Data from the Phase III TROPIC study, which was the basis for the June 2010 U.S. Food and Drug Administration (FDA) approval of the novel taxane cabazitaxel (Jevtana? ) was published in the October 2, 2010 print edition of The Lancet in an article titled ?Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial.?

The data demonstrated that cabazitaxel in combination with prednisone reduced the risk of death by 30% in men with metastatic castration-resistant prostate cancer (also known as metastatic hormone refractory prostate cancer, or mHRPC) whose disease progressed following treatment with a docetaxel-containing treatment regimen. The microtubular network is essential for mitotic and interphase cellular functions. Cabazitaxel is a microtubule inhibitor derived from the taxane, docetaxel. Like other taxanes, cabazitaxel acts by binding tubulin and promoting microtubule polymerization and preventing disassembly.

The drug is approved in combination with prednisone for the treatment of patients with metastatic hormone refractory prostate cancer (mHRPC) previously treated with a docetaxel-based treatment regimen.In November 2009 the FDA granted fast track designation for cabazitaxel. The rolling new drug application (NDA) submission was completed in March 2010 and was granted priority review in April 2010. Cabazitaxel was approved by the FDA less than three months later. A registration dossier of cabazitaxel is also under regulatory review by other regulatory authorities, including the European Medicines Agency EMEA.

The TROPIC study was conducted in 146 trial sites in 26 countries, including the U.S. This multicenter, Phase III, randomized registration trial assessed 755 mCRPC patients whose disease had progressed following treatment with docetaxel-based chemotherapy.

Patients were randomly assigned to receive cabazitaxel plus prednisone/prednisolone or mitoxantrone (Novantrone, OSI Oncology) plus prednisone/prednisolone (378 and 377 patients, respectively), for up to a maximum of 10 cycles. The primary endpoint was overall survival. Secondary endpoints included progression-free survival, tumor response rate, tumor progression, prostate-specific antigen (PSA) response, PSA progression, pain response, and pain progression. Disease progression was defined as tumor progression, PSA progression or pain progression. Other secondary endpoints were overall safety of cabazitaxel in combination with prednisone, pharmacokinetics of cabazitaxel and its metabolite in this patient population, and the effect of prednisone on the pharmacokinetics of cabazitaxel.

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?Jevtana is the first approved therapy to fill a critical gap among patients with the most advanced stage of prostate cancer and is the first therapeutic option for these patients shown to prolong survival,? said Oliver Sartor, M.D., Piltz Professor for Cancer Research at Tulane Medical School, New Orleans, and North American principal investigator for the pivotal TROPIC trial.

Commenting on the new treatment options, Johann de Bono, M.D. from the Royal Marsden NHS Foundation and the Institute of Cancer Research in the United Kingdom explained that cabazitaxel is the first drug to show a survival benefit in patients whose disease has progressed after standard chemotherapy with docetaxel and for whom there are currently no other approved treatment options available. Dr de Bono is the study?s principle investigator and lead auditor of the article in The Lancet.“Sanofi-aventis Oncology is tackling cancer on all fronts to provide new solutions that make a difference in patients’ lives,” said Debasish Roychowdhury, M.D., Senior Vice President, Head of Global Oncology, sanofi-aventis.

“The publication of this pivotal trial in The Lancet underscores the importance of the study, which is the first to demonstrate an overall survival advantage in patients with metastatic hormone refractory prostate cancer whose disease has progressed following treatment with a docetaxel-containing treatment regimen.”

Study Results
In the TROPIC Study 755 men were allocated to two treatment groups (377 mitoxantrone, 378 cabazitaxel) and were included in the intention-to-treat analysis. The of the results of the study showed that the combination of cabazitaxel and prednisone significantly reduced the risk of death by 30% [HR=0.70 (95% CI: 0.59-0.83); P<0.0001], with an improvement in median overall survival of 15.1 months versus 12.7 months in the mitoxantrone combination arm. In addition, patients in the cabazitaxel combination arm showed a significantly higher rate of investigator-assessed tumour response (14.4 [95% CI: 9.6-19.3; P<0.001]) compared with those in the mitoxantrone combination arm (4.4 [95% CI: 1.6-7.2; P<0.001]).

Adverse reactions
In the TROPIC Study, the most common (?10%) adverse reactions (grade 1-4) were neutropenia, anemia, leukopenia, thrombocytopenia, diarrhea, fatigue, nausea, vomiting, constipation, asthenia, abdominal pain, hematuria, back pain, anorexia, peripheral neuropathy, pyrexia, dyspnea, dysguesia, cough, arthralgia, and alopecia. The most common (?5%) grade 3-4 adverse reactions in patients who received cabazitaxel were neutropenia, leukopenia, anemia, febrile neutropenia, diarrhea, fatigue, and asthenia. The most common adverse reactions leading to treatment discontinuation in the cabazitaxel group were neutropenia and renal failure. Treatment discontinuations due to adverse drug reactions occurred in 18% of patients who received Jevtana and 8% of patients who received mitoxantrone. Deaths due to causes other than disease progression within 30 days of last study drug dose were reported in 18 (5%) cabazitaxel patients and 3 (less than 1%) mitoxantrone-treated patients. The most common fatal adverse reactions in cabazitaxel patients were infections (n=5) and renal failure (n=4). One death was due to diarrhea-induced dehydration and electrolyte imbalance.

Results from the TROPIC study were presented earlier this year at the 2010 Genitourinary Cancers Symposium in San Francisco, California. And update with the final outcomes was presented here at the American Society of Clinical Oncology (ASCO) 2010 Annual Meeting.

Global incidence
Worldwide, prostate cancer ranks third in cancer incidence and sixth in cancer mortality in men. In the U.S., prostate cancer remains the second most common cause of cancer death among men after lung cancer. In 2009, an estimated 192,000 new cases were anticipated in the U.S., while 27,000 men were expected to have died from the disease. For many patients with prostate cancer, their disease continues to progress despite prior treatment ? including surgical and/or hormonal castration followed by chemotherapy. Metastatic prostate cancer indicates that the cancer has spread to the lymph nodes or other parts of the body, particularly the bones. Castration resistant/hormone-refractory prostate cancer means that the cancer has continued to grow despite the suppression of male hormones that fuel the growth of prostate cancer cells. An estimated 10-20% of patients with prostate cancer are diagnosed when the cancer has already metastasized.

Other therapies
Cabazitaxel will not compete with the recently approved immunotherapy, sipuleucel-T (Provenge, Dendreon), for the treatment of asymptomatic or minimally symptomatic metastatic, castration-resistant prostate cancer (mCRPC). Sipuleucel-T is an autologous active cellular immunotherapy made from the patient’s own white blood cells and stimulates a patient’s immune system to respond against the cancer. This treatment needs to be manufactured indi
vidually for each patient. Cabazitaxel is considered ?complementary? to sipuleucel-T and other agents under investigation because it has been studied and approved in men who have mCRPC who have failed docetaxel. Sipuleucel-T is indicated for the treatment of asymptomatic or minimally symptomatic

– De Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Shen L, et al. Cabazitaxel or mitoxantrone with prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel: Final results of a multinational phase III trial (TROPIC). J Clin Oncol 28:15s, 2010 (suppl; abstr 4508)
– De Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I, Gravis G, Bodrogi I, Mackenzie MJ, Shen L, Roessner M, Gupta S, Sartor AO; TROPIC Investigators. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010 Oct 2;376(9747):1147-54
– Dorff TB, Quinn DI. Cabazitaxel in prostate cancer: stretching a string. Lancet. 2010 Oct 2;376(9747):1119-20

Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, et al Sipuleucel-T immunotherapy for castration-resistant prostate cancer. 2010 Jul 29;363(5):411-22.

Clinical Trials
XRP6258 Plus Prednisone Compared to Mitoxantrone Plus Prednisone in Hormone Refractory Metastatic Prostate Cancer (TROPIC)
Provenge? (Sipuleucel-T) Active Cellular Immunotherapy Treatment of Metastatic Prostate Cancer After Failing Hormone Therapy.

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