A Phase II Trial of AEZS-108 in Castration- and Taxane-Resistant Prostate Cancer

Background: AEZS-108 (zoptarelin doxorubicin) is a cytotoxic hybrid molecule consisting of doxorubicin covalently coupled with a luteinizing hormone-releasing hormone (LHRH) analogue, which selectively targets doxorubicin to tumor cells expressing LHRH receptors. We report the clinical efficacy of AEZS-108 in a phase II trial in men with metastatic castrate-resistant prostate cancer who had disease progression after taxane-based chemotherapy. Patients and Methods: Patients received AEZS-108 210 mg/m² intravenously every 3 weeks. The primary end point was clinical benefit defined as nonprogression at 12 weeks with no dose-limiting toxicities (DLTs) or other toxicities requiring termination of treatment. Secondary end points included response rate, pain response, progression-free survival (PFS), and overall survival (OS). Circulating tumor cells (CTCs) were captured and tested for LHRH receptors, as well as for internalization of AEZS-108 using autofluorescence. Results: Twenty-five patients were enrolled; 20 patients had at least 1 measurable lesion at baseline. Patients received a median of 5 cycles (range, 1-9) and 44% of patients received at least 6 cycles with 2 patients who completed ≥ 8 cycles. Considering clinical benefits, 13 patients (52%) remained progression-free at 12 weeks with no DLT or other toxicities requiring termination of treatment. For clinical response according to Response Evaluation Criteria in Solid Tumors version 1.1 criteria, 1 patient (4%) experienced a confirmed partial response (PR) within 12 weeks, 14 patients (56%) had stable disease (SD), and 8 patients (32%) had disease progression. For maximal prostate-specific antigen (PSA) response, 1 patient (4%) experienced a confirmed PR within 12 weeks, 21 patients (84%) had SD, and 3 patients (12%) had disease progression as denoted by their best PSA response. Pain improved in 13 (59%) patients. The median PFS was 3.8 months (95% confidence interval [CI], 2.1-4.4), and median OS was 6.0 months (95% CI, 4.2-10.1) with a median follow-up of 16.1 months (range, 3.2-36.1). Baseline CTC enumeration was an independent predictor of OS but not PFS. Conclusion: AEZS-108 showed activity in patients who were pretreated, a subset typically very difficult to treat, and maintained an acceptable safety profile.