Sunitinib lowers PSA in some advanced prostate cancer pts
BARCELONAThe addition of sunitinib (Sutent) to docetaxel (Taxotere) plus prednisone can delay disease progression and improve PSA levels in some men with metastatic castrate-resistant prostate cancer, according to a report by Amado J. Zurita, MD, assistant professor of genitourinary medical oncology, M.D. Anderson Cancer Center.
Metastatic castrate-resistant prostate tumors typically overexpress receptors for vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), two of the key cell-surface targets for sunitinib, an oral drug that has emerged as a first-line treatment for renal cell carcinoma (see article on page 30), Dr. Zurita said at the 14th European Cancer Conference (ECCO abstract 4025).
An earlier study had showed that imatinib (Gleevec), which targets only PDGF receptors, significantly reduced PSA levels in several patients with castrate-resistant prostate tumors. It was reasonable to think that sunitinib, with its dual binding to PDGF and VEGF, would improve upon that, Dr. Zurita said.
Preliminary data from an ongoing phase I/II multicenter study of sunitinib in combination with docetaxel and prednisone, the first to evaluate this new drug in the prostate cancer setting, suggest that this is the case, at least for some patients. For others, the drug actually increased PSA levels.
Four doses tested
Dr. Zurita's trial involved 25 men with metastatic and progressive prostate cancer despite medical or surgical castration. Patients began with a 6-week lead-in period of 50 mg sunitinib once daily for 4 weeks, followed by a 2-week rest. They were then assigned to four treatment groups of differing docetaxel/sunitinib dose levels: The first three cohorts received 60 mg/m2 of IV docetaxel plus escalating doses of oral sunitinib (12.5 mg, 37.5 mg, and 50 mg). The final cohort received 75 mg/m2 of docetaxel and 37.5 mg of sunitinib. Docetaxel was given every 3 weeks. All the men also took 5 mg prednisone twice daily.
During the lead-in period, sunitinib showed a curious trivalent effect on PSA levels. Seven patients had a mean PSA decline of 40%, with three of them showing a greater than 50% decrease. In contrast, 12 patients showed a steep mean rise in PSA of 273% followed by a drop during the 2-week rest period. Six others showed steady mean increases of 73% that did not drop back down during the rest period.
The combination of docetaxel and sunitinib produced PSA reductions of greater than 50% below baseline levels in 10 of the 25 patients (40%). Four of the 20 patients (20%) with measurable disease at baseline had a partial tumor response, based on RECIST criteria, and 11 (55%) had stable disease. Five patients progressed during the year-long follow-up period.
Based on the phase I results, the researchers determined that docetaxel 75 mg/m2 plus sunitinib 37.5 mg represented the optimal dose levels for the ongoing phase II portion of the trial. Sunitinib was generally well tolerated at this dose, and did not significantly add to the side-effect burden of docetaxel plus prednisone.
The key question remains: Which men are most likely to respond to the sunitinib/docetaxel combination? "Preliminary observations suggest that PSA reduction during the lead-in (sunitinib-only) phase likely predicted for later response to the combination," Dr. Zurita said. Evaluation of the predictive value of the lead-in PSA kinetics in determining later response is still ongoing.