Abstract 1685: In vivo efficacy of PSMA ADC in combination with enzalutamide in castration-resistant prostate cancer
Authors: DiPippo Vincent A. , Nguyen Holly M. , Brown Lisha G. , Olson William C. , Vessella Robert L. , Corey Eva 
Published: August 2015

Despite multiple new treatment options for patients with castration-resistant prostate cancer (CRPC), the overall survival benefit still remains relatively short. Therefore, it is possible that combining these and other new agents can potentially broaden individual therapeutic windows by achieving greater efficacy and improved safety profiles. Prostate-specific membrane antigen antibody-drug conjugate (PSMA ADC), a fully human anti-PSMA antibody linked to monomethylauristatin E (MMAE), is currently in phase 2 development for the treatment of CRPC. We have previously demonstrated significant efficacy of PSMA ADC in advanced prostate cancer patient-derived xenografts and moreover have also shown synergy between PSMA ADC and enzalutamide (ENZ) in vitro. The objective of the current studies was to evaluate the efficacy of PSMA ADC in combination with ENZ to inhibit CRPC patient-derived xenografts (PDX) in a preclinical setting.

First, we performed a pilot study to determine a sub-optimal dose for PSMA ADC, using LuCaP 96CR, a model of CRPC with high PSMA expression that previously showed significant regressions in response to PSMA ADC. Animals bearing subcutaneous LuCaP 96CR were treated with a single dose of PSMA ADC (1, 2, or 5 mg/kg, IP) or a non-PSMA targeted ADC (5 mg/kg) and followed for up to 10 weeks. PSMA ADC demonstrated dose-dependent efficacy, and based on the results, a single dose of PSMA ADC (2 mg/kg) was selected for combination treatment with ENZ (50 mg/kg; 5x/week, oral gavage). The effects of the PSMA ADC+ENZ combination were compared to PSMA ADC alone, ENZ alone, and placebo control. At six weeks after the beginning of treatment the changes in tumor volume were: fold increases of enrollment tumor volume in control (4.9 ± 0.40); ENZ (2.83 ± 0.37); and PSMA ADC (1.6 ± 0.43); and decrease in tumor volume in the combination group (0.28 ± 0.10). In the control and ENZ groups all tumors were progressing at 6 weeks, while in the PSMA ADC group there were 4 tumors that had decreased tumor volume, and all 11 animals in the PSMA ADC + ENZ groups had regressing tumors. The tumor growth inhibition was also reflected by changes in serum PSA. Most interestingly, a 12-week follow up and survival analysis show that all three treatments resulted in significant survival benefits but the combination therapy effects were the most pronounced resulting in ENZ vs PSMA ADC+ENZ HR = 0.09 with P = 0.0415 and with no deaths observed in the combination group. No significant negative side effects were associated with the combination treatment. Additional post-treatment analyses are underway.

In summary, our results clearly indicate that the combination of PSMA ADC+ENZ possesses strong antitumor activity in the LuCaP 96CR model that is much more pronounced than the inhibitory effects of either agent alone. These results provide a strong rationale for clinical testing of PSMA ADC in combination with androgen-directed treatment strategies.

Citation Format: Vincent A. DiPippo, Holly M. Nguyen, Lisha G. Brown, William C. Olson, Robert L. Vessella, Eva Corey. In vivo efficacy of PSMA ADC in combination with enzalutamide in castration-resistant prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1685. doi:10.1158/1538-7445.AM2015-1685