Jevtana: Official web site of manufacturer
Cabazitaxel
INTRODUCTION
Cabazitaxel (previously XRP-6258, trade name Jevtana) is a semi-synthetic derivative of a natural taxoid. It was developed by Sanofi-Aventis and was approved by the U.S. Food and Drug Administration (FDA) for the treatment of hormone-refractory prostate on June 17, 2010. It is a microtubule inhibitor, and the fourth taxane to be approved as a cancer therapy. Cabazitaxel in combination with prednisone is a treatment option for hormone-refractory prostate cancer following docetaxel-based treatment.
Cabazitaxel: wikipedia.org
Metastatic castration-resistant prostate cancer (mCRPC) is prostate cancer that is resistant to medical (e.g. hormonal) or surgical treatments that lower testosterone, and has spread to other parts of the body.
Metastatic castration-resistant prostate cancer
Despite advances in screening and treatment, prostate cancer remains a leading cause of cancer death among men, with an expected 29,720 deaths in 2013. While the use of prostate-specific antigen (PSA) screening increased early disease detection and therapy, a subset of patients inevitably develop metastatic disease, which is considered incurable. Androgen-deprivation therapy via surgical orchiectomy or gonadotropin-releasing hormone agonists or antagonists leads to castrate levels of testosterone and is temporarily effective in most patients with advanced prostate cancer. However, eventual progression results in a lethal disease phenotype known as metastatic castration-resistant prostate cancer (mCRPC). mCRPC was historically thought to be chemotherapy resistant, but recent studies have demonstrated that this is not the case.
Biology of progressive, castration-resistant prostate cancer: directed therapies targeting the androgen-receptor signaling axis, 2005
Cancer statistics, 2013
Targeting the androgen receptor signalling axis in castration-resistant prostate cancer, 2012
Taxanes
Drugs
Chemoterapy
MOLECULE AND IUPAC NAME
The chemical name of cabazitaxel is (2α,5β,7β,10β,13α)-4-acetoxy-13-({(2R,3S)-3[(tertbutoxycarbonyl) amino]-2-hydroxy-3-phenylpropanoyl}oxy)-1-hydroxy-7,10-dimethoxy-9oxo-5,20-epoxytax-11-en-2-yl benzoate – propan-2-one(1:1).
Cabazitaxel has the following structural formula:
POSOLOGY
Injection 60 mg/1.5 mL is a sterile, non-pyrogenic, clear yellow to brownish-yellow viscous solution and is available in single-use vials containing 60 mg cabazitaxel (anhydrous and solvent free) and 1.56 g polysorbate 80. Each mL contains 40 mg cabazitaxel (anhydrous) and 1.04 g polysorbate 80. JEVTANA requires two dilutions prior to intravenous infusion.
Molecule and IUPAC name; Posology
MECHANISM OF ACTION
Cabazitaxel is a microtubule inhibitor. Cabazitaxel binds to tubulin and promotes its assembly into microtubules while simultaneously inhibiting disassembly. This leads to the stabilization of microtubules, which results in the inhibition of mitotic and interphase cellular functions.
Mechanism of action
Additionally, taxanes inhibit androgen receptor (AR) signaling by binding cellular microtubules and the microtubule-associated motor protein dynein, and consequently preventing AR nuclear translocation. Paclitaxel was the first taxane to receive regulatory approval in the United States as an anticancer therapy. Docetaxel, a second-generation semisynthetic taxane analog with better tolerability and cytotoxicity, was initially approved by the US Food and Drug Administration in 1996 for the treatment of advanced breast cancer. Treatment with docetaxel every 3 weeks was associated with a significant improvement in overall survival compared with mitoxantrone, and additionally led to improvement in other secondary endpoints such as pain and quality of life. In the SWOG 99-16 trial, patients with mCRPC were randomized to receive estramustine and docetaxel versus mitoxantrone and prednisone, and again docetaxel was associated with a significant benefit in overall survival. However, due to concerns that estramustine/docetaxel coadministration is comparably associated with more significant myelosuppression and gastrointestinal toxicities, docetaxel plus prednisone has become the standard of care for the first-line treatment of progressive mCRPC in the past decade.
Taxane-induced blockade to nuclear accumulation of the androgen receptor predicts clinical responses in metastatic prostate cancer, 2011
Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer, 2004
Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer, 2004
TROPIC STUDY
A strategic decision was made to proceed directly to a randomized, multicenter phase III study known as TROPIC. In the TROPIC study, 755 men with mCRPC who previously received docetaxel chemotherapy were randomized to receive either cabazitaxel 25 mg/m2 (n = 378) or mitoxantrone 12 mg/m2 (n = 377) every 3 weeks for a maximum of 10 cycles, concurrently with prednisone 10 mg daily. To ensure docetaxel resistance, an interim protocol amendment mandated that study subjects must have received a cumulative dose of docetaxel greater than 225 mg/m2, with only 8% (n = 59) of study subjects failing to meet this requirement. Additionally, half of the patients enrolled had at least one site of soft tissue metastasis, with 25% having visceral disease, indicating that patients in the study generally had advanced mCRPC.
At the first interim analysis, with a median follow up of 12.7 months, median overall survival was 15.1 months for the cabazitaxel group versus 12.7 months for the mitoxantrone group, corresponding to a 30% reduction in relative risk of death (hazard ratio 0.70, 95% confidence interval 0.59–0.83, p < 0·0001). Other clinical endpoints, including PSA response and progression, objective tumor progression and pain progression all favored the cabazitaxel treatment arm. A recent updated analysis 2 years after the original TROPIC data cutoff (March 2012) confirmed a sustained survival benefit with longer follow up, with cabazitaxel treatment being predictive of survival over 2 years.
Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial, 2010
Impact of cabazitaxel on 2-year survival and palliation of tumour-related pain in men with metastatic castration-resistant prostate cancer treated in the TROPIC trial, 2012
PHARMACOKINETICS
In phase I studies, the decline in plasma concentrations after cabazitaxel administration demonstrated triphasic kinetics: first phase with a mean half life (t1/2) of 2.6 min; second phase with a mean t1/2 of 1.3 h; and a prolonged third phase with a mean t1/2 of 77.3 h. Cabazitaxel is equally distributed between blood and plasma.
Cabazitaxel: more than a new taxane for metastatic castrate-resistant prostate cancer?, 2012
METABOLISM
Cabazitaxel is mainly metabolized by the liver [cytochrome P450 (CYP)3A4/5 > CYP2C8], with seven plasma metabolites, and additionally 20 metabolites when excreted. Approximately 80% of cabazitaxel is excreted within 14 days of administration, primarily in the feces (76%). Renal excretion is responsible for 3.7% (2.3% as unchanged drug).
Cabazitaxel is primarily metabolized by CYP3A in vivo and its pharmacokinetics is expected to be affected by both inducers and inhibitors of CYP3A.
Cabazitaxel plus prednisone for metastatic castration-resistant prostate cancer progressing after docetaxel: results from the German compassionate-user programme, 2013
CONCLUSION
The clinical development of cabazitaxel has provided an important proof of principle that targeted therapy to overcome a specifically identified mechanism of resistance in the treatment of mCRPC is possible. In this case, a novel taxane was demonstrated to have clinical activity in docetaxel-resistant mCRPC. Given that mCRPC remains incurable, even with the advent of multiple new therapies, each approved drug will have a place in both extending survival and improving patient quality of life. Cabazitaxel represents a therapeutic option for men with metastatic CRPC whose condition has progressed on docetaxel and is associated with a survival advantage.
