ENDOLA Study Demonstrates Promise of Olaparib Triplet in Endometrial Cancer

Treatment with the combination of olaparib (Lynparza) in combination with metronomic cyclophosphamide and metformin demonstrated a significant non-progression rate in patients with recurrent advanced or metastatic endometrial cancer, according to findings from the ENDOLA trial (NCT02755844).¹

In the dose-escalation phase of ENDOLA, olaparib was started at 150 mg twice daily in cycle 1 and escalated up to 300 mg twice daily. Using the continual reassessment method, the recommended phase 2 trial dose was then confirmed to be 300-mg olaparib twice daily plus 50-mg metronomic cyclophosphamide once daily plus 500-mg metformin thrice daily.

In an evaluation of this dose in the phase 2 portion of the trial, the non-progression rate at 10 weeks was 61.5% (95% CI, 42.8%-80.2%) in the 14 evaluable patients. The overall response rate (ORR) was 20.8%, with a disease-control rate of 66.6%.¹

“In patients with recurrent endometrial cancer, there is a need for innovative approaches beyond first-line treatment,” Benoit You, MD, academic staff physician in the Medical Oncology department at Lyon University Hospital in France, said in a presentation during the AACR Annual Meeting 2022. “There was a very strong rationale to create a chemotherapy-free triplet regimen with olaparib—a PARP inhibitor—with metronomic cyclophosphamide—known to be an effective alkylating chemotherapy—and metformin—cited for its inhibition of the P13K pathway and reducing the circulation of IGF1 and the activation of this pathway. We could expect a cytogenic effect from these 3 drugs.”

ENDOLA was a phase 1/2 open-label, dose-escalation trial evaluating olaparib with metronomic cyclophosphamide and metformin in elderly, heavily pretreated patients with recurrent advanced endometrial cancer. A dose-limiting toxicity (DLT) assessment period was implemented every 6 weeks within the 28-day cycles and the optimal dose was determined as that associated with probability of a DLT in less than 20% of patients.

In phase 1, 5.9% of patients experienced a dose-limiting toxicity; specifically, they experienced grade 3 fatigue during cycle 1 with the 150-mg olaparib dose level.

Of the 35 patients enrolled, 31 patients were evaluable—17 patients were in phase 1 and 14 patients were in phase 2.

Notably, the median age was 69 years (range, 46-80), and more than half of the patient population was previously treated with at least 4 lines of therapy (4-5 lines, 25.8%; ≥ 6, 29%).

Most patients had endometroid carcinoma (58.1%), while the remaining had serous carcinoma (11%) or carcinosarcoma (6.5%). Most patients did not receive prior treatment with radiation therapy (93.5%) or immunotherapy (93.5%). Additionally, some patients were previously treated with endocrine therapy, including acetate of megestrol (9.6%), tamoxifen (6.5%), or an aromatase inhibitor (12.9%).¹

Aside from establishing the recommended phase 2 trial dose of the triplet, the other primary end points in the phase 1 component of the study were safety, dose-limiting toxicities, and treatment-related adverse events (TRAEs).

TRAEs were observed in more than 10% of evaluable patients. Notable TRAEs included: asthenia/fatigue (all grade, 61.3%; grade 3/4, 12.9%), lymphopenia (all grade, 38.7%; grade 3/4, 32.3%), neutropenia (all grade, 32.3%; grade 3/4, 16.1%), and thrombocytopenia (all grade, 29.0%; grade 3/4, 6.5%).

Twelve patients (38%) had a dose reduction, including 9 who had at least 2 reductions. Study treatment discontinuation due to toxicity occurred for 2 patients (6%).¹

In the phase 2 portion, investigators evaluated the non-progression rate at 10 weeks. The null hypothesis was a P0 of 20% and the alternative hypothesis was a P1 of at least 50%. In the first stage, out of 10 patients, at least 3 needed to have a success to continue onto the second stage. And once in the second stage, out of 17 patients, at least 6 were required to have a success for the trial to be considered positive. Imaging assessment was performed every other cycle.

A secondary end point in the phase 2 component of note was progression-free survival (PFS). The median PFS was 5.1 months (95% CI, 3.7-8.1); specifically, for patients with endometroid carcinomas, the median was 7.5 months (95% CI, 5.1-8.9), and for patients with serous carcinomas, it was 4.3 months (95% CI, 2.7-5.8).¹

In his presentation, You compared the PFS data to that of the KEYNOTE-755 trial (NCT03517499), in which patients with advanced endometrial cancer who had previously received at least 1 platinum-based chemotherapy regimen received either 20-mg lenvatinib (Lenvima) orally once daily plus 200-mg pembrolizumab (Keytruda) intravenously every 3 weeks (n = 411) or physician’s choice chemotherapy (n = 416). In this phase 3 trial, the median PFS for those who received the doublet was 7.2 months (95% CI, 5.7-7.6) vs 3.8 months (95% CI, 3.6-4.2) with chemotherapy alone (HR, 0.60; 95% CI, 0.50-0.72; P < .001). The ORR was 31.9% (95% CI, 27.4%-36.6%) vs 14.7% (95% CI, 11.4%-18.4%).² Specifically, for patients with endometroid carcinomas, the median was 7.6 months, and for patients with serous carcinomas, it was 5.7 months.³

“Notably, most of these patients [in KEYNOTE-755] were treated in second-line treatment and were younger,” You added. “So, we consider that [olaparib plus metronomic cyclophosphamide plus metformin] is a chemotherapy-free regimen that warrants further investigation.”

You said the translational research tied to this study includes the effect of PI3K and PAR pathways in PBMCs, CA-125, and IGF1 kinetics, and circulating tumor DNA, along with DNA repair and PI3K-AMT-mTor biomarkers. This research is ongoing, You concluded.

_References

_{1. You B, Leary A, Rodrigues M, et al. Safety and efficacy of OLAparib combined to metronomic cyclophosphamide and metformin in recurrent advanced/metastatic ENDOmetrial cancer patients: ENDOLA trial. Presented at: 2022 AACR Annual Meeting; April 8-13, 2022. New Orleans, LA. Abstract CT005.}

_{2. Makker V, Colombo N, Casado Herráez A, et al; Study 309–KEYNOTE-775 Investigators. Lenvatinib plus pembrolizumab for advanced endometrial carcinoma. N Engl J Med. 2022;386(5):437-448. doi:10.1056/NEJMoa2180330}

_{3. Colombo N, Lorusso D, Casado Herráez A, et al. Outcomes by histology and prior therapy with lenvatinib plus pembrolizumab vs treatment of physician’s choice in patients with advanced endometrial cancer (Study 309/KEYNOTE-775). Ann Oncol. 2021;32(suppl 5):S729-S730. doi:10.1016/j.annonc.2021.08.1169}