ASCO: Agents Emerging for Hormone-Refractory Prostate Cancer

CHICAGO, June 2 -- Second-line agents for hormone-refractory prostate cancer are emerging to fill an unmet need, researchers said here.

Leading this panoply of investigational drugs is satraplatin, according to a panel of presenters at an industry-supported satellite symposium held in conjunction with the American Society of Clinical Oncology meeting.

Several first-line treatments are approved for advanced prostate cancer that progresses despite hormone deprivation. These include intravenous bone-seeking radioisotopes, bisphosphonates, and chemotherapy agents.

The only one shown to impact overall survival, though, has been docetaxel (Taxotere), said Oliver Sartor, M.D., of the Dana-Farber Cancer Institute in Boston.

"For a long time, chemotherapy had a minimal role in prostate cancer," said Cora Sternberg, M.D., of the San Camillo Forlanini Hospital in Rome. "This all changed in 2004 when docetaxel was approved."

It has become a standard of care in first-line therapy, she said.

But, after primary chemotherapy fails, oncologists have been left to empiric and often symptom-directed second-line therapy because there are no FDA approved agents for this indication, Dr. Sartor said.

"Docetaxel failures represent a tremendous challenge," he added.

Radioisotopes strontium-89 (Metastron) and samarium-153 (Quadramet) are FDA approved for relief of pain from bone metastases, but "the need for additional therapies in hormone-refractory prostate cancer is considerable," he said.

Many agents are being studied for this indication in clinical trials, he added.

A particularly promising group is the oral platinum analogs as second-line chemotherapy, said Mark McKeage, M.D., Ph.D., of the University of Auckland in New Zealand.

After many years of development, it looks like new agents are going to emerge, he said. "This is an exciting time for oral platinum analogues."

The leading candidate is satraplatin, Dr. McKeage said. It works by binding to and distorting the structure of DNA to arrest the cell cycle, he said.

Because satraplatin does not use active transport mechanisms, it can overcome tumor resistance to other platinum analogues that use active transport mechanisms, he said.

In vitro and in vivo experiments indicate that it may have at least additive antitumor activity in taxane-resistant tumors and may enhance radiation effects as well, he said.

In a phase III study, satraplatin showed a significant benefit in PSA progression and progression free survival though the trial was stopped early when Bristol-Myer Squibb stopped developing the drug, Dr. Sternberg said.

The companies that took over development of satraplatin, GPC Biotech and Pharmion, started the phase III registration Satraplatin and Prednisone Against Refractory Cancer (SPARC) trial, Dr. Sternberg said.

The trial showed a 33% increase in progression-free survival for progressive, metastatic hormone-refractory prostate cancer even among patients with prior docetaxel treatment, she said. Time to pain progression was improved 36% too, she said.

"Satraplatin offers significant clinical benefit in these patients," Dr. Sternberg said. "We have a new oral second-line option for these patients."

Picoplatin is another platinum analogue in development, though it primarily for intravenous administration, Dr. McKeage said.

Another strategy is epigenetic modulation, most frequently targeting DNA or histone methylation as a reversible change that affects prostate cancer development and growth, said Howard Scher, M.D., of the Memorial Sloan-Kettering Cancer Center and Cornel Weill Medical College in New York.

An example is vorinostat (Zolinza), a histone deacetylase inhibitor approved for the treatment of cutaneous T-cell lymphoma.

It illustrates the difficulty of clinical trials of epigenetic modulation, he said.

In preclinical trials, the drug appeared to inhibit tumor growth without detectable toxicity. But when it reached clinical trials, rapid prostate-specific antigen elevations were seen among men taking low doses while cellular differentiation was seen at higher doses, he said.

Moving these drugs from clinical trials to clinical practice may require a change in the approach to trial design, Dr. Scher said.

"Focus less on when a treatment is working and more to when it has failed?insuring that treatment is given a chance to work," he suggested.

Yet another strategy with promising agents is molecular targeting, said David Quinn, M.D., Ph.D., of the University of Southern California in Los Angeles.

Sorafenib is one drug that has shown promise as a cell-differentiating agent in late stage prostate cancer by affecting downstream molecular signals of vascular endothelial growth factor (VEGF) and Raf-kinase, he noted.

Again, though, trial design has been a challenge.

In androgen-independent prostate cancer patients, a phase II trial of sorafenib (Nexavar), which is approved for treatment of advanced renal cell carcinoma, showed interesting results on bone scans but was halted for lack of benefit by prostate-specific antigen effects.

"Other markers of response need to be tested," Dr. Quinn said.

Other molecular targeted agents being studied include sunitinib (Sutent) and thalidomide (Thalomid), he added.