Ipilimumab 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

Summary

Background

Ipilimumab is a fully human monoclonal antibody that binds cytotoxic T-lymphocyte antigen 4 to enhance antitumour immunity. Our aim was to assess the use of ipilimumab after radiotherapy in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel chemotherapy.

Methods

We did a multicentre, randomised, double-blind, phase 3 trial in which men with at least one bone metastasis from castration-resistant prostate cancer that had progressed after docetaxel treatment were randomly assigned in a 1:1 ratio to receive bone-directed radiotherapy (8 Gy in one fraction) followed by either ipilimumab 10 mg/kg or placebo every 3 weeks for up to four doses. Non-progressing patients could continue to receive ipilimumab at 10 mg/kg or placebo as maintenance therapy every 3 months until disease progression, unacceptable toxic effect, or death. Patients were randomly assigned to either treatment group via a minimisation algorithm, and stratified by Eastern Cooperative Oncology Group performance status, alkaline phosphatase concentration, haemoglobin concentration, and investigator site. Patients and investigators were masked to treatment allocation. The primary endpoint was overall survival, assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00861614.

Findings

From May 26, 2009, to Feb 15, 2012, 799 patients were randomly assigned (399 to ipilimumab and 400 to placebo), all of whom were included in the intention-to-treat analysis. Median overall survival was 11·2 months (95% CI 9·5–12·7) with ipilimumab and 10·0 months (8·3–11·0) with placebo (hazard ratio [HR] 0·85, 0·72–1·00; p=0·053). However, the assessment of the proportional hazards assumption showed that it was violated (p=0·0031). A piecewise hazard model showed that the HR changed over time: the HR for 0–5 months was 1·46 (95% CI 1·10–1·95), for 5–12 months was 0·65 (0·50–0·85), and beyond 12 months was 0·60 (0·43–0·86). The most common grade 3–4 adverse events were immune-related, occurring in 101 (26%) patients in the ipilimumab group and 11 (3%) of patients in the placebo group. The most frequent grade 3–4 adverse events included diarrhoea (64 [16%] of 393 patients in the ipilimumab group vs seven [2%] of 396 in the placebo group), fatigue (40 [11%] vs 35 [9%]), anaemia (40 [10%] vs 43 [11%]), and colitis (18 [5%] vs 0). Four (1%) deaths occurred because of toxic effects of the study drug, all in the ipilimumab group.

Interpretation

Although there was no significant difference between the ipilimumab group and the placebo group in terms of overall survival in the primary analysis, there were signs of activity with the drug that warrant further investigation.

Funding

Bristol-Myers Squibb.

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.