Daniel P. Petrylak, MD
Since its approval eight years ago, docetaxel has become the standard of care for first-line chemotherapy in castration-resistant prostate cancer (CRPC). And now, as novel targeted therapies are being developed, the role of docetaxel in combination with new agents is not yet clear, according to Daniel P. Petrylak, MD, professor of medicine at Columbia University Medical Center/New York Presbyterian Hospital in New York City.
“We need a biological way to tell which treatments to administer,” said Petrylak, who spoke at the 5th Annual Interdisciplinary Prostate Cancer Congress in New York City on March 31.
Docetaxel has been studied in combination with a number of new therapies, but so far, results of phase III studies have been disappointing: To date, no studies of novel therapies combined with docetaxel and prednisone have demonstrated improvement in their designated endpoints. However, several promising combination trials are ongoing.
Dasatinib (Sprycel, Bristol-Myers Squibb), approved for treatment of adults with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase, demonstrated encouraging results in a phase I-II study in 46 patients with CRPC.1 Dasatinib targets both the tumor and bone microenvironment in CRPC via the Src pathway, Petrylak said.
In the phase I-II study, 18 of 30 patients with measurable disease had a partial PSA response.1 Treatment with dasatinib also resulted in improvement in bone markers, with 87% of patients experiencing decreases in urinary N-telopeptide and 76% showing a decrease in bone-specific alkaline phosphatase levels. The combination of dasatinib and docetaxel was generally well tolerated; 28% of patients had grade 3-4 toxicity. The results led to the development of a phase III trial of docetaxel with and without dasatinib in 1500 patients with metastatic CRPC with evidence of progression.2 The trial’s primary endpoint is overall survival; results are expected in February 2013.
Inhibition of clusterin, another therapeutic target, is being explored in the ongoing SYNERGY trial. Clusterin is a protein expressed in several cancers, including prostate cancer; overexpression confers resistance to hormone therapy, chemotherapy, and radiation therapy, both in vitro and in vivo, Petrylak said.
The phase III SYNERGY study is evaluating firstline docetaxel, with and without custirsen (OGX- 011, Teva Pharmaceutical Industries) in patients with metastatic CRPC, with a primary endpoint of overall survival.3 Custirsen blocks the production of clusterin, and results of phase II trials in prostate cancer suggest that the drug may provide an overall survival benefit and durable pain palliation. Results of the phase III SYNERGY trial are expected in late 2013. Custirsen has received Fast Track designation from the FDA.
Another promising novel therapy for prostate cancer is cabozantinib (XL184, Exelixis), a tyrosine kinase inhibitor that blocks both MET and VEGFR2. MET and its ligand HGF drive tumor cell invasion and metastasis, and MET and VEGFR2 together promote angiogenesis, Petrylak said. Furthermore, bone metastases are associated with high levels of MET expression. “Although cabozantinib is a bone-targeted agent, soft-tissue responses have also been seen,” Petrylak said.
In a phase II randomized discontinuation trial presented at the American Society of Clinical Oncology 2011 annual meeting, cabozantinib demonstrated clinical activity regardless of prior docetaxel treatment in men with metastatic CRPC, particularly in patients with bone disease.4 Of 65 evaluable patients, 86% (56) had complete or partial resolution on bone scan as early as week six. In 28 patients receiving narcotics for bone pain, 64% had improved pain and 46% decreased or halted narcotics. Objective tumor shrinkage occurred in 84% of patients. Randomization was halted and patients unblinded due to high rates of bone scan resolution and pain relief. However, Petrylak said, looking at the results in terms of docetaxel pretreatment status is a misnomer. “We want to think in terms of a biological continuum and look for markers.”
In summary, Petrylak said, results of phase III trials combining docetaxel with novel targeted agents have been disappointing so far. However, he said, several combination trials are still under way, and a number of new agents in development demonstrate promising activity in CRPC.