Phase II Trial of Bevacizumab, Thalidomide, Docetaxel, and Prednisone in Patients With Metastatic Castration-Resistant Prostate Cancer

Clinical Center, National Cancer Institute, National Institutes of Health, Bethesda, MD.

Metastatic castration-resistant prostate cancer (CRPC) is a leading cause of cancer death in men.

The current recommended treatment of patients with CRPC is the chemotherapeutic agent docetaxel. Previous studies show a median overall survival (OS) of 19.2 months for patients receiving docetaxel and prednisone compared with 16.3 months for patients receiving mitoxantrone and prednisone. In an effort to prolong survival in this patient population, various antiangiogenic agents have been studied in combination with docetaxel.

Angiogenesis plays an important role in the progression of prostate cancer and is inversely associated with survival rates. In a previous randomized phase II clinical trial of patients with CRPC we found that, compared with docetaxel alone, docetaxel plus thalidomide was associated with a higher prostate-specific antigen (PSA) response rate (51% v 37%) and improved OS (25.9 v 14.7 months). Picus conducted a phase II study testing docetaxel in combination with bevacizumab and estramustine. The promising activity of this combination led to a phase III study comparing docetaxel and prednisone with docetaxel, bevacizumab, and prednisone. The antitumor activity in these phase II studies suggests a potential role for antiangiogenic therapy in combination with chemotherapy in the treatment of metastatic CRPC.

On the basis of these studies and the knowledge that a complex array of genes control tumor activity, it can be inferred that an optimal antiangiogenic approach will require a combination of different types of treatments. Since thalidomide and bevacizumab act through different mechanisms, it has been hypothesized that these two drugs would be excellent candidates for a treatment cocktail. Thalidomide appears to inhibit the action of basic fibroblast growth factors, endothelial cell proliferation, circulating endothelial cells, and expression of tumor necrosis factor , while bevacizumab acts selectively by neutralizing vascular endothelial growth factor. Thus, we evaluated the combination of bevacizumab, thalidomide, and docetaxel first for safety in mouse models and then for efficacy in patients with metastatic CRPC as a phase II clinical trial.

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 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 50%, and 88% achieved a PSA decline of 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.