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


METHODS
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.


METHODS
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.


CONCLUSIONS
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.


RESULTS
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.
Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.
Nader
N
Al Nakouzi
Department of Medical Oncology, Val de Grâce Hospital, Paris, France.
Sylvestre
S
Le Moulec
Department of Cancer Medicine, Gustave Roussy, Cancer Campus, Grand Paris, University of Paris-Sud, and INSERM U981, Villejuif, France.
Laurence
L
Albigès
Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.
Chris
C
Wang
Department of Medical Oncology, Institut Curie, Paris, France.
Philippe
P
Beuzeboc
Department of Medical Oncology, CHU de Bordeaux, Bordeaux, France.
Marine
M
Gross-Goupil
Pitié-Salpetrière Hospital, Paris, France.
Thibault
T
de La Motte Rouge
Institut de Cancérologie de la Loire, Saint-Etienne, France.
Aline
A
Guillot
Biostatistics and Epidemiology unit, Institut Gustave Roussy, Cancer Campus, Grand Paris, Villejuif, France.
Dorota
D
Gajda
Department of Cancer Medicine, Gustave Roussy, Cancer Campus, Grand Paris, University of Paris-Sud, and INSERM U981, Villejuif, France. Electronic address: massard@igr.fr.
Christophe
C
Massard
Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.
Martin
M
Gleave
Department of Cancer Medicine, Gustave Roussy, Cancer Campus, Grand Paris, University of Paris-Sud, and INSERM U981, Villejuif, France.
Karim
K
Fizazi
Department of Cancer Medicine, Gustave Roussy, Cancer Campus, Grand Paris, University of Paris-Sud, and INSERM U981, Villejuif, France. Electronic address: yohann.loriot@gustaveroussy.fr.
Yohann
Y
Loriot
D000368:Aged; D000369:Aged, 80 and over; D000726:Androgen Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D000736:Androstenes / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001549:Benzamides; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018572:Disease-Free Survival; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005602:France; D006801:Humans; D007610:Kallikreins / Q000097:blood; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D017430:Prostate-Specific Antigen / Q000097:blood; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D011944:Receptors, Androgen / Q000187:drug effects* / Q000378:metabolism; D012189:Retrospective Studies; D015398:Signal Transduction / Q000187:drug effects; D043823:Taxoids / Q000009:adverse effects / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome
C410798:AR protein, human; D000726:Androgen Antagonists; D000736:Androstenes; D001549:Benzamides; D009570:Nitriles; D011944:Receptors, Androgen; D043823:Taxoids; D000077143:Docetaxel; D010669:Phenylthiohydantoin; C552428:cabazitaxel; C540278:enzalutamide; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen; C089740:abiraterone
Abiraterone; Cabazitaxel; Metastatic; Prostate cancer