A randomised phase II trial of docetaxel versus docetaxel plus carboplatin in patients with castration-resistant prostate cancer who have progressed after response to prior docetaxel chemotherapy: The RECARDO trial

Highlights

• Re-treatment with docetaxel monotherapy is safe and effective in selected patients.

• The median progression-free survival in this group was 12.7 months.

• Addition of carboplatin does not improve the progression-free or overall survival.

• Addition of carboplatin resulted in more gastrointestinal and infectious adverse events.

Abstract

Background

Docetaxel is standard first-line chemotherapy for patients with metastatic castration–resistant prostate carcinoma (mCRPC). Docetaxel re-challenge has never been tested in a prospective randomised controlled study. As some studies support the addition of carboplatin to docetaxel, we performed a phase II trial investigating the combination of docetaxel plus carboplatin versus docetaxel re-treatment in docetaxel pre-treated mCRPC patients.

Methods

Patients with mCRPC with a progression-free interval of ≥3 months after initial docetaxel treatment were randomised between docetaxel 75 mg/m² or docetaxel 60 mg/m² plus carboplatin AUC4. The primary end-point was progression-free survival (PFS; PSA/RECIST).

Results

Owing to insufficient recruitment, the study was discontinued early after inclusion of 75 patients (targeted 150) PFS and overall survival (OS) were comparable between both groups (median PFS 12.7 months (95% CI 9.9–17.5 months) with docetaxel monotherapy and 11.7 months (95% CI 8.5–21.0 months) with combination therapy (p = 0.98); OS 18.5 months (95% CI 11.8–24.5 months) versus 18.9 months (95% CI 16.0–23.7 months) (p = 0.79). An interim analysis (SEQTEST) showed that the null hypothesis could already be excepted, and no significant difference between both study arms was expected if inclusion would be completed. The incidence of grade 3–4 infections and gastrointestinal side-effects was numerical higher in the carboplatin arm (p = 0.056).

Conclusion

This early terminated study suggests no benefit from the addition of carboplatin to docetaxel re-treatment in patients with mCRPC, whereas the combination resulted in more toxicity. Re-treatment with docetaxel monotherapy appears to be feasible, save and effective for patients with mCRPC and an initial good response to docetaxel.

Trial registration

NTR3070.

Introduction

Docetaxel is the standard first-line chemotherapeutic treatment for patients with symptomatic metastatic castration–resistant prostate carcinoma (mCRPC) or asymptomatic patients with progressive disease [1]. In 2004, two randomised phase III trials showed a survival benefit for docetaxel as first-line treatment for these patients, as well as pain relief and improvement in quality of life (QoL) [2], [3].

After response to docetaxel, at some point, progression will occur. At the start of this study in 2010, mitoxantrone was the only approved second-line chemotherapeutic agent. Two different studies showed better pain palliation and QoL for the combination of mitoxantrone with steroids compared with steroids alone. Nevertheless, there was no survival benefit for the combined therapy and the PSA response rates of 10–20% after second-line treatment with mitoxantrone were modest [4], [5], [6], [7].

Nowadays, there are several different treatment options with cabazitaxel as a second-line cytotoxic agent, enzalutamide and abiraterone as hormone-blocking agents, radiopharmaceuticals as radium-233 and sipuleucel-T immunotherapy [8], [9], [10], [11], [12]. Although all these agents have a proven survival benefit and are all registered for treatment in the post-docetaxel setting, they all have their own limitations and side-effects, and effects on survival are still modest.

Previous phase II studies supported the use of platinum chemotherapy in the management of mCRPC and suggested a synergistic effect when carboplatin is combined with docetaxel [13], [14]. In mCRPC patients refractory to docetaxel, a median progression-free survival (PFS) of 3–6.5 months with an overall survival (OS) of 12.4–15.8 months has been described with combination therapy of carboplatin and docetaxel [15], [16]. Recently, molecular profiling has shown a role for DNA repair defects (in BRCA 1/2 germline variants) in advanced prostate cancer. This makes these tumours more sensitive for treatment with platinum compounds which exert their antitumour effect through covalent adducts with cellular DNA resulting in DNA damage [17]. Moreover, treatment of docetaxel-naïve patients with clinical features of an anaplastic prostate carcinoma with docetaxel plus carboplatin resulted in stable disease in 65% of the patients after 12 weeks and a median OS of 16 months [18].

There is also evidence from retrospective data and small cohorts of patients that patients with an initial good response to docetaxel might benefit from a re-challenge with single-agent docetaxel. In these patients, docetaxel was mostly discontinued after receiving the planned number of treatment cycles, without severe side-effects [19], [20], [21]. In the trial of Bracarda et al. [21], 98 patients were re-treated after an initial response to docetaxel (median interval between treatments was 8.3 months), with a median PFS of 16.4 months . In the prospective cohort study of Di Lorenzo et al. [22], 45 patients with an initial biochemical remission of at least 5 months were re-treated with docetaxel. The median PFS was 5 months (range 2–8 months) with an overall survival of 13 months.

The progression-free interval (PFI) after first-line docetaxel seems to be associated with the response rate and PFS after re-challenge [20].

Since both docetaxel re-treatment as well as docetaxel combined with carboplatin seem to be appealing second-line treatment options for a selected patient group, we performed this phase II study comparing both treatment regimens.

This study is the first phase II randomised study prospectively assessing the activity of docetaxel plus carboplatin relative to that of re-treatment with docetaxel monotherapy in mCRPC patients with an initial response but progression on prior docetaxel-based treatment.