Zoptarelin Doxorubicin Falls Short in Phase III Endometrial Cancer Trial

Emese Zsiros, MD, PhD

Emese Zsiros, MD, PhD

Zoptarelin doxorubicin (Zoptrex), a hybrid molecule combining an LHRH-agonist and doxorubicin, failed to improve median overall survival (OS) in a phase III advanced endometrial cancer trial, according to the manufacturer of the treatment, Aeterna Zentaris.

In results from the pivotal ZoptEC trial, median OS was 10.9 months for women with locally advanced, recurrent, or metastatic endometrial cancer assigned to zoptarelin compared with 10.8 months for patients assigned to doxorubicin alone.

“Despite the promising phase II results, the phase III trial, in a large number of patients, unfortunately did not confirm any survival benefit with the new drug formulation,” said Emese Zsiros, MD, PhD, who reviewed the findings for OncLive. “Although doxorubicin is considered to be an active second-line agent in endometrial cancer, the overall response rate is still very low, and the new formulation did not improve the efficacy of this treatment,” said Zsiros, an assistant professor of oncology in the department of gynecologic oncology/Center for Immunotherapy at Roswell Park Cancer Institute.

Researchers also found that zoptarelin did not improve progression-free survival (PFS) compared with doxorubicin and that there was no meaningful difference in safety between the 2 treatments.

“Therefore, the results of the study are not supportive to pursue regulatory approval,” Richard Sachse, MD, PhD, chief scientific officer at Aeterna Zentaris, said in a statement.

“We are very disappointed with the outcome of the ZoptEC phase III clinical study,” added Aeterna Zentaris CEO David A. Dodd. “Based on this outcome, we do not anticipate conducting clinical trials of Zoptrex with respect to any other indications.”

Women participating in ZoptEC (N = 512) were randomly assigned in a 1:1 ratio to 267 mg/m² IV of zoptarelin or 60 mg/m² IV of doxorubicin every 3 weeks for up to 9 cycles. The primary endpoint was OS, and secondary endpoints included PFS, objective response-rate, and clinical benefit rate. Response was evaluated every 3 cycles during treatment, then every 12 weeks until progression.

Researchers proceeded to phase III following a phase II study in Germany and Bulgaria conducted from April 2008 to November 2009. Based on those results, Emons et al concluded that zoptarelin had “significant activity and low toxicity” in women with stage 3/4 LHRH-positive endometrial cancer.

In the phase II trial, patients (N = 44) received 267 mg/m² of IV zoptarelin on day 1 of a 21-day cycle. Patients underwent 6 to 8 cycles of treatment.

Overall response rate was 23% in that study with a clinical benefit rate of 70%. Two patients (5%) had a complete response, 1 that lasted for 8 months and 1 that lasted for 23 months. Eight (19%) patients had a partial response and 20 (47%) had stable disease. Nine (21%) patients had progressive disease, and 4 patients were not evaluable.

Median OS was 15 months and median time to progression was 7 months.

The most common grade 3/4 adverse events were neutropenia (12%) and leucopenia (9%).

This marks the second setback for Aeterna Zentaris this year. The company announced in January that macimorelin (Macrilen), a ghrelin agonist for evaluating adult growth hormone deficiency (AGHD), failed in phase III testing. Dodd said that the company is still planning to submit a new drug application for macimorelin later this year in hopes of bringing the drug to market early in 2018.

“Our focus has now shifted entirely to filing our new drug application for Macrilen and, if the product is approved, to its commercial launch as soon as possible,” he said. “We continue to believe in the potential that Macrilen provides for us to become a focused specialty pharmaceutical company.”

The FDA rejected macimorelin in 2014, saying that Aeterna Zentaris would have to conduct a new trial to demonstrate efficacy.

Emons G, Grigor G, Harter P, et al. Efficacy and safety of AEZS-108 (LHRH agonist linked to doxorubicin) in women with advanced or recurrent endometrial cancer expressing LHRH receptors: a multicenter phase 2 trial (AGO-GYN5). Int J Gynecol Cancer. 2014;24:260-265.