The Prostate Cancer Foundation recently released a manuscript titled "Report to the Nation on Prostate Cancer 2004," which detailed, in nearly 100 pages, the disease's effect on the United States.

Among its findings is that prostate cancer surfaces once in every six American men. That's alarming in itself, but consider that a man is 33 percent more likely to get prostate cancer than a woman is breast cancer, and the disease appears even more threatening.

Prostate cancer is particularly complex - it has varying degrees of aggression, different stages of progression and many treatment options. There isn't a consensus on how to tackle it, which can be problematic.

But there are guidelines.

For localized prostate cancer, a man has several options. If he's older and the cancer isn't aggressive, he can do nothing, which is called "watchful waiting." For younger men and others, surgery and radiation are options.

If the prostate cancer is advanced, or if the cancer returns after surgery or radiation, many physicians begin hormonal therapy, which is designed to turn off the production of male hormones, called androgens, that cancer cells thrive on. Hormone treatment sometimes is sandwiched around radiation.

Hormone therapy can lower prostate specific antigen (PSA) levels until they are undetectable, but in general the effects are temporary - most men stop seeing a benefit after 18 to 24 months. From there, patients might turn to chemotherapy.

In fact, the FDA recently approved a new chemotherapy regimen for prostate cancer, giving hope to hormone-refractory (also called androgen-independent) prostate cancer patients. For those, chemotherapy "is the biggest advance," said Michael Carducci, associate professor of oncology and urology at Johns Hopkins University School of Medicine in Baltimore. "We thought chemo did not work, but now we have chemotherapy that shows a survival benefit." While chemotherapy "will not be the be-all and end-all," he said, it's another piece of ammunition against a multi-faceted foe.

More data: Prostate cancer is the most common non-skin cancer in the U.S. and it attacks about 230,000 new men annually, the report said. It kills 30,000 men per year. The total annual cases are expected to grow to 300,000 as the baby boomer generation ages. There certainly is a need for more and better therapies, and that's where biotechnology comes in.

Help Might Be On The Way

The report mentioned Gleevec (imatinib), from Novartis AG, and Iressa (gefitinib), from AstraZeneca plc, and commented that "the clinical experience" for those two drugs in androgen-independent prostate cancer "has been disappointing." Hope remains, though, and trials continue.

There also are several classes of drugs pushing products to the top of the development chain: proteasome inhibitors, endothelin-1 and angiogenesis inhibitors, and vaccines and antibodies.

The report mentioned Millennium Pharmaceuticals Inc.'s Velcade (bortezomib