Platinum Priority – Prostate CancerEditorial by Bertrand Tombal on pp. 236–237 of this issueCabazitaxel Remains Active in Patients Progressing After Docetaxel Followed by Novel Androgen Receptor Pathway Targeted Therapies
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)
- et al.
Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study
Lancet Oncol
(2012) - et al.
Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial
Lancet
(2010) - et al.
Clinical activity of abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after enzalutamide
Ann Oncol
(2013) - et al.
Antitumour activity of enzalutamide (MDV3100) in patients with metastatic castration-resistant prostate cancer (CRPC) pre-treated with docetaxel and abiraterone
Eur J Cancer
(2014) - et al.
Enzalutamide in castration-resistant prostate cancer patients progressing after docetaxel and abiraterone
Eur Urol
(2014) - et al.
Antitumour activity of docetaxel following treatment with the CYP17A1 inhibitor abiraterone: clinical evidence for cross-resistance?
Ann Oncol
(2012) - et al.
Taxanes: still a major weapon in the armamentarium against prostate cancer
Eur Urol
(2013) - et al.
Cross-resistance between taxanes and new hormonal agents abiraterone and enzalutamide may affect drug sequence choices in metastatic castration-resistant prostate cancer
Eur J Cancer
(2013) - et al.
Combining carboplatin and etoposide in docetaxel-pretreated patients with castration-resistant prostate cancer: a prospective study evaluating also neuroendocrine features
Ann Oncol
(2009) - et al.
Targeting continued androgen receptor signaling in prostate cancer
Clin Cancer Res
(2011)
The association of p21((WAF-1/CIP1)) with progression to androgen-independent prostate cancer
Clin Cancer Res
Abiraterone and increased survival in metastatic prostate cancer
N Engl J Med
Abiraterone in metastatic prostate cancer without previous chemotherapy
N Engl J Med
Increased survival with enzalutamide in prostate cancer after chemotherapy
N Engl J Med
Cited by (0)
- †
These authors contributed equally to this work.