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European UrologyVolume 63, issue 6, pages e67-e86, June 2013
Taxanes: Still a Major Weapon in the Armamentarium Against Prostate Cancer
Published online 23 January 2013, pages 983 - 985
Refers to article:
Cabazitaxel Plus Prednisone for Metastatic Castration-resistant Prostate Cancer Progressing After Docetaxel: Results from the German Compassionate-use Programme
Accepted 28 August 2012
June 2013 (Vol. 63, Issue 6, pages 977 - 982)
Docetaxel-based chemotherapy is standard first-line chemotherapy in patients with metastatic castration-resistant prostate cancer (mCRPC). Two randomised phase 3 trials have shown improved overall survival in chemo-naïve patients with castration-resistant prostate cancer (CRPC) treated with docetaxel-prednisone, alone or in combination with estramustine, as compared to mitoxantrone-prednisone  and . However, almost 50% of patients do not respond to docetaxel. Known molecular mechanisms of resistance to docetaxel involve decreased cellular drug accumulation due to overexpression of membrane-bound efflux proteins (P-glycoprotein [P-GP]), expression of tubulin isotypes (overexpression of beta-III tubulin), and defects in apoptosis. Some gene-expression signatures have been associated with docetaxel resistance of prostate cancer (PCa) cells, but no single “druggable” driver pathway has emerged to target and circumvent such resistance.
Until recently, limited chemotherapy options were available for patients failing first-line docetaxel. A docetaxel “rechallenge” is associated with a high response rate but no demonstration of improved survival in patients with an interval of at least 3 mo since the last docetaxel cycle . Carboplatin-etoposide is associated with moderate activity, which is only slightly increased in patients with cancers displaying a neuroendocrine differentiation , and mitoxantrone is associated with very modest activity in this setting. Cabazitaxel (XRP6258), a tubulin-binding taxane drug, showed potent antitumour activity comparable with docetaxel in docetaxel-sensitive cell lines and exhibited more potent cytotoxic activity than docetaxel in cancer cell lines with acquired resistance to docetaxel due to P-GP overexpression. The TROPIC international phase 3 trial showed that cabazitaxel improves overall survival compared to mitoxantrone-prednisone with a 30% risk reduction of death (hazard ratio: 0.70; 95% confidence interval, 0.59–0.83; p < 0.0001) in men with metastatic CRPC whose disease had progressed during or after treatment with a docetaxel-based regimen . Cabazitaxel was the first agent to be associated with improved overall survival in men with mCRPC who failed first-line docetaxel-based chemotherapy, and it is now considered a reasonable option for patients in this setting. However, concerns have been raised regarding its safety in daily-practice use because cabazitaxel resulted in increased treatment-related mortality (4.9%) due to febrile neutropenia along with severe diarrhoea in patients enrolled in the TROPIC trial.
In this issue of the journal , Heidenreich and colleagues report safety results of mCRPC patients treated within a compassionate-use programme in Germany, with the implementation of an awareness programme for physicians on proactive management of adverse events (AEs). Granulocyte colony-stimulating factor (G-CSF) was administered prophylactically in 15 patients (13.5%) during cycle 1. Grade 3 and 4 treatment-emergent AEs were recorded in 34 patients (30.6%) and 18 patients (16.2%), respectively. Grade 3/4 gastrointestinal toxicity was identified in 4.5% of the patients. Toxicity led to death in four patients (3.6%). A prostate-specific antigen (PSA) response defined as a PSA reduction of ≥50% was achieved in 35 of 93 patients (37.6%), and the mean progression-free survival was 3.78 mo (range: 0.7–31.47 mo). Although the pattern of toxicity observed in this program compares better then that reported in TROPIC, the toxicity-related death rate remains high and leaves room for improvement.
In similar programs conducted in 20 European countries, primary prophylaxis of febrile neutropenia with G-CSF was recommended for high-risk patients, as per European Society for Medical Oncology (ESMO) and American Society of Clinical Oncology (ASCO) guidelines. Consequently, lower rates of febrile neutropenia (5.4%) and treatment-related deaths (2.3%) were observed in 746 patients from this registry . So far, no potent clinical or biological factor is available to predict serious AEs from cabazitaxel. In the German experience, all deaths occurred after cycle 1, and none of the patients who received G-CSF died of toxicity. In addition, none of the patients who died of toxicity had experienced significant haematotoxicty during the previous docetaxel therapy, begging the question of whether G-CSF should be given to all patients on cabazitaxel. Importantly, prior extensive radiotherapy or concurrent serious illness were exclusion criteria in both the TROPIC trial and in early access programmes.
To further reduce the risk of severe toxicity for patient candidates for cabazitaxel, simple recommendations should be implemented:
- • Respect the exclusion criteria used in previous experiences (mainly prior extensive radiotherapy and concurrent serious illnesses).
