Phase II trial of bevacizumab, thalidomide, docetaxel, and prednisone in patients with metastatic castration-resistant prostate cancer

Abstract

PURPOSE We previously demonstrated that thalidomide appears to add to the activity of docetaxel in metastatic castration-resistant prostate cancer (CRPC). Phase II studies combining docetaxel with bevacizumab have had substantial antitumor activity. We hypothesized that the combination of docetaxel plus these antiangiogenic drugs with different targets would have substantial clinical activity. To explore safety and efficacy, this was tested in mice and in human patients. PATIENTS AND METHODS Preclinical efficacy of the combination therapy was evaluated in PC3 xenograft mice. Sixty patients with progressive metastatic CRPC received intravenous docetaxel and bevacizumab plus oral thalidomide and prednisone. The primary end point was a prostate-specific antigen (PSA) decline of > or = 50%. Secondary end points included time to progression, overall survival, and safety. Results In the mouse model, combination therapy of docetaxel, bevacizumab, and thalidomide inhibited tumor growth most effectively. In the clinical trial, 90% of patients receiving the combination therapy had PSA declines of > or = 50%, and 88% achieved a PSA decline of > or = 30% within the first 3 months of treatment. The median time to progression was 18.3 months, and the median overall survival was 28.2 months in this group with a Halabi-predicted survival of 14 months. While toxicities were manageable, all patients developed grade 3/4 neutropenia. CONCLUSION The addition of bevacizumab and thalidomide to docetaxel is a highly active combination with manageable toxicities. The estimated median survival is encouraging, given the generally poor prognosis of this patient population. These results suggest that definitive clinical trials combining antiangiogenic agent combinations with docetaxel are warranted to improve treatment outcomes for patients with metastatic CRPC.

Fig 1.

Efficacy of therapeutic agents in PC3 xenograft mouse models following vehicle (solid circle), docetaxel (solid square), thalidomide (solid triangle), or bevacizumab (inverted solid triangle) alone; a dual combination of docetaxel and thalidomide (solid diamond), docetaxel and bevacizumab (open circle), thalidomide and bevacizumab (open square); and a combination of docetaxel, thalidomide, and bevacizumab (open triangle). Values are means from five to eight mice. Doc, docetaxel; Thal, thalidomide; BV, bevacizumab.

Fig 2.

Maximum percent change in prostate-specific antigen (PSA) from baseline in patients.

Fig 3.

Kaplan-Meier analysis of (A) progression-free survival and (B) overall survival for all patients on study.

Fig 4.

Changes in circulating apoptotic endothelial cells (CAECs) at 6 weeks. PSA, prostate-specific antigen.