Efficacy of new advanced prostate cancer treatment affirmed

September 1, 2010

In men with metastatic castration- resistant prostate cancer who progressed after docetaxel (Taxotere)-based therapy, treatment with cabazitaxel (Jevtana) was associated with significantly better overall survival compared with mitoxantrone (Novantrone).

The findings were reported at the American Society of Clinical Oncology annual meeting in Chicago by first author Johann S. de Bono, MD, PhD, of Royal Marsden NHS Foundation Trust and the Institute of Cancer Research, Sutton, United Kingdom. The updated results were from a data cutoff of March 10, 2010, when the median follow-up was 13.7 months and 585 of 755 participants had died.

Oliver Sartor, MD, co-principal investigator for TROPIC (Treatment of Hormone-Refractory Prostate Cancer Previously Treated with a Taxotere-Containing Regimen), told Urology Times that cabazitaxel, a semisynthetic taxoid that was developed specifically to overcome taxane resistance, "is the first treatment to show a survival benefit in patients with metastatic castrate-resistant prostate cancer after failure of docetaxel-based therapy."

TROPIC enrolled men with Eastern Cooperative Oncology Group performance status 0-2 who had normal organ function and experienced prostate cancer progression during or after receiving docetaxel.

Patients who received previous treatment with mitoxantrone were excluded, and the eligibility criteria were amended after the first 59 patients were treated so that patients enrolled going forward had to have received at least three courses of docetaxel or a cumulative dose of ≥225 mg/m2 .

Men were randomized 1:1 to receive IV infusions of either mitoxantrone, 12 mg/m2 , or cabazitaxel, 25 mg/m2 , every 3 weeks for up to 10 cycles. All patients also received oral prednisone/prednisolone, 10 mg daily.

'Significant' differences in survival

In the updated analysis, cabazitaxel, which was recently approved by the FDA, increased median overall survival by 2.4 months compared with mitoxantrone (15.1 months vs. 12.7 months), and significantly reduced the risk of death by 28% (p<.0001). The overall survival benefit was consistent across various subgroups of patients, including among those who progressed during their last docetaxel treatment and those who progressed within 3 months of discontinuing docetaxel, with patients who received fewer than three courses of docetaxel being the notable exception.

The study results also showed statistically significant differences favoring cabazitaxel in secondary efficacy analyses of progression-free survival, tumor response, PSA response, tumor progression, and PSA progression. There was no treatment-related difference in pain response, but only a small number of patients were evaluated for this endpoint, Dr. de Bono reported.

The safety data showed increased risks of febrile neutropenia and diarrhea with cabazitaxel. Risks of myelosuppression adverse events were also higher for cabazitaxel as was the rate of toxic death (4.9% vs. 1.9%), although the latter difference was not apparent considering the 235 patients enrolled in North America.

Dr. de Bono suggested the high rates of myelosuppression adverse events in both groups are due in part to the fact that the patients represented a relatively sick population with extensive bone disease and that geographic differences in the toxic death rate may reflect that on average, North American patients were enrolled with less advanced disease. He said that the safety profile of cabazitaxel is manageable, although proactive management of treatment-related side effects, particularly neutropenia and diarrhea, will be important with the use of this drug.

Discussing the research, Ian F. Tannock, MD, PhD, of Princess Margaret Hospital, Toronto, commented that based on its demonstrated survival benefit, cabazitaxel will likely become the standard of care for treating men with metastatic castrate-resistant prostate cancer who fail docetaxel-based therapy. However, he called for more information about the effects of cabazitaxel on quality of life and especially relating to neurotoxicity in this population of men with late-stage prostate cancer, considering that residual neuropathy is the most worrying toxicity affecting men who complete docetaxel.

Dr. de Bono, Dr. Sartor, and co-authors of this study disclosed financial interest or other relationship with sanofi-aventis. Dr. Tannock has acted as a consultant to sanofi-aventis and other companies developing drugs for prostate cancer, and has received contributions to his research fund.