Cabazitaxel: A novel taxane for metastatic castration-resistant prostate cancer-current implications and future prospects

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Abstract

Recent advances in the management of prostate cancer have shown considerable development with time and many novel therapeutic agents have been approved over the past years. For patients with metastatic castration-resistant prostate cancer (mCRPC), initially docetaxel was the standard chemotherapy but once they became refractory to docetaxel, no treatment improved survival. This scenario changed in June 2010 when the US Food and Drug Administration (FDA) approved Cabazitaxel as a new therapeutic option for patients with mCRPC resistant to docetaxel. Cabazitaxel, being a novel tubulin-binding taxane with poor affinity for P-glycoprotein, decreases the chances of resistance. It has shown antitumor activity in preclinical, phase I, II and III clinical studies in docetaxel-resistant tumors. This article summarises the background, pharmacodynamic, kinetics and clinical development of cabazitaxel for the treatment of castration-resistant prostate cancer. Future development and rational use of this drug in other tumors is under therapeutic investigation.

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Most cited references 27

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Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study.

Howard Scher, Tomasz M. Beer, Celestia Higano … (2010)

MDV3100 is an androgen-receptor antagonist that blocks androgens from binding to the androgen receptor and prevents nuclear translocation and co-activator recruitment of the ligand-receptor complex. It also induces tumour cell apoptosis, and has no agonist activity. Because growth of castration-resistant prostate cancer is dependent on continued androgen-receptor signalling, we assessed the antitumour activity and safety of MDV3100 in men with this disease. This phase 1-2 study was undertaken in five US centres in 140 patients. Patients with progressive, metastatic, castration-resistant prostate cancer were enrolled in dose-escalation cohorts of three to six patients and given an oral daily starting dose of MDV3100 30 mg. The final daily doses studied were 30 mg (n=3), 60 mg (27), 150 mg (28), 240 mg (29), 360 mg (28), 480 mg (22), and 600 mg (3). The primary objective was to identify the safety and tolerability profile of MDV3100 and to establish the maximum tolerated dose. The trial is registered with ClinicalTrials.gov, number NCT00510718. We noted antitumour effects at all doses, including decreases in serum prostate-specific antigen of 50% or more in 78 (56%) patients, responses in soft tissue in 13 (22%) of 59 patients, stabilised bone disease in 61 (56%) of 109 patients, and conversion from unfavourable to favourable circulating tumour cell counts in 25 (49%) of the 51 patients. PET imaging of 22 patients to assess androgen-receptor blockade showed decreased (18)F-fluoro-5alpha-dihydrotestosterone binding at doses from 60 mg to 480 mg per day (range 20-100%). The median time to progression was 47 weeks (95% CI 34-not reached) for radiological progression. The maximum tolerated dose for sustained treatment (>28 days) was 240 mg. The most common grade 3-4 adverse event was dose-dependent fatigue (16 [11%] patients), which generally resolved after dose reduction. We recorded encouraging antitumour activity with MDV3100 in patients with castration-resistant prostate cancer. The results of this phase 1-2 trial validate in man preclinical studies implicating sustained androgen-receptor signalling as a driver in this disease. Medivation, the Prostate Cancer Foundation, National Cancer Institute, the Howard Hughes Medical Institute, Doris Duke Charitable Foundation, and Department of Defense Prostate Cancer Clinical Trials Consortium. Copyright 2010 Elsevier Ltd. All rights reserved.

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Selective inhibition of CYP17 with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer.

Mitch Dowsett, L Molife, Elizabeth Folkerd … (2009)

It has been postulated that castration-resistant prostate cancer (CRPC) commonly remains hormone dependent. Abiraterone acetate is a potent, selective, and orally available inhibitor of CYP17, the key enzyme in androgen and estrogen biosynthesis. This was a phase I/II study of abiraterone acetate in castrate, chemotherapy-naive CRPC patients (n = 54) with phase II expansion at 1,000 mg (n = 42) using a two-stage design to reject the null hypothesis if more than seven patients had a prostate-specific antigen (PSA) decline of > or = 50% (null hypothesis = 0.1; alternative hypothesis = 0.3; alpha = .05; beta = .14). Computed tomography scans every 12 weeks and circulating tumor cell (CTC) enumeration were performed. Prospective reversal of resistance at progression by adding dexamethasone 0.5 mg/d to suppress adrenocorticotropic hormone and upstream steroids was pursued. A decline in PSA of > or = 50% was observed in 28 (67%) of 42 phase II patients, and declines of > or = 90% were observed in eight (19%) of 42 patients. Independent radiologic evaluation reported partial responses (Response Evaluation Criteria in Solid Tumors) in nine (37.5%) of 24 phase II patients with measurable disease. Decreases in CTC counts were also documented. The median time to PSA progression (TTPP) on abiraterone acetate alone for all phase II patients was 225 days (95% CI, 162 to 287 days). Exploratory analyses were performed on all 54 phase I/II patients; the addition of dexamethasone at disease progression reversed resistance in 33% of patients regardless of prior treatment with dexamethasone, and pretreatment serum androgen and estradiol levels were associated with a probability of > or = 50% PSA decline and TTPP on abiraterone acetate and dexamethasone. CYP17 blockade by abiraterone acetate results in declines in PSA and CTC counts and radiologic responses, confirming that CRPC commonly remains hormone driven.

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Isolation of a human prostate carcinoma cell line (DU 145).

D. Mickey, Joshua Stone, R. Stone … (1978)

A long-term tissue culture cell line has been derived from a human prostate adenocarcinoma metastatic to the brain. The cell line, DU 145, has been passaged 90 times in vitro over a period of 2 years. The cells are epithelial, grow in isolated islands on plastic Petri dishes, and form colonies in soft agar suspension culture. Karyotypic analysis demonstrates an aneuploid human karyotype with a modal chromosome number of 64. Distinctive marker chromosomes (a translocation Y chromosome, metacentric minute chromosomes and three large acrocentic chromosomes) have been identified. Electron microscopy of the original tumor tissue and of the tissue culture cell line show a remarkable similarity in cell organelle structure.

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Author and article information

Journal

Journal ID (nlm-ta): J Pharmacol Pharmacother

Journal ID (iso-abbrev): J Pharmacol Pharmacother

Journal ID (publisher-id): JPP

Title: Journal of Pharmacology & Pharmacotherapeutics

Publisher: Medknow Publications & Media Pvt Ltd (India )

ISSN (Print): 0976-500X

ISSN (Electronic): 0976-5018

Publication date (Print): Oct-Dec 2013

Volume: 4

Issue: 4

Pages: 230-237

Affiliations

[1] Department of Pharmacology, Subharti Medical College, Subhartipuram, Meerut Bypass, Meerut, Uttar Pradesh, India

Author notes

Address for correspondence: Afroz Abidi, C/O S.I.S Abidi, Mass Products India Ltd, Mill Road, Aishbagh, Lucknow - 226 004, Uttar Pradesh, India. E-mail: afrozabidi@ 123456gmail.com

Article

Publisher ID: JPP-4-230

DOI: 10.4103/0976-500X.119704

PMC ID: 3825997

PubMed ID: 24250198

SO-VID: 7552b8c9-bc69-48ce-abd0-c01f840ca830

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Cabazitaxel: A novel taxane for metastatic castration-resistant prostate cancer-current implications and future prospects

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Most cited references 27

Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study.

Selective inhibition of CYP17 with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer.

Isolation of a human prostate carcinoma cell line (DU 145).

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