- • Restrict the prescription for cabazitaxel to well-trained oncologists.
- • Inform the patient cautiously about the risks and benefits of cabazitaxel and make sure that he understands the importance of contacting the medical team immediately in case of fever.
- • Ensure the patient immediate access to an adequate medical environment in case of fever and/or diarrhoea.
- • Use prophylactic G-CSF at least per ESMO/ASCO recommendations (eg, could systematic use reduce the toxicity-related death rate to near zero).
- • Reduce the dosage of cabazitaxel if necessary.
The approved dose of 25 mg/m2, which is feasible for most patients, is still being challenged because the phase 1 trials of cabazitaxel achieved discordant results. Two phase 3 trials are ongoing to compare two doses for safety and antitumour efficacy in mCRPC (20 mg/m2 and 25 mg/m2): FIRSTANA (ClinicalTrials.gov, NCT01308567) in chemotherapy-naïve patients, and PROSELICA (ClinicalTrials.gov, NCT01308580) in patients previously treated with docetaxel.
Both abiraterone and enzalutamide showed survival benefits when used in patients progressing after docetaxel. Abiraterone was also associated with dramatic improvement in progression-free survival in the chemo-naïve setting. Consequently, chemotherapy, including cabazitaxel, may be used mostly in late-stage, heavily treated disease, raising the question of its safety in postabiraterone (and prednisone) and/or postenzalutamide spaces. This emphasises the importance of the FIRSTANA and PROSELICA trials regarding whether a lower dose of cabazitaxel should be used in this population of patients, including the elderly. Another currently raised issue is which patients should be offered cabazitaxel in the context of a moving therapeutic landscape, with abiraterone, enzalutamide, and radium-223 providing a survival improvement in patients with docetaxel-treated mCRPC. Preclinical studies suggest that while interfering with tubulin, taxanes impede the androgen receptor translocation into the nucleus (although it is likely that taxanes do not kill cells mostly through this mechanism). These studies, along with recent clinical data from a retrospective study suggesting a reduced efficacy of docetaxel in abiraterone-resistant patients , bring up the possibility of cross-resistance between taxanes and the new-generation endocrine therapies. However, very recent data from another retrospective study showed that cabazitaxel remains active in patients pretreated by both docetaxel and abiraterone: A PSA response rate (defined as a PSA decline ≥50%) was observed in 56% (18 of 32 patients) .
The critical issues are now how to set the optimal sequencing; how to best select patients for cabazitaxel; and, even more important, how to best individualise treatment. Even if biomarkers predicting response/resistance and toxicity for new drugs (cabazitaxel, abiraterone, enzalutamide, radium-223) are not well known, available data suggest that the activity of subsequent endocrine manipulations is modest in patients with a short (<1-yr) duration of response to androgen-deprivation therapy . This simple factor will probably be used in the near future to help decision making for CRPC patients, since the anticancer activity of taxanes is maintained in patients with this phenotype of undifferentiated and aggressive cancers.
Based on their clinical activity in late-stage disease, taxanes are being investigated in earlier PCa stages. For example, docetaxel was shown to significantly improve progression-free survival in GETUG 15, a phase 3 trial focusing on patients (n = 380) with hormone-naïve metastatic PCa . In this trial, overall survival was not significantly improved in the docetaxel arm, likely because the majority of patients from the control arm subsequently received docetaxel as they progressed to the mCRPC stage. Based on the paradigm of other epithelial cancers (breast, colorectal, and lung) in which the use of chemotherapy in patients with localised disease was associated with improved overall survival, taxanes are currently being studied in high-risk localised PCa together with standard care. About 10 such phase 3 trials using docetaxel are currently ongoing, although only preliminary data from one trial, GETUG 12 (n = 413 patients) are currently available. The proportion of patients achieving undetectable PSA was significantly increased in the docetaxel arm and toxicity was limited, with no toxicity-related deaths and no major detrimental impact on quality of life . Because the number of events (relapse or deaths) has been less than expected, the Independent Data Monitoring Committee recommended that survival analysis be performed when a median follow-up of 7 yr is reached; this is expected by approximately 2013–2014. In the meantime, the large academic PEACE-2 phase 3 trial assessing cabazitaxel in patients with localised disease and a very high risk of relapse (at least two risk factors) has been designed and is about to start accruing in Europe in 2013. The more effort we put into rapidly accruing our patients for these programs (and others), the sooner we will better define the optimal use of taxanes for patients with PCa.
Conflicts of interest
Drs. Fizazi and Loriot are investigators for Sanofi/Aventis-sponsored trials, and Dr. Loriot receives esearch funding from Sanofi/Aventis.
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Department of Cancer Medicine, Institut Gustave Roussy and University of Paris Sud, Villejuif, France
© 2013 European Association of Urology, Published by Elsevier B.V.
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