At the on-going AUA Meeting, Dr. Howard Scher along with a collaborating group of medical oncologists reported their data from a Phase I-II trial of MDV3100 in castration-resistant prostate cancer (CRPC).

MDV3100 is an oral androgen receptor (AR) antagonist (androgen blocker). Their findings show that it binds to the androgen receptors (AR) on the surface of prostate cancer cells with greater affinity then other currently used drugs and prevents nuclear translocation of AR with greater efficiency than bicalutamide (casdoex).

MDV3100 uses a different pathway so, unlike bicalutamide, MDV3100 blocks DNA binding of AR, causing tumor cell apoptosis and more importantly, it has demonstrated no known agonist activity when AR is over expressed. The bottom line result is that unlike bicalutamide, MDV3100 will not stimulate AR as an agonist, or feed the cancer.

For the purpose of the study, the anti-tumor activity of MDV3100 was assessed by PSA measures, soft tissue, osseous disease and circulating tumor cells (CTC). Survival benefits were not assessed in these trials.

Men included in the trial had progressive castration-resistant prostate cancer and were enrolled in sequential groups of 3-6 men at 30, 60, 150, 240, 360, 480, and 600 mg/day. Once the safety of a dose was established, enrollment was expanded at doses > 60 mg/day to include approximately 24 additional men per group.

A total of 140 men were enrolled. PSA declines (>50% from baseline) occurred in 62% (40/65) of chemotherapy-naïve and 51% (38/75) of post-chemotherapy men. Twenty-five chemotherapy-naive and 34 post-chemo patients had evaluable soft tissue disease at baseline. Partial responses were seen in 36% (9/25) of chemo-naïve and 12% (4/34) of post-chemo men.

Stable disease was observed in 44% (11/25) of chemo-naïve and 53% (18/34) of post-chemo men. For men with baseline bone metastasis, there was evidence of radiographic stabilization in 63% (26/41) of chemo-naïve and 51% (35/68) of post-chemo men.

Median time to PSA progression was not reached in chemo-naïve men and was 186 days for post-chemo men. Median time to radio-graphic progression was not reached in chemo-naive men and was 201 days in post-chemo men.

CTC counts are known to correlate with disease progression in men with castration-resistant prostate cancer. A favorable CTC count is <5 cells while an unfavorable count is >5 cells/7.5cc of blood. CTC counts on 60 of 65 chemo-naive men showed 91% (40/44) with favorable pretreatment counts maintained favorable post-treatment counts, while 75% (12/16) converted from unfavorable to favorable post-treatment. CTC counts on 68 of 75 post-chemo men showed favorable retention for 91% (30/33) and unfavorable to favorable conversion for 37% (13/35).

Fatigue was the most frequently reported adverse event of MDV3100. There were 2 witnessed seizures (1 each at 600 and 360 mg/day); both men were taking concomitant medications that could cause seizures. Maximum tolerated dose of 240 mg/day was selected. A Phase 3 placebo-controlled survival trial in post-docetaxel CRPC men is underway.

MDV3100 clearly has the potential to replace the current standard of care, bicalutamide (casdoex). It looks to be an excellent androgen blocker with fewer possible downsides.

Presented at the AUA Meeting by Howard I. Scher, Tomasz M. Beeb, Celestia S. Higano, Christopher Logothetis, Mary-Ellen Taplin, Eleni Efstathiou, and Mohammad; May 29 – June 3, 2010 – Moscone Center, San Francisco, CA USA

Joel T Nowak, MA. MSW