June 14, 2010 (Chicago, Illinois) — For the first time, a therapy has shown a survival benefit in men with metastatic castration-resistant prostate cancer (mCRPC) after failure on docetaxel-based chemotherapy.
In a phase 3 trial of 755 patients, the investigational drug cabazitaxel, developed by Sanofi-Aventis, was used as a second-line therapy and increased survival by 28%, compared with standard-therapy mitoxantrone (Novantrone, OSI Oncology).
Men randomized to the cabazitaxel group had a median survival of 15.1 months, compared with 12.7 months for men in the mitoxantrone group; the difference was statistically significant (hazard ratio, 0.72; 95% confidence interval, 0.61 - 0.84; P < .0001).
The new data on cabazitaxel — an update of final outcomes from the TROPIC study — were presented here at the American Society of Clinical Oncology (ASCO) 2010 Annual Meeting. The median follow-up in TROPIC was 12.8 months.
The results were presented earlier in the year at the 2010 Genitourinary Cancers Symposium in San Francisco, California.
Now at ASCO, the data have been updated, and the drug was hailed as "clearly a major advance in secondary chemotherapy for advanced prostate cancer" by Nicholas J. Vogelzang, MD, from US Oncology in Woodlands, Texas, at a Highlights of the Day session.
Cabazitaxel has been submitted to the US Food and Drug Administration (FDA) and could be approved as early as the summer of 2010, according to a TROPIC investigator.
Concerns About Toxicity
However, one prostate cancer expert had reservations and questions about the drug's toxic death rate, study dose, adverse effects, and impact on quality of life.
Ian Tannock, MD, PhD, from the University of Toronto in Ontario, who was not involved in the study, said that cabazitaxel is likely to become the "standard of care" in the setting of second-line chemotherapy for advanced prostate cancer.
But he has concerns about its use and highlighted the importance of one adverse effect, neuropathy, in these men.
"By far the most worrying toxicity is the residual neuropathy," said Dr. Tannock, who was the discussant of the study.
Dr. Tannock described neuropathy as a "major impairment to quality of life."
There were no data presented on cabazitaxel and neuropathy, Dr. Tannock told the ACSO audience.
He noted that cabazitaxel was not the only potential cause of neuropathy in these men, because "many patients will have had fatigue and neuropathy related to disease and prior to [receiving] docetaxel," referring to the first-line treatment for men with disease resistant to hormone therapy.
"I hope the investigators will have data about the effects of treatment on patient-centered symptoms and quality of life," said Dr. Tannock.
Quality-of-life data will not be forthcoming from TROPIC, said one of the trial's colead investigators, Oliver Sartor, MD, from Tulane Cancer Center in New Orleans, Louisiana.
"We did not formally assess quality of life," Dr. Sartor told Medscape Oncology. There were "concerns" about the use of validation instruments in the trial's global setting, said Dr. Sartor about the trial, which took place at 146 centers in 26 countries. He also said that there has been a "move in the FDA to minimize patient-reported quality-of-life outcomes."
Toxic Death Rate Concern
Dr. Tannock was also concerned about the number of treatment-related deaths with cabazitaxel — approximately 5% of all patients treated with the agent in TROPIC.
"The toxic death rate is concerning," he said.
However, Dr. Sartor pointed out that there was a geographic variance with this data. Less than 1% of patients treated in North America died on the therapy. But in Europe, the rate was 4.9% in patients receiving cabazitaxel, compared with 3.0% in patients receiving mitoxantrone.
Dr. Sartor suspects that the difference is the result of "better management of toxicities, including neutropenia," in North America.
Febrile neutropenia was highlighted as an adverse event of concern by study coauthor Sebastian de Bono, MD, PhD, from the Institute of Cancer Research in Sutton, United Kingdom, who presented the study results at ASCO on behalf of Dr. Sartor and their international coinvestigators.
The rate of grade 3 or higher febrile neutropenia was 7.5% in the cabazitaxel group, compared with 1.3% in the mitoxantrone group.
"Proactive management of side effects is recommended," said Dr. de Bono, referring to febrile neutropenia and other adverse events, the most common of which was diarrhea (all grades: 46.6% for cabazitaxel vs 10.5% for mitoxantrone).
However, Dr. Tannock was concerned about possible "severe toxicity" with cabazitaxel "outside the setting of a clinical trial."
"I do not believe the lower toxic death rate in North America will translate into general oncologic practice," said Dr. Tannock.
Dr. Tannock was also concerned that the dose of cabazitaxel used in the study (25 mg/m2) was too high, and suggested that 20 mg/m2 would have been more appropriate. "I do question the choice of that dose," he said.
However, during the study presentation, Dr. de Bono noted that there was a "good delivery" of study doses and that only 9.8% of men in the cabazitaxel group and 5.1% of men in the mitoxantrone group required dose reductions.
Cabazitaxel will not compete with the recently approved Provenge , said Dr. Sartor. Instead, the chemotherapy is "complementary" to Provenge and other agents under investigation, he told Medscape Oncology earlier in the year.
Provenge is indicated for the treatment of mCRPC, whereas cabazitaxel has been studied in men who have mCRPC but who have also failed docetaxel.
The study was funded by Sanofi-Aventis. Dr. Sartor reports being a consultant or advisor to, and receiving honoraria and research funding from, Sanofi-Aventis. Dr. Tannock reports being or having been a consultant or advisor to Alpharadin, Cougar Biotechnology, Sanofi-Aventis, and Novacea, and receiving research funding from the same companies and from Threshold.
American Society of Clinical Oncology (ASCO) 2010 Annual Meeting: Abstract 4508. Presented June 6, 2010.