Docetaxel and atrasentan versus docetaxel and placebo for men with advanced castration-resistant prostate cancer (SWOG S0421): a randomised phase 3 trial

Summary

Background

The endothelin pathway has a role in bone metastases, which are characteristic of advanced prostate cancer. Atrasentan, an endothelin receptor antagonist, has shown activity in prostate cancer. We therefore assessed its effect on survival in patients with castration-resistant prostate cancer with bone metastases.

Methods

In a double-blind phase 3 trial, men with metastatic castration-resistant prostate cancer, stratified for progression type (prostate-specific antigen or radiological), baseline pain, extraskeletal metastases, and bisphosphonate use, were randomly assigned in a 1:1 ratio to docetaxel (75 mg/m² every 21 days, intravenously) with atrasentan (10 mg/day, orally) or placebo for up to 12 cycles and treated until disease progression or unacceptable toxicity. Patients who did not progress on treatment were permitted to continue atrasentan or placebo for up to 52 weeks. Coprimary endpoints were progression-free survival (PFS) and overall survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00134056.

Findings

498 patients were randomly assigned to the atrasentan group and 496 to the placebo group. The trial was halted early for futility in April, 2011, after a planned interim analysis. Median PFS was 9·2 months (95% CI 8·5–9·9) in the atrasentan group and 9·1 months (8·4–10·2) in the placebo group (hazard ratio 1·02, 0·89–1·16; p=0·81). Median overall survival was 17·8 months (16·4–19·8) in the atrasentan group versus 17·6 months (16·4–20·1) in the placebo group (1·04, 0·90–1·19; p=0·64). 278 (57%) of 492 patients in the atrasentan group had grade 3 and greater toxicity compared with 294 (60%) of 486 in the placebo group (p=0·22). Three deaths in the atrasentan group and seven in the placebo group were judged to be possibly or probably due to protocol treatment.

Interpretation

Atrasentan, when added to docetaxel, does not improve overall survival or PFS in men with castration-resistant prostate cancer and bone metastases; therefore, single-agent docetaxel should remain as one of the standard treatments.

Funded

National Cancer Institute, Sanofi-Aventis, and Abbott Laboratories.

Introduction

Prostate cancer is an androgen-dependent disease. Androgen deprivation has been standard systemic treatment for patients with metastatic hormone-sensitive disease. Despite a high initial response rate, resistance to androgen deprivation occurs in most patients by 18 months,¹ culminating in castration-resistant prostate cancer. Subsequent treatment with docetaxel prolonged overall survival without a reduction in quality of life compared with palliative mitoxantrone in two studies of patients with castration-resistant prostate cancer,2, 3 resulting in docetaxel becoming the standard of care for this cancer.

In addition to the characteristic androgen dependence, prostate cancer has other distinguishing features. These include a proclivity to spread to bone and produce sclerotic, osteoblast-predominant metastases. More than 90% of men with fatal prostate cancer have bone metastases.⁴ The endothelin pathway was delineated as being crucial for the initiation and maintenance of bone metastases from prostate cancer.5, 6 Increased endothelin-receptor A expression was also noted with advanced tumour stage and grade in primary and metastatic prostate cancer.⁵ Endothelin 1 and endothelin receptor A interaction is crucial for stimulation by prostate cancer cells of osteoblast proliferation and migration and production of osteoblastic metastases.⁷ Subsequently, small molecule inhibitors of this interaction were developed and showed inhibition of the development and progression of metastases in preclinical models.⁸ Results from single agent trials of orally bioavailable small molecule inhibitors, such as atrasentan and zibotentan, suggested activity against prostate cancer, particularly in patients with bone metastases. Atrasentan delayed time to disease progression in a subgroup of patients from a phase 3 trial compared with placebo, whereas zibotentan improved overall survival compared with placebo alone in a randomised phase 2 study.9, 10, 11 Preclinical data from a bone metastasis model of prostate cancer suggested synergy between atrasentan and docetaxel.¹² A phase 1/2 study of atrasentan with docetaxel and prednisone in men with metastatic castration-resistant prostate cancer showed safety at full doses of atrasentan and docetaxel with reasonable activity based on serum prostate-specific antigen (PSA) and Response Evaluation Criteria In Solid Tumors (RECIST, version 1.0).¹³

We therefore tested the hypothesis that there would be an additive or synergistic effect between atrasentan and docetaxel in patients with castration-resistant prostate cancer with bone metastasis.