Phase II Randomized Study of Figitumumab plus Docetaxel and Docetaxel Alone with Crossover for Metastatic Castration-Resistant Prostate Cancer

Abstract

Purpose: Figitumumab is a human IgG 2 monoclonal antibody targeting insulin-like growth factor 1 receptor (IGF-1R), with antitumor activity in prostate cancer. This phase II trial randomized chemotherapyna€ ve men with progressing castration-resistant prostate cancer to receive figitumumab every 3 weeks with docetaxel/prednisone (Arm A) or docetaxel/prednisone alone (Arm B1). At progression on Arm B1, patients could cross over to the combination (Arm B2).Experimental Design: Prostate-specific antigen (PSA) response was the primary endpoint; response assessment on the two arms was noncomparative and tested separately; H 0 ¼ 0. Results: A total of 204 patients were randomized and 199 treated (Arm A: 97; Arm B1: 102); 37 patients crossed over to Arm B2 (median number of cycles started: Arm A ¼ 8; B1 ¼ 8; B2 ¼ 4). PSA responses occurred in 52% and 60% of Arms A and B1, respectively; the primary PSA response objective in Arm A was not met. Median PFS was 4.9 and 7.9 months, respectively (HR ¼ 1.44; 95% confidence interval, 1.06-1.96). PSA response rate was 28% in Arm B2. The figitumumab combination appeared more toxic, with more treatment-related grade 3/4 adverse events (75% vs. 56%), particularly hyperglycemia, diarrhea, and asthenia, as well as treatment-related serious adverse events (41% vs. 15%), and all-causality grade 5 adverse events (18% vs. 8%).Conclusion: IGF-1R targeting may merit further evaluation in this disease in selected populations, but combination with docetaxel is not recommended.

The insulin-like growth factor (IGF) axis as an anticancer target in prostate cancer

“…The authors of this study concluded that the combination of figitumumab at a maximum feasible dose of 20 mg/m 2 and docetaxel at 75 mg/m 2 is safe and well tolerated in patients with no substantial alteration in the pharmacokinetics [62]. Recently De Bono et al published data from the Phase II study investigating the effect of docetaxel alone compared to figitumumab + docetaxel in metastatic CRPC on PSA response [63]. Results from 204 patients showed that in the figitumumab + docetaxel arm, the primary PSA response endpoint was not reached.…”

“…Results from 204 patients showed that in the figitumumab + docetaxel arm, the primary PSA response endpoint was not reached. Moreover treatment-related severe adverse events were more frequent compared to the docetaxel arm [63]. Another study evaluated the biological and clinical effects of figitumumab in patients with localized PCa.…”

Growth hormone, insulin-like growth factor system and carcinogenesis

“…The primary endpoint, the prostate-specific antigen (PSA) response, did not improve significantly with figitumumab therapy. Nevertheless, a PSA response of 28% was observed in patients treated with the combination after disease progression with docetaxel/prednisone alone, suggesting that figitumumab might be more active post-docetaxel than in the docetaxel-naïve patients [27].…”

Taxane Resistance in Prostate Cancer Mediated by AR-Independent GATA2 Regulation of IGF2

“…Finally, PCa clinical trials of agents targeting IGF signaling have not yet shown clear efficacy. These include a trial of ADT combined with cixutumumab (anti-IGF1R antibody) in metastatic hormone-sensitive PCa (SWOG S0925, 2014, J Clin Oncol., abstract 5006), and a trial of figitumumab (anti-IGF1R antibody) plus docetaxel in CRPC (de Bono et al, 2014).…”