Elsevier

European Urology

Volume 68, Issue 2, August 2015, Pages 228-235
European Urology

Platinum Priority – Prostate Cancer
Editorial by Bertrand Tombal on pp. 236–237 of this issue
Cabazitaxel Remains Active in Patients Progressing After Docetaxel Followed by Novel Androgen Receptor Pathway Targeted Therapies

https://doi.org/10.1016/j.eururo.2014.04.015Get rights and content

Abstract

Background

Cabazitaxel, abiraterone acetate (AA), and enzalutamide have been approved for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) following docetaxel chemotherapy. Whether taxanes and next-generation androgen receptor (AR) axis inhibitors are cross-resistant or not is a subject of debate.

Objective

To evaluate the antitumour activity of cabazitaxel in mCRPC pretreated with abiraterone or enzalutamide.

Design, setting, and participants

The antitumour activity of cabazitaxel was assessed in patients with mCRPC and progressive disease after treatment with docetaxel and AA. In parallel, cabazitaxel antitumour activity was studied in enzalutamide-resistant models.

Outcome measurements and statistical analysis

Changes in prostate-specific antigen (PSA) levels and progression-free survival were used to determine the activity of cabazitaxel treatment. Cell proliferation, immunofluorescence, and AR transactivation assay were used in enzalutamide-resistant models.

Results and limitations

A total of 79 patients who had progressive mCRPC after docetaxel (median: 8 cycles; range: 4–12 mo), and AA (median: 4.8 mo; range:1–55 mo) received cabazitaxel 25 mg/m2 every 3 weeks (median: 6 cycles; range:1–15 cycles). A PSA decline ≥30% was achieved in 48 patients (62%; 95% confidence interval [CI], 51–73), and a decline ≥50% was achieved in 28 patients (35%; 95% CI, 25–47). The median progression-free survival and overall survival were 4.4 and 10.9 mo, respectively. In vitro, cabazitaxel decreased cell viability in both enzalutamide-sensitive and enzalutamide-resistant prostate cancer cells within the same range of concentrations. PC3, an AR-negative cell line, exhibited similar sensitivity to cabazitaxel.

Conclusions

Cabazitaxel and AR-pathway inhibitors are not cross-resistant. Preclinical data suggest that cabazitaxel activity does not act mainly through AR axis inhibition.

Patient summary

The antitumour activity of cabazitaxel, a chemotherapy agent, was studied in prostate cancer resistant to conventional hormonal therapy and to more recent endocrine therapies (abiraterone or enzalutamide). Cabazitaxel retained anticancer activity in more than half of the cases.

Introduction

Greater understanding of the biology of metastatic castration-resistant prostate cancer (mCRPC) over the last decade has led to multiple agents being added to the therapeutic armamentarium [1]. Resistance to castration involves androgen receptor (AR) modifications and extratesticular ligand biosynthesis, and, at least in some cases, non–AR axis-related mechanisms of activated cell proliferation [1], [2]. In patients with mCRPC, two AR axis inhibitors have improved overall survival (OS): abiraterone, a CYP17 inhibitor [3], [4], [5], and enzalutamide, an AR inhibitor [6]. Cabazitaxel, a second-generation taxane [7], radium-223, [8], and sipuleucel-T [9] have also improved OS in patients with mCRPC raising the question of how these agents should be used to achieve optimal medical management.

Some evidence suggests cross-resistance between these agents. Retrospectives analyses provide data that enzalutamide has limited activity in patients progressing after abiraterone with similar data regarding reverse sequential administration of enzalutamide followed by abiraterone [10], [11], [12], [13]. The issue of cross-resistance between taxanes and AR-targeted agents was brought to the fore following preclinical and clinical data showing that taxanes may also interfere with AR itself [14], [15], [16]. A retrospective study of docetaxel in 35 abiraterone-pretreated mCRPC patients showed that abiraterone-refractory patients were unlikely to respond to subsequent docetaxel-based chemotherapy [17]. However, subanalyses from the AFFIRM study demonstrated the efficacy of enzalutamide despite previous docetaxel exposure, suggesting that cross-resistance may not occur between the two drugs [18].

Because cabazitaxel has been approved for the treatment of docetaxel-pretreated CRPC patients and is currently being investigated in chemotherapy-naive mCRPC patients, our aim was to determine whether cabazitaxel efficacy may be affected by AR-pathway inhibitors.

Section snippets

Patients

Using systematic chart reviews, we identified the records of all patients with mCRPC previously treated with docetaxel and abiraterone (sometimes followed by enzalutamide) and receiving cabazitaxel as third-line therapy in five institutions in France. All patients were required to have castrate levels of testosterone, and castration was maintained with luteinising hormone-releasing hormone agonists during subsequent therapies. The following data were collected for all patients from the medical

Cabazitaxel retains clinical activity in abiraterone-pretreated patients

To investigate the activity of cabazitaxel in patients pretreated with AR-pathway inhibitors, we retrospectively collected clinical data from 79 patients previously treated with docetaxel and abiraterone, and subsequently treated with cabazitaxel between September 2011 and April 2013. Table 1 shows the patient characteristics. All patients treated with third-line cabazitaxel had received first-line chemotherapy with docetaxel (median: 8 cycles; range: 3–15 cycles) and then abiraterone in the

Discussion

In this study, we provided evidence for anticancer activity of cabazitaxel in mCRPC patients pretreated with docetaxel and abiraterone. PSA responses were found in a large proportion of 79 patients with mCRPC progressing after docetaxel and abiraterone. Preclinical data suggest that cabazitaxel-induced inhibition of AR nuclear translocation is a late event resulting from MC. Furthermore, we found no difference between cabazitaxel and docetaxel in their ability to inhibit AR-induced PSA gene

Conclusions

Cabazitaxel remains active in patients progressing after docetaxel followed by novel AR-pathway targeted therapies. Even our preclinical data suggest that cabazitaxel activity is not mainly mediated through direct AR inhibition, AR is still relevant in the abiraterone and enzalutamide resistance setting because PSA is often increasing when the patient develops resistance to abiraterone or enzalutamide, paving the way to a combination of cabazitaxel and AR-pathway inhibitors.

References (29)

  • K. Fizazi et al.

    The association of p21((WAF-1/CIP1)) with progression to androgen-independent prostate cancer

    Clin Cancer Res

    (2002)
  • J.S. de Bono et al.

    Abiraterone and increased survival in metastatic prostate cancer

    N Engl J Med

    (2011)
  • C.J. Ryan et al.

    Abiraterone in metastatic prostate cancer without previous chemotherapy

    N Engl J Med

    (2013)
  • H.I. Scher et al.

    Increased survival with enzalutamide in prostate cancer after chemotherapy

    N Engl J Med

    (2012)
  • Cited by (0)

    These authors contributed equally to this work.

    View full text