Cabazitaxel Remains Active in Patients Progressing After Docetaxel Followed by Novel Androgen Receptor Pathway Targeted Therapies.

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 25mg/m(2) 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.

• Authors: Nader Al Nakouzi, Sylvestre Le Moulec, Laurence Albigès, Chris Wang, Philippe Beuzeboc, Marine Gross-Goupil, Thibault de La Motte Rouge, Aline Guillot, Dorota Gajda, Christophe Massard, Martin Gleave, Karim Fizazi, Yohann Loriot
• Journal: European urology (Eur Urol) Vol. 68 Issue 2 Pg. 228-35 (Aug 2015) ISSN: 1873-7560 [Electronic] Switzerland
• PMID: 24837187 (Publication Type: Journal Article, Multicenter Study)
• Copyright: Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Chemical References

• AR protein, human
• Androgen Antagonists
• Androstenes
• Benzamides
• Nitriles
• Receptors, Androgen
• Taxoids
• Docetaxel
• Phenylthiohydantoin
• cabazitaxel
• enzalutamide
• KLK3 protein, human
• Kallikreins
• Prostate-Specific Antigen
• abiraterone

Topics

• Aged
• Aged, 80 and over
• Androgen Antagonists (adverse effects, therapeutic use)
• Androstenes (adverse effects, therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Benzamides
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Disease-Free Survival
• Docetaxel
• Dose-Response Relationship, Drug
• Drug Resistance, Neoplasm
• France
• Humans
• Kallikreins (blood)
• Kaplan-Meier Estimate
• Male
• Middle Aged
• Molecular Targeted Therapy
• Nitriles
• Phenylthiohydantoin (adverse effects, analogs & derivatives, therapeutic use)
• Prostate-Specific Antigen (blood)
• Prostatic Neoplasms, Castration-Resistant (drug therapy, metabolism, mortality, pathology)
• Receptors, Androgen (drug effects, metabolism)
• Retrospective Studies
• Signal Transduction (drug effects)
• Taxoids (adverse effects, therapeutic use)
• Time Factors
• Treatment Outcome