Antitumor activity of PSMA ADC after progression on docetaxel in a mouse xenograft model of human prostate cancer

Abstract

3030 Background: Currently, there are no approved therapies for castration-resistant metastatic prostate cancer that has progressed following docetaxel therapy. Prostate-specific membrane antigen (PSMA) is an attractive target for antibody-targeted therapy of prostate cancer due to its abundant and restricted expression on the surface of prostate cancer cells. We have developed a novel antibody-drug conjugate (ADC) by linking a fully human PSMA monoclonal antibody to monomethylauristatin E (MMAE), a potent tubulin inhibitor. Here, we describe the use of PSMA ADC in a mouse model to treat xenografted human prostate tumors that have progressed following docetaxel therapy. Methods: Nude mice were implanted subcutaneously with 5 x 106 C4–2 human prostate cancer cells. Animals were first randomized to receive weekly intravenous (IV) doses of either 2 mg/kg docetaxel (n = 50) or vehicle (n = 10). Docetaxel significantly reduced tumor growth (p = 0.025) during the initial phase of the study; however, most of the tumors later progressed. When the tumor volume of an animal in the docetaxel group exceeded 400 mm3, the animal was rerandomized to receive continued docetaxel therapy (n = 18) or weekly IV doses of 6 mg/kg PSMA ADC (n = 18). Treatment effects were assessed by measuring tumor volume and overall survival. When tumor volume was assessed to be ≥2,000 mm3, animals would be sacrificed. Results: At 134 days following tumor implantation, the survival rate was 100% for animals in the PSMA ADC treatment group; 94% of these mice had tumor sizes <100 mm3. In the continued docetaxel treatment group, 14 of 18 animals that were sacrificed when their tumors exceeded 2,000 mm3; the survival rate was 22%. Therefore, PSMA ADC treatment significantly shrank tumors and increased overall survival of animals compared to continued docetaxel treatment (p < 0.0001). Conclusions: PSMA ADC had antitumor activity in mice to xenografted human prostate tumors that had progressed following docetaxel treatment. Treatment with PSMA ADC significantly extended survival in this setting. [Table: see text]