PARP Inhibitor-Based Triplet Promising in Endometrial Cancer

NEW ORLEANS — A triplet combination of the PARP inhibitor olaparib (Lynparza), metronomic cyclophosphamide, and metformin was feasible and showed encouraging efficacy in elderly, heavily pretreated patients with recurrent, advanced endometrial carcinoma, according to results from the ENDOLA trial presented here.

The combination achieved a non-progression rate of 61.5% (95% CI 42.8-80.2) at 10 weeks in 14 evaluable patients.

The overall response rate was 20.8% and the disease control rate 66.6%, reported Benoit You, MD, PhD, of Lyon University Hospital in France, during a session of the annual meeting of the American Association for Cancer Research.

“The ENDOLA trial data really supports the use of PARP inhibitors in endometrial cancer,” said discussant Rowan Miller, MBBS, PhD, of University College London. “This triplet combination — olaparib, metformin, and cyclophosphamide — really merits further evaluation.”

You also reported a median progression-free survival (PFS) of 5.1 months (95% CI 3.7-8.1) for the evaluable cohort of patients, with a PFS of 7.5 months (95% CI 5.1-8.9) for those with endometrioid carcinomas and 4.3 months (95% CI 2.7-5.8) for patients with serous carcinomas.

He noted that the current reference treatment of pembrolizumab (Keytruda) plus lenvatinib (Lenvima) had a median PFS of 7.2 months, including 7.6 months for endometrioid carcionoma and 5.7 months for serous carcinoma, as previously reported in the KEYNOTE-775 trial.

“Most of those patients were treated in the second line and were younger,” You pointed out.

“It is worth noting that in the KEYNOTE trial, the backbone was standard-of-care chemotherapy, which had a PFS of only 3.8 months, with the ENDOLA results being far superior to this,” Miller observed. She also pointed out that results from the NRG-GY012 study, which compared the combination of cediranib plus olaparib versus both as monotherapy, showed a median PFS of 5.5 months, “which is comparable to that seen in the ENDOLA trial, despite these patients having far fewer lines of treatment.”

The ENDOLA trial enrolled 35 patients at six French centers from September 2016 to November 2019, 31 of whom were assessable. Seventeen patients were included in the phase I component of the study, which assessed safety, and the remainder in phase II to assess the efficacy of the combination in terms of non-progression at 10 weeks.

Recommended drug doses in phase II were olaparib 300 mg twice daily, metronomic cyclophosphamide at 50 mg daily, and metformin 500 mg daily.

Of the 31 patients in the study, 18 had endometrial carcinoma, 11 serous carcinoma, and two had carcinosarcoma.

The median age of the trial population was 69 years, and 54.8% of patients had four or more lines of previous therapy, with about a quarter of these having received at least six lines of therapy. More than 90% had no prior radiotherapy or treatment with immunotherapy, while nine patients had previous endocrine therapy.

Regarding safety, most treatment-related adverse events in the entire cohort of 31 patients were grade 1 or 2 in nature. The most common were anemia (71%), asthenia/fatigue (61.3%), nausea (54.8%), lymphopenia (38.7%), diarrhea (32.3%), neutropenia (32.3%), and thrombocytopenia (29.0%).

Dose reductions were reported in 12 patients, including nine who had at least two reductions. “This is something we can see in our routine practice, where there is a small proportion of patients who really don’t tolerate PARP inhibitors,” You explained.

Two patients discontinued treatment due to toxicity.

You said there was a strong rationale for the design of this triplet regimen. “We thought that the metronomic dosing of chemotherapy would be associated with anti-angiogenic 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.”

“It is a probability that there will be a biomarker-defined subgroup that will have the greatest response and the translational data will be key for defining this,” said Miller. ” There are numerous ongoing trials looking at PARP inhibitors in endometrial cancer as both monotherapy and in combinations in the adjuvant, maintenance, and recurrence setting.”

Many of these are incorporating biomarkers, she added. “With time, we hope the results of these studies will further define the role of PARP inhibitors in endometrial cancer.”