Vinorelbine Used in Refractory Prostate Ca

NEW YORK--The vinca alkaloid vinorelbine tartrate (Navelbine)has demonstrated clinical efficacy in hormone refractory prostatecancer as measured by time to disease progression, performancestatus, and pain indices, as well as bone scans and PSA analysis,Howard A. Burris, III, MD, told Oncology News International.

"One of the problems in dealing with prostate cancer is thatwe traditionally evaluate drugs by looking at an objective responserate. But in prostate cancer, the paucity of patients with measurabledisease has prevented this as an endpoint," said Dr. Burris,director of clinical research at the Cancer Therapy and ResearchCenter and director of drug development at Brooke Army MedicalCenter, San Antonio.

With chemotherapy producing a steady 10% to 20% response rate,the focus tends to shift to palliative advantages. Though theseendpoints need to be validated, they do appear to be useful forevaluating new drugs for hormone refractory prostate cancer, Dr.Burris said.

In the San Antonio trial, the vinorelbine schedule was 22 mg/m²IV, weekly for 8 weeks, and then repeated every other week. The20 patients enrolled averaged more than five cycles or 5 monthsof therapy--"a good prognostic sign," Dr. Burris said.Patients experienced only mild toxicities and brief neutropenia.

A positive response was defined as a greater than 25% change frombaseline in one endpoint. By this measure, six of the 20 patientswere positive responders, producing a clinical benefit rate of30%--33%, if two patients who discontinued for personal reasonswere not included. Dr. Burris earlier reported these findingsat the Chemotherapy Foundation Symposium XII, sponsored by MountSinai School of Medicine.

The Texas researchers were also encouraged by the fact that nineother patients experienced stable disease while only three hadtruly progressive disease.

All six responders had improvement in Karnofsky status and painindices, and three were able to discontinue analgesics entirely.The range of PSA reductions was wide, between 3 and 80 ng/mL,probably because some patients enrolled with relatively low PSAscores, he said.

"Where to head next?" Dr. Burris asked. Phase II trialsof vinorelbine are being conducted by other investigators, hesaid. "In San Antonio, we're carrying out a phase I triallooking at lower doses of estramustine [Emcyt] in combinationwith vinorelbine to see if we can, in fact, improve on the efficacyof the combination without adding to the toxicity."

If the results are encouraging, a phase III trial will be conductedusing vinorelbine plus or minus estramustine versus estramustineor prednisone alone, he said. "Certainly, there's great debateover what's being used as a control arm. Estramustine remainsthe only cytotoxic drug that is approved for prostate cancer.Many people feel that a steroid would be appropriate control therapyas well."

Vinorelbine's mechanism of action involves the binding of microtubule associated proteins, which blocks the assembly of more microtubules."Estramustine ends up producing somewhat the same result,"Dr. Burris said.

He noted that preclinical studies showed estramustine and vinblastineto have additive or superadditive effects and different toxicityprofiles. Like vinblas-tine, vinorelbine's toxicity profile largelycenters around myelosuppression, while estramustine's centersaround GI toxicity. Estramustine also lacks cross resistance toother cytotoxic compounds.

"But with vinblastine there's a very small threshold betweenwhere we see cytotoxicity and where we see the neurotoxicity ofthe compound. The threshold is greater with vinorelbine,"he said.

In fact, very low vinorelbine levels are needed to stop mitoticmicrotubule assembly, and much greater levels are required beforeneurotoxicity is seen, "a potentially significant advantage,"he said.