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Randomized phase III study of docetaxel with or without risedronate in patients with bone metastases from castration-resistant prostate cancer (CRPC): The Netherlands Prostate Study (NePro).

4518 Background: Bisphosphonates, including risedronate (R), an oral third generation pyridinyl bisphosphonate, exert antitumor activity in vitro and in vivo. Animal models have shown synergistic activity of bisphosphonates and taxanes. This study aimed to investigate the potential benefit of adding R to docetaxel based chemotherapy in patients with metastatic CRPC.


METHODS
CRPC patients with bone metastasis, and no prior bisphosphonate use were randomly assigned to receive docetaxel (D) 75 mg/m² every 3 weeks and prednisone 5 mg bid as first line chemotherapy, with or without R 30 mg oral od. Upon progression patients in the D alone arm were offered R. The study was designed as a randomized open label phase II, with extension into a phase III study. The primary endpoint was time to progression (TTP). A composite endpoint of objective progression by RECIST criteria, PSA progression, or pain progression, whichever occurred first, was applied. Secondary endpoints were 50% PSA response rate, pain response, objective response (all confirmed responses), duration of PSA response, overall survival (OS) and toxicity profiles. The study had 80% power to detect an improvement of 30% (from 6 to 7.8 months [mos]) in median TTP in the DR group (2-sided α= 0.05).


RESULTS
From Jan 2004 to April 2010, 592 men (301 D vs 291 DR) were randomized. Baseline demographics were similar in both groups. Median follow-up was 37 mos. Median number of cycles was 9 in both groups. TTP was 7.8 vs 6.9 mos (p=0.6) for D and DR, respectively. PSA response rates (64% D vs 63% DR) and pain response (28% D vs 31% DR) were not significantly different between both arms. OS was 18.0 mos for D vs 19.7 mos for DR (p=0.6). Grade 3 /4 toxicity rates were similar. Clinically relevant hypocalcaemia, potentially associated with R, was observed in 1 patient in each arm. No cases of osteonecrosis of the jaw were observed.


CONCLUSIONS
We found no benefit of the addition of the third generation bisphosphonate risedronate, in the setting of effective first line docetaxel based chemotherapy, as indicated by the lack of improvement in TTP, PSA and pain response and overall survival.