Original article
Sequencing new agents after docetaxel in patients with metastatic castration-resistant prostate cancer

https://doi.org/10.1016/j.critrevonc.2015.07.013Get rights and content

Highlights

  • Our data confirm potential cumulative survival benefit of using NAs sequentially after docetaxel.

  • There is no a clear superiority of any one of the analyzed strategies.

  • There is a suggestion that a CABA-based sequence seems to offer a possible OS advantage.

  • Prospective trials are needed to drawn definitive conclusions.

Abstract

Background

Two new hormonal agents (NHAs), abiraterone and enzalutamide, and one chemotherapeutic agent, cabazitaxel (CABA) improved overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) who progress after docetaxel. Although several analyses of patient cohorts receiving a sequence of two different new agents (NAs) after docetaxel have been published, no definite conclusions can be drawn regarding the best treatment strategy.

Materials and methods

All published studies reporting monthly OS rates of mCRPC patients receiving third-line NA after having previously received docetaxel and another NA have been analyzed. The treatments were merged into three groups: one NHA followed by another, one NHA followed by CABA, and CABA followed by one NHA. The cumulative monthly OS rates in each group were determined using a weighted-average approach.

Results

Thirteen retrospective studies including 1016 patients who received NHA/NHA (469), NHA/CABA (318) or CABA/NHA (229) were evaluated. The 12-month OS rates were 28.5%, 61.3%, and 76.4%, respectively. There were no statistically significant differences in terms of known prognostic factors.

Conclusions

Although the retrospective nature of the studies and potential selection biases, our data seem to confirm the potential cumulative survival benefit of using the NAs sequentially after docetaxel. There was no clear superiority of any one of the three strategies, but a sequence that includes CABA seems to suggest a possible OS advantage.

Introduction

Over the last few years, it has been demonstrated that cabazitaxel (CABA, a new taxane) (de Bono et al., 2010), abiraterone acetate (ABI, a CYP17 inhibitor) (CYP17 de Bono et al., 2011), and enzalutamide (ENZA, a new generation androgen-receptor antagonist) (Scher et al., 2012) improve the overall survival (OS) of patients with metastatic castration-resistant prostate cancer (mCRPC) who progress after docetaxel treatment. This has significantly increased the number of available second-line therapeutic options which, until few years ago, were limited to mitoxantrone (Tannock et al., 1996) or (in selected cases) a docetaxel rechallenge (Caffo et al., 2012), which offered pain palliation or temporary disease control but provided no demonstrated survival advantage.

The availability of these new agents (NAs) has led to the possibility of using them sequentially in the hope of obtaining a cumulative survival benefit and so, in everyday clinical practice, they have been administered as third-line treatments in patients who have previously received them as second line after docetaxel. However, this practice is not yet supported by clinical trial data, and evidence of possible cross-resistance (van Soest et al., 2013) has reinforced the debate concerning the best sequence to use in order to maximize their efficacy.

The studies published so far have analyzed cohorts of patients receiving one specific third-line NA after another administered as second line (Loriot et al., 2013, Noonan et al., 2013, Sonpavde et al., 2015, Thomsen et al., 2014, Sella et al., 2014, Al Nakouzi et al., 2014, Schmid et al., 2014, Badrising et al., 2014, Thomson et al., 2014, Stevenson et al., 2014, Caffo et al., 2014, Zhang et al., 2015, Azad et al., 2014, Wissing et al., 2015, Bianchini et al., 2014, Schrader et al., 2014, Pezaro et al., 2014, Albiges et al., 2012, Sandhu et al., 2014, Roeder et al., 2014, Vera-Badillo et al., 2014, Scholz et al., 2014, Cheng et al., 2014, Bournakis et al., 2013). However, the retrospective nature of these studies, their small sample size, the evaluation of objective endpoints not always comparable across studies and the short follow-up, do not yet allow any definite conclusions to be drawn concerning the anti-tumour activity, tolerability and cost-effectiveness of the various sequences.

The aim of this systematic review and descriptive analysis is to explore the clinical outcomes of mCRPC patients who were treated with third-line NAs after having previously received docetaxel and another NA, evaluating whether there is a potentially better sequence strategy than the other

Section snippets

Evidence acquisition

The analysis was made in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines (Liberati et al., 2009).

Data sources and searches

The Medline and Embase databases were searched for English-language articles published between January 2012 and March 2015 using the search terms “prostate cancer” (and related terms) and the individual names of the NAs (“abiraterone acetate”, “cabazitaxel” and “enzalutamide”). The search was extended to American Society of Clinical Oncology (ASCO)

RESULTS

Fig. 1 shows the detailed search flow chart relating to selected articles and abstracts.

All studies included in the present analysis evaluated clinical outcomes of patients receiving two different NA in the post-docetaxel setting. Of the 25 potential reports identified, thirteen (involving 1016 patients) were considered for the analysis (Loriot et al., 2013, Noonan et al., 2013, Sonpavde et al., 2015, Sella et al., 2014, Al Nakouzi et al., 2014, Schmid et al., 2014, Badrising et al., 2014,

Discussion

To the best of our knowledge, this is the first paper providing a systemic review and summary descriptive analysis of published studies of the sequential use of NAs after docetaxel treatment in patients with mCRPC. On the basis of our data, no single NA seems to be clearly superior to the others in a third-line setting, although the sequences including CABA may lead to a possible advantage.

Clinicians involved in treating advanced mCRPC are now enjoying a similar “embarrassment of riches” to

Conclusions

The retrospective nature of included studies, the limited cohort size, the short follow-up of most of them as well as the heterogeneity of patient population across studies and the inevitable selection and methodological biases require caution in the interpretation of the results. Our analysis does not allow any definite conclusions to be drawn, and the suggestion that sequences including CABA may lead to better disease control needs to be prospectively validated in larger series, ideally

Conflict of interest

Bria E.: consultant for Celgene; Honoraria from Eli-Lilly, MSD, Astra-Zeneza. Tortora G.: consultant for Novartis, Pfizer and GSK. Caffo O.: Honoraria from Janssen, Sanofi Aventis, Astellas.

Other authors have no conflicts of interest to declare.

Acknowledgments

This work was partially supported by grants of the Italian Association for Cancer Research (AIRC) (MFAG 14282) and of Italian Ministry of Education, Universities and Research (MIUR)—Interest National Research Project (PRIN) (2009 × 23L78_005) without any implication in study design, data collection, data analysis, data interpretation or writing of the paper.

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