Combination of Bevacizumab and Docetaxel in Docetaxel-Pretreated Hormone-Refractory Prostate Cancer: A Phase 2 Study

doi:10.1016/j.eururo.2008.01.082

European Urology

Volume 54, Issue 5, November 2008, Pages 1089-1096

https://doi.org/10.1016/j.eururo.2008.01.082 Get rights and content

Abstract

Objective

Although the taxanes represent the most active agents for the first-line treatment of metastatic hormone-refractory prostate cancer (HRPC), most patients eventually progress while receiving taxane-based treatments. No agents are approved for second-line therapy in HRPC, but common standard practice for the oncologists is to treat patients also after docetaxel failure.

Methods

Twenty highly pretreated patients with HRPC received bevacizumab (10 mg/kg) and docetaxel (60 mg/m²) every 3 wk. All patients had bone metastases and eight had measurable lesions.

Results

Eleven patients (55%) had major prostate-specific antigen (PSA) responses, and 3 (37.5%) had objective responses. Seven major PSA responses were recorded in the same patients who had reported a >50% PSA decrease after first-line docetaxel. However, four major PSA responses were observed in patients previously nonresponsive to docetaxel alone. The treatment was well tolerated.

Conclusions

Our results show that the combination of bevacizumab and docetaxel is active and well tolerated. Continued investigation of bevacizumab with cytotoxic chemotherapy is warranted in HRPC.

Introduction

The American Cancer Society has estimated that, during 2007, about 218,890 new cases of prostate cancer will be diagnosed in the United States and that approximately 27,050 men will die of metastatic disease [1]. The mainstay of treatment for metastatic prostate cancer is androgen deprivation. Unfortunately, most men eventually become resistant to hormonal manipulation, developing what is defined as hormone-refractory prostate cancer (HRPC) [2].

In 2004, two pivotal trials of docetaxel-based chemotherapy (CT) were reported and, for the first time, a survival benefit was observed for CT in HRPC [3], [4]. Thus, the results from those studies have changed the expectations of treatment outcome in these patients from pure palliation to improved survival, representing a significant milestone in the treatment of the disease.

Although the taxanes represent the most active CT agents for the first-line treatment of metastatic HRPC, most patients eventually progress while receiving taxane-based treatments.

Trials are now focusing on improving the efficacy of docetaxel by combining it with novel biologic agents. New cytotoxic agents are investigated in several ongoing studies to define their role for second-line treatment of HRPC [2]. So far no agents are approved for second-line therapy in HRPC, but common standard practice for the oncologists is to treat patients also after docetaxel failure.

Bevacizumab (Avastin; Genentech, San Francisco, CA, USA) is a recombinant humanized antivascular endothelial growth factor (anti-VEGF) antibody that specifically inhibits VEGF, has activity in multiple cancer cell lines, and is synergistic with several chemotherapeutic agents [5]. Randomized trials in metastatic colorectal cancer have already showed that bevacizumab added to CT improves progression-free survival (PFS) and overall survival compared with CT alone [6], [7]. In vitro and in vivo preclinical studies show that VEGF protects endothelial cells against the antiangiogenic effects of docetaxel and that this action is inhibited by anti-VEGF monoclonal antibody [8].

These observations provided our rationale to combine docetaxel and bevacizumab in patients with HRPC who were highly pretreated, had World Health Organization performance status (PS) 0–1, and were motivated to receive treatment, considering that no therapy has been approved in this setting.

Section snippets

Patients and methods

Main eligibility criteria included patients with HRPC who had been previously treated with docetaxel CT as first-line treatment, disease progression (biochemical or objective) to previous CT, and a treatment-free interval from previous CT of ≥6 wk. Second-line CT (mitoxantrone, vinorelbine, or other chemotherapeutic agents) and bisphosphonate agents (pamidronate, zoledronate, clodronate, etc) were permitted. Patients also were required to have adequate major organ function, including normal

Results

Between April 2005 and December 2006, 20 patients from four different institutions were enrolled. All patients were assessable for biochemical response and toxicity data. Patient characteristics are shown in Table 2.

All patients had received several hormonal therapies for metastatic disease and at least two prior CT regimens for the hormone-refractory status. All patients had biochemically or objectively progressed after docetaxel first-line therapy. The median number of docetaxel cycles was 8

Discussion

Treatments for most patients with HRPC remain difficult. Although the development of taxane-based first-line regimens has resulted in improved response rates and survival, adequate systemic second-line chemotherapy is needed [2]. Several regimens have been tested in this setting. Nevertheless, no second-line treatment has been approved so far [10], [11], [12], [13].

We assessed the efficacy and safety of bevacizumab and docetaxel in a small group of highly pretreated patients with HRPC. Our

Conclusions

Findings from the present paper are worthy of attention, because they clearly demonstrate that the combination of bevacizumab–docetaxel deserves further assessment. In this respect, a randomized phase 2 study comparing docetaxel alone versus the combination in this set of patients is warranted.
Financial disclosures: None.

Acknowledgement statement: We thank BoldFace Editors for linguistic revision.

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Prostate CancerCombination of Bevacizumab and Docetaxel in Docetaxel-Pretreated Hormone-Refractory Prostate Cancer: A Phase 2 Study

Abstract

Objective

Methods

Results

Conclusions

Introduction

Section snippets

Patients and methods

Results

Discussion

Conclusions

Eur Urol

Eur Urol

Eur Urol

Cancer statistics 2007

CA Cancer J Clin

Hormone refractory prostate cancer. Where are we going?

Drugs

Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer

N Engl J Med

Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer

N Engl J Med

Prostate Cancer
Combination of Bevacizumab and Docetaxel in Docetaxel-Pretreated Hormone-Refractory Prostate Cancer: A Phase 2 Study