New chemo-free triplet regimen shows promise for endometrial cancer

A triplet regimen combining the PARP inhibitor olaparib with metronomic cyclophosphamide and metformin showed favourable signals for heavily pretreated women with advanced endometrial carcinoma, the phase I/II ENDOLA study suggests.

“In patients with recurrent advanced endometrial carcinomas, innovative treatments are needed after platinum chemotherapy (CT),” said presenter Dr Benoit You from Lyon University Hospital, France, at AACR 2022. “There was a very strong rationale for combining these three drugs because endometrial carcinoma is characterized by frequent DNA repair alteration.”

“There is also very frequent alteration of PI3K-AKT-mTor and IGF1R pathways. [As such,] we designed this CT-free triplet regimen, thinking it would be more effective than the standard CT [for this patient group],” You continued.

The aim of ENDOLA was to assess the safety (phase I) and efficacy (phase II) of the triplet regimen in women with endometrial carcinoma who had recurred following first-line CT with carboplatin-paclitaxel (n=35 [31 evaluable]; median age 69 years). More than half of the evaluable cases were endometrioid (n=18), while the remainder were either serous (n=11) or carcinosarcoma (n=2). [AACR 2022, abstract CT005]

In phase I (n=17), olaparib dose was escalated from 150 mg to 300 mg BID with continued re-assessment, aiming at defining the recommended phase II trial dose. Metronomic cyclophosphamide was given at a dose of 50 mg QD, while metformin 500 mg was given TID. Phase II (n=14) looked at the efficacy of the triplet regimen in terms of non-progression rate at 10 weeks.

In the phase I part, only one dose-limiting toxicity was observed – grade 3 fatigue during cycle 1 with olaparib 150 mg, suggesting that the regimen was well tolerated.

In phase II, non-progression rate at 10 weeks was 61.5 percent, achieving the study’s primary endpoint. “We are expecting more than 50 percent. [Hence,] this was a positive trial,” You said. Overall response rate was 20.8 percent and disease control rate was 66.6 percent.

Median progression-free survival was 5.1 months. “[This] is promising compared with those observed with CT or an immunotherapy-based combination in [another study],” he continued.

Three treatment-related serious adverse events were reported: grade 3 fatigue, grade 4 lymphopenia, and grade 4 lymphopenia and neutropenia. “[These were] mainly haematologic toxicities because patients had been previously treated with CT,” You explained.

About 40 percent of participants required dose reductions by up to two dose levels, said You. “[This means our patients] were not tolerating their dose very well. [However,] this is what we see now in routine practice with PARP inhibitors.”

“[Overall, our findings demonstrate that] olaparib 300 mg BID could be safely combined with daily metformin 1,500 mg and metronomic cyclophosphamide 50 mg in heavily pretreated patients with advanced endometrial carcinoma,” said You. Considering that most of the participants were elderly – with a majority receiving several lines of CT (ie, up to six in 40 percent of participants), “[we can] consider the triplet CT-free combination effective.”

You called for further investigation of this combination regimen in a phase III trial. Biomarker analysis is underway to identify which patients can best benefit from this innovative CT-free regimen.