A randomized, open-label, phase II study of MDV3100 alone or in combination with leuprolide and dutasteride as neoadjuvant therapy to prostatectomy in intermediate and high-risk prostate cancer.

Abstract

TPS4695 Background: MDV3100 is a potent androgen receptor (AR) signaling inhibitor (ARSI) that inhibits AR signaling via three mechanisms: inhibition of androgen binding to AR, inhibition of AR nuclear translocation, and inhibition of nuclear AR-DNA binding. In vivo, MDV3100 induces significant prostate cancer apoptosis, an effect not seen with anti-androgens. To date, the use of neoadjuvant androgen deprivation therapy has not led to an improvement in time to PSA progression (Soloway 2002; Aus 2002). While serum androgens may be suppressed using luteinizing hormone-releasing hormone agonists, intratumoral levels of androgens remain, driving continued AR signaling and prostate cancer survival. More effective inhibition of AR signaling may improve local and systemic disease control. Methods: MDV3100-07 will assess the effect of 6 mos of neoadjuvant AR blockade with AR inhibition alone (MDV3100) or in combination with maximal suppression of androgens (MDV3100 +leuprolide [L] + dutasteride [D]). Eligible patients will have treatment-naive localized prostate cancer and be candidates for radical prostatectomy. Patients must have either PSA > 10 ng/mL or Gleason score ≥ 7 (4 + 3) with ≥3 cores containing tumor. Patients with evidence of metastatic/nodal disease are excluded. All patients receive MDV3100 (160 mg/d PO); those randomized to MDV3100+L+D therapy also receive L (22.5mg IM q3m) and D (0.5 mg/day PO). Serum/tumor androgen levels will be serially assessed. Tissue from the diagnostic and prostatectomy specimens will be evaluated for androgen levels, AR signaling profiles, and selected markers of apoptosis and mitotic indices. The primary efficacy endpoint is pathological complete response (pCR) rate at time of radical prostatectomy. For each arm, the percent of patients who achieve a pCR will be compared to the percent pCR in patients treated with neoadjuvant leuprolide, estimated to be 5% in a mixed low-to-intermediate risk population. Target Accrual: 40 pts will be randomized 1:1 to MDV3100 or MDV3100+L+D therapy. Keywords:MDV3100, prostate cancer, androgen receptor, anti-androgen, Phase 2, neoadjuvant.