In a phase II study, about 40% of men with clinically localized, high-risk prostate cancer were free of biochemical recurrence at 18 months when treated with neoadjuvant docetaxel (Taxotere) and ketoconazole followed by surgical excision, according to research presented at the AUA annual meeting.
Chicago-In a phase II study, about 40% of men with clinically localized, high-risk prostate cancerwere free of biochemical recurrence at 18 months when treated with neoadjuvant docetaxel (Taxotere) and ketoconazole followed by surgicalexcision, researchers from the University of Kansas, Kansas City, reported at the AUA annual meeting.
"Although we're quite happy with the results, it's not quite the silver bullet we'd like to have. It's a step in the right direction," said first author Paul R. Womble, MD, a urology resident working under the direction of Jeffrey M. Holzbeierlein, MD, and colleagues.
Dr. Womble told Urology Times that a synergistic effect between ketoconazole and docetaxel was suggested in a phase I study and cited other studies showing that ketoconazole may increase intracellular retention of other chemotherapeutic drugs. Ketoconazole also inhibits production of testicular and adrenal androgen and has antiproliferative effects in vitro in prostate cancer.
This study involved 22 men with localized, high-grade prostate cancer who had a mean PSA level of 25.3 ng/mL. To be eligible as participants, they had to have a PSA greater than 20 ng/mL, a Gleason score greater than 7, and the presence of primary Gleason grade 4 or higher or clinical stage T2b or greater disease.
In all, 77.2% had a Gleason score greater than 8, and the most common clinical stage was cT1c.
The men were treated with ketoconazole, 400 mg twice daily, and docetaxel, 55 mg/m2 in four cycles given 21 days apart. Dosing adjustments were made for significant toxicities. After completion of neoadjuvant therapy, the men underwent radical retropubic prostatectomy.
"Seventy-three percent of the patients tolerated the therapy well and completed all four courses," Dr. Womble said. All patients reported fatigue, 81.8% had alopecia, 77.3% experienced nausea, and 54.3% had neutropenia. National Cancer Institute grade 3 or 4 toxicity occurred in 72.7%.
A downgrade in the Gleason sum occurred in 45.5%, although there was no significant pathologic downstaging.
At a median follow-up of 18 months, 42% of men maintained no biochemical evidence of disease. Seven patients had biochemical recurrence and underwent salvage therapy; six of the seven maintained undetectable PSA levels.
At the final follow-up, however, only eight patients (42.1%) have been continuously disease-free since surgery without further therapy. Seven patients received additional therapy after radical prostatectomy due to failure of the PSA to attain nadir after surgery; six of these had an undetectable PSA at a median of 18 months.
"More studies will need to be done to determine how to treat these patients preoperatively, if that is a possibility," said Dr. Womble.
Funding was provided by sanofi-aventis.