Background: Luteinizing hormone-releasing hormone receptors (LHRH-R) are expressed in ~86% of prostate cancers, with sustained expression despite prolonged exposure to LHRH agonists. Limited expression of LHRH-R on normal cells suggests LHRH-R may be a therapeutic target for prostate cancer. Zoptarelin doxorubicin is a cytotoxic hybrid molecule linking doxorubicin to an LHRH analog that selectively targets doxorubicin to cancer cells expressing LHRH-R. Methods: This Phase 2 trial evaluated the clinical benefit of zoptarelin doxorubicin for metastatic castration-resistant prostate cancer (mCRPC) following androgen deprivation therapy and ≥1 taxane-based regimen. The primary endpoint was clinical benefit (CB) defined as progression-free survival (PFS) per RECIST v1.1 at 12 weeks with no dose-limiting toxicities (DLT) or other toxicities resulting in treatment cessation. Secondary endpoints were time to overall progression, response rate, pain response, overall survival (OS), and PSA response. Results: Of 25 patients enrolled, 20 had ≥1 measurable lesion at baseline with PFS ≥12 weeks achieved in 56% and PSA response of PR (4%) and SD (84%). Median PFS and OS were 3.8 and 6.0 months, respectively. Reduced pain was reported by 59%. Treatment was well tolerated, with no cardiotoxicity and neutropenia (all grades) the most common hematologic adverse event. Conclusions: This phase 2 trial demonstrated clinical benefit in 56% of patients with no DLT or other toxicity requiring treatment termination. These results suggest a role for zoptarelin doxorubicin for mCRPC following progression on second- and third-line hormonal therapy. Clinical trial information: NCT01240629