ArticlesIpilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial
Introduction
Prostate cancer is the second most frequently diagnosed cancer worldwide and is the second leading cause of cancer deaths in men.1 Prostate cancer that progresses despite castrate concentrations of testosterone is termed castration-resistant prostate cancer.2, 3 Recently, several treatments have been approved for metastatic castration-resistant prostate cancer after progression with docetaxel chemotherapy, each of which extended overall survival compared with controls.4, 5, 6, 7 However, new treatments that provide durable disease control are still needed.
Prostate cancer tissues are often infiltrated by inflammatory cells,8, 9 suggesting that this cancer is the target of a host immune response. This response can be constrained by various mechanisms that undermine antitumour immunity.9, 10, 11, 12, 13 As such, a goal of immunotherapy is to overcome these constraints to enhance tumour regression.14, 15 Currently, the only approved immunotherapeutic approach for prostate cancer is a vaccine that targets prostatic acid phosphatase, sipuleucel-T, which has been shown to extend overall survival for patients with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer, but does not affect prostate-specific antigen (PSA) concentration, induce tumour regression, or increase progression-free survival.16 Prostvac VF, a vaccinia virus-based PSA vaccine, is another antigen-specific immunotherapy17 that is currently in phase 3 testing for minimally symptomatic metastatic castration-resistant prostate cancer (ClinicalTrials.gov number NCT01322490), but also has not shown an effect on PSA concentration, tumour regression, or progression-free survival.
Ipilimumab is a fully human monoclonal antibody that binds to the inhibitory cytotoxic T-lymphocyte antigen 4 (CTLA-4) and thereby enhances antitumour immunity.18 Responses triggered by ipilimumab are not believed to be antigen specific, and instead result from prevention of the CTLA-4-mediated downregulation of T-lymphocyte activity. On the basis of results showing increased overall survival in patients with advanced melanoma in phase 3 trials, ipilimumab has been approved for the treatment of advanced melanoma in more than 40 countries at a dose of 3 mg/kg.19, 20 Notably, a proportion of patients with melanoma who received ipilimumab within the clinical development programme remained alive more than 2 years after treatment, suggesting the potential for long-term survival.21, 22, 23 Ipilimumab has side-effects that are related to its immune-based mechanism of action, but these are generally manageable using standard treatment algorithms, including proactive monitoring and early intervention with corticosteroids.
Prostate cancer was one of the first malignant diseases in which CTLA-4 blockade was tested in preclinical models.15, 24 Clinical potential for this treatment was subsequently confirmed in several studies of patients with metastatic castration-resistant prostate cancer,25, 26, 27 including a phase 1/2 dose-escalation trial of ipilimumab in chemotherapy-naive and chemotherapy-pretreated patients.27 Evidence from both preclinical and clinical studies suggests that radiotherapy might activate the immune system.28, 29, 30, 31, 32 Thus, radiotherapy is a rational modality to stimulate immune priming amenable to subsequent amplification by ipilimumab. Consistent with this hypothesis, the combination of immunotherapy and radiotherapy in a transgenic mouse model that spontaneously develops prostate cancer was shown to result in antitumour T-cell activation, but only when radiotherapy was given before immunotherapy.28 Although the precise mechanisms by which radiotherapy promotes immunotherapeutic responses remain unknown, radiotherapy might sensitise tumour cells to killing by antigen-specific cytotoxic T lymphocytes.29 Radiotherapy also promotes the local infiltration of immune cells into the tumour,30 and might trigger antitumour immune responses at locations distant from the original site of irradiation (abscopal effect).31, 32 In the clinical setting, the combination of radiotherapy and ipilimumab at 10 mg/kg is well tolerated in patients with metastatic castration-resistant prostate cancer.27
On the basis of existing evidence, phase 3 trials of ipilimumab for patients with metastatic castration-resistant prostate cancer were initiated in chemotherapy-naive (ClinicalTrials.gov number NCT01057810) and post-docetaxel populations. Here, we report results from a phase 3 trial of ipilimumab after radiotherapy in patients with metastatic castration-resistant prostate cancer who progressed after docetaxel chemotherapy.
Section snippets
Study design and patients
In this randomised, double-blind, controlled phase 3 trial (CA184-043), done in 191 centres across 26 countries, we enrolled male patients aged 18 years or older with histologically or cytologically confirmed adenocarcinoma of the prostate, at least one bone metastasis that could be irradiated or warranted irradiation in the clinical judgment of the investigator, testosterone concentration less than 1·74 nmol/L, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
Results
From May 26, 2009, to Feb 15, 2012, 799 patients were randomly assigned: 399 to the ipilimumab group and 400 to the placebo group (figure 1). Baseline patient characteristics were balanced across groups, and were indicative of advanced disease (table 1). 12 (3%) of 399 patients in the ipilimumab group and eight (2%) of 400 patients in the placebo group discontinued before receiving the assigned treatment; of these patients, six (2%) and four (1%), respectively, received radiotherapy only. Of
Discussion
The primary objective of this phase 3 study was to assess the ability of ipilimumab to extend overall survival compared with placebo in patients with metastatic castration-resistant prostate cancer who had progressed after docetaxel chemotherapy, due to the strong evidence of an endogenous immune response against prostate cancer cells (panel). The proportional hazards assumption was violated in the primary analysis, in which no difference in overall survival was noted between patients who
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