NEW DRUG FOR PROSTATE CANCER

March 4, 2010 — There might be another chemotherapeutic agent on the way for metastatic prostate cancer.

In a phase 3 trial, the investigational drug cabazitaxel (Sanofi- Aventis) used as a second-line therapy increased survival by 30% in men with metastatic prostate cancer, compared with the standard therapy of mitoxantrone (Novantrone, OSI Oncology).

Men in 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, 0.70; 95% confidence interval, 0.59 - 0.83; P < .0001).

The median follow-up was 12.8 months.

All of the men in the study had metastatic disease that progressed despite hormone therapy and docetaxel-based chemotherapy; they were subsequently randomized to either cabazitaxel or mitoxantrone.

"Cabazitaxel will add to our armamentarium in metastatic prostate cancer," said Oliver Sartor, MD, Piltz Professor for Cancer Research at Tulane Cancer Center in New Orleans, Louisiana, and lead author of the cabazitaxel study. The study was discussed during a press conference preceding the upcoming 2010 Genitourinary Cancers Symposium (GUCS) in San Francisco, California.

GUCS is cosponsored by the American Society for Clinical Oncology (ASCO), the American Society for Radiation Oncology, and the Society of Urologic Oncology.

The overall survival benefit of cabazitaxel was "consistent across subgroups," added Dr. Sartor. The subgroup data will be delineated when the study is presented at GUCS on March 5.

"The study results were better than what we projected" added Dr. Sartor. The study had 90% power to detect a 25% reduction in the hazard rate for death in the cabazitaxel group after 511 events.

"It's a very important finding," said Nicholas J. Vogelzang, MD, chair and medical director of the Developmental Therapeutics Committee of US Oncology, who moderated the press conference.

The improved overall survival benefit seen with cabazitaxel is comparable to that seen with docetaxel, said Dr. Vogelzang. Docetaxel is indicated as a first-line treatment for men with metastatic disease who progress on hormone therapy and are, thus, "castration resistant," he added.

Despite the array of potential new agents in the metastatic prostate cancer setting, there is still no drug approved for patients who fail docetaxel, Dr. Sartor pointed out.

The potential new agents include abiraterone (Johnson & Johnson), MDV3100 (Medivation), and the adenovirus/prostate-specific antigen (Ad/PSA) vaccine Provenge (Dendreon).

Dr. Sartor does not see cabazitaxel competing with other agents; instead, he sees its being complementary.

The safety profile of cabazitaxel was "predictable and manageable" said Dr. Sartor. However, he highlighted the 7.5% rate of grade3/4 febrile neutropenia in patients receiving cabazitaxel; the rate was 1.3% in the mitoxantrone group. "Febrile neutropenia needs to be watched," he cautioned.

The most frequent grade 3/4 toxicity was neutropenia, which was observed in 81.7% of patients treated with cabazitaxel and in 58% treated with mitoxantrone.

More Data to be Presented at ASCO

The new phase 3 trial, known as TROPIC (Treatment of Hormone-Refractory Metastatic Prostate Cancer Previously Treated With a Taxotere-Containing Regimen), was conducted at 132 centers in 26 countries from January 2007 to October 2008. The trial involved 755 men with metastatic prostate cancer that was castration resistant. Median age was 68 years and 84% were white.

Men were randomized to either cabazitaxel 25 mg/m² or mitoxantrone 12 mg/m² 3 times a week; both groups received 10 mg/day of prednisone.

Dr. Sartor said that other trials of new agents in this setting have used either placebo or prednisone as the comparator. Mitoxantrone was a "better choice" because the drug "represented an opportunity for patients to get active treatment," said Dr. Sartor.

The primary end point of the TROPIC was overall survival. The secondary end points included progression-free survival, tumor response rates, PSA response, and PSA progression. All end points favored the cabazitaxel group. Data on these end points will be presented at the 2010 ASCO annual meeting, according to press materials released at GUCS.

An estimated 15,000 to 20,000 men with metastatic prostate cancer in the United States are treated annually with docetaxel. However, "docetaxel is not curative" said Dr. Sartor. These patients could all potentially move on to be treated with cabazitaxel, if approved, he added.

Patients eventually become resistant to docetaxel because of the multidrug resistant (MDR) pump, a mechanism in prostate cancer cells that pumps a drug out of the cancer cell before it can exert its effects, said Dr. Sartor. The MDR pump is seemingly unable to recognize cabazitaxel.

Dr. Sartor noted that findings from this study will form the basis of a submission to the US Food and Drug Administration for approval of cabazitaxel.

Other studies are being planned to assess the effectiveness of cabazitaxel earlier in the course of prostate cancer treatment, before patients stop responding to docetaxel. "We anticipate this chemotherapy will show value in some patients," he said.

Cabazitaxel will also be studied in other tumor types, Dr. Sartor told reporters attending the press teleconference.

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. Vogelzang reports being a consultant or advisor to Allos Therapeutics, Ambit, Amgen, Bayer, Celgene, Genentech, Keryx, Novartis, Onyx, Pfizer, Wilex, Honoraria, Amgen, ArQule, Bayer, Clinical Care Options, Cougar Biotechnology, Genentech, Imedex, Lippincott, Williams and Wilkins, Novartis, Onyx, Pfizer, and Wyeth; he also reports receiving research funding from Argos Therapeutics, ArQule, AstraZeneca, Cougar Biotechnology, Endocyte, GlaxoSmithKline, Keryx, Medarex, Novartis, Pfizer, Wilex.

2010 Genitourinary Cancers Symposium (GUCS): Abstract 9. Presented March 5, 2010.