (6.5%).
A total of 12 patients required dose reductions, 9 with at least two dose reductions. “This is something we can see in our routine practice, where there is a small proportion of patients who really do not tolerate PARP inhibitors,” Dr. You noted. Two patients discontinued treatment due to toxicity.
The translational analysis of the study is ongoing and includes the effect of PI3K and PARP pathways in peripheral blood mononuclear cells, CA-125, IGF1 kinetics, and circulating tumor DNA, along with DNA repair and PI3K-AMT-mTOR biomarkers.
Expert Point of View: Rowan Miller, MBBS, PhD
“It is worth noting that in the KEYNOTE-775 trial, the backbone was standard-of-care chemotherapy, which had a median progression-free survival of just 3.8 months, with the ENDOLA results being superior to this,” continued invited study discussant Dr. Miller.
“An ongoing study that compared the combination of the VEGF inhibitor cediranib plus olaparib vs both as monotherapy showed a median progression-free survival of 5.5 months, which is comparable to that seen in the ENDOLA trial, despite these patients having far fewer lines of treatment,” she continued.
“There may be a biomarker-defined subgroup that will have the greatest response, and the translational data will be key for defining this,” Dr. Miller said. “There are numerous ongoing trials looking at PARP [poly (ADP-ribose) polymerase] inhibitors in endometrial cancer as both monotherapy and in combinations in the adjuvant, maintenance, and recurrence settings.”
Many of these trials will incorporate biomarkers. “With time, we hope the results of these studies will further define the role of PARP inhibitors in endometrial cancer,” Dr. Miller stated.
DISCLOSURE: The study was supported by AstraZeneca and the French National Cancer Institute. Dr. You has served as a consultant to MSD, AstraZeneca, GlaxoSmithKline, Roche, Seagen, and Myriad. Dr. Miller has served as a consultant to MSD, AstraZeneca, GSK, Clovis Oncology, Roche, Ellipses, and Shionogi.
1. You B, Leary A, Rodrigues M, et al: L Safety and efficacy of olaparib combined to metronomic cyclophosphamide and metformin in recurrent advanced/metastatic endometrial cancer patients: ENDOLA trial. 2022 AACR Annual Meeting. Abstract CT005. Presented April 10, 2022.
2. Makker V, Colombo N, Casado Herráez A, et al: Lenvatinib plus pembrolizumab for advanced endometrial carcinoma. N Engl J Med 386:437-448, 2022.