PARP Inhibitor-Based Triplet Regimen ‘Feasible’ For Advanced Endometrial Carcinoma

By Lynda Williams, medwireNews Reporter 

medwireNews: Combining olaparib with metronomic cyclophosphamide and metformin may offer a novel approach for patients with advanced endometrial carcinoma, the ENDOLA trial investigators have reported at the 2022 AACR Annual Meeting in New Orleans, Louisiana, USA. 

Presenting author Benoit You, from Hospices Civils de Lyon in France, explained that the triplet regimen is designed to target the frequently detected endometrial carcinoma characteristics of defective DNA repair and alterations in the PI3K-AKT-mTOR and IGFR pathways. 

He hypothesised that there would be a “synergistic effect by the three drugs” to maximise PARP inhibition, with metronomic cyclophosphamide expected to induce anti-angiogenic effects known to aid the efficacy of PARP inhibitors via the downregulation of the DNA repair protein RAD51 and homologous recombination, and a similar RAD51 downregulation also achieved by metformin inhibition of PI3K. 

The open-label trial recruited 31 patients aged a median of 69 years, over half of whom had previously received four or more lines of prior treatment (4–5 lines, 25.8%; 6 or more lines, 29.0%). The majority (58.1%) of participants had endometrioid carcinoma, 11.0% serous carcinoma and 6.5% carcinosarcoma. 

The phase I dose-escalation part of the study included 17 patients who were given olaparib twice daily at doses of 150–300 mg, with a gradual introduction of cyclophosphamide 50 mg/day and metformin 500 mg thrice daily. 

The only dose-limiting toxicity in this phase was one case of grade 3 fatigue during cycle 1 of olaparib 150 mg twice daily; the recommended olaparib dose for phase II was therefore fixed at 300 mg twice daily plus metronomic cyclophosphamide and metformin. 

The primary endpoint of the phase II part of the trial on this regimen was achieved, with 61.5% of 14 patients free from progression at 10 weeks. The objective response rate was 20.8% and the disease control rate 66.6%. 

Benoit You reported a complete response in a patient with carcinosarcoma, as well as partial responses in patients with endometrioid and serous carcinoma histology. Median progression-free survival (PFS) was 5.1 months, ranging from 4.3 months in the serous carcinoma group up to 7.5 months for those with endometrioid carcinoma. 

The presenter also described treatment tolerability as “very good”, although dose reductions were required in 38% of the whole study cohort, including multiple reductions in nine patients, and two (6%) discontinuations related to toxicity. 

The most common treatment-related adverse events were haematological, including grade 3–4 lymphopenia (32.3%), anaemia (16.1%), neutropenia (16.1%), thrombocytopenia (6.5%), and grade 3–4 fatigue (12.9%). 

Benoit You summarised that “the triplet combination was feasible in an elderly, heavily pretreated population of patients and with recurrent advanced endometrial carcinoma.” 

The presenter compared the findings with the median PFS of 7.2 months achieved in the KEYNOTE-775 trial of pembrolizumab plus lenvatinib versus chemotherapy, including a median 7.6 months for endometrioid cancer and 5.7 months for serous carcinoma. He noted the similar outcomes to those of the ENDOLA trial despite the KEYNOTE-775 regimen being given mostly as a second-line therapy and to a younger population. 

“We consider that this chemotherapy-free regime warrants further investigation”, the investigator concluded, adding that translational research assessing biomarkers is ongoing for the study. 

Session discussant Rowan Miller, from University College London Hospital in the UK, praised the “strong scientific rationale” for combining the agents in the study and said there were “promising signs of activity” in the heavily pretreated population, meriting “further evaluation”. 

She added that response would likely be linked to biomarkers and therefore “translational analysis is key”. 

Reference 

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. AACR Annual Meeting 2022; New Orleans, Louisiana, USA: 8–13 April.