Association of rash with outcomes in a randomized phase II trial evaluating cetuximab in combination with mitoxantrone plus prednisone after docetaxel for metastatic castration-resistant prostate cancer

This randomized phase II clinical trial analyzed the efficacy of combining cetuximab with mitoxantrone plus prednisone in men with progressive metastatic castrate-resistant prostate cancer after receiving docetaxel. Although the time to progression and overall survival did not improve with the addition of cetuximab, a hypothesisgenerating analysis strongly suggests that men receiving cetuximab and developing a rash may benefit clinically. Purpose: Cetuximab (C), a chimeric monoclonal antibody that binds epidermal growth factor receptor (EGFR), is active against androgen-independent prostate cancer cell lines and might enhance the activity of chemotherapy. The efficacy of combining cetuximab with mitoxantrone (M) plus prednisone (MP) was evaluated in progressive metastatic castrateresistant prostate cancer (CRPC) after receiving docetaxel. Materials and Methods: Patients with progression after receiving docetaxel were eligible and randomized 2:1 to CMP or MP. Therapy was mitoxantrone 12 mg/m 2 intravenously (I.V.) on day 1, oral prednisone 10 mg daily in both arms, and cetuximab 250 mg/m 2 I.V. (400 mg/m 2 day 1, cycle 1) on days 1, 8, and 15 in the CMP arm. Cycles were repeated every 21 days. Radiologic assessments of disease and PSA (prostate-specific antigen) occurred every 4 cycles. The primary endpoint was time to progression (TTP). Results: A total of 115 patients were enrolled, 75 in the CMP and 40 in the MP arm: the median TTP was 4.9 and 6.6 months, respectively; the measurable disease response rate was 2% and 4%, the PSA response rate 7.7% and 17.6%, and median survival 11.9 and 15.7 months, respectively. Key grade 3-4 toxicities were neutropenia 44% and 25.6%, anemia 6.7% and 7.7%, thrombocytopenia 6.7% and 2.6%, and fatigue 8% in both arms. In an unplanned exploratory analysis, median TTP with (n 24) and without rash (n 51) in the CMP arm was 10.3 months vs. 2.8 months (P .004). On multivariable analysis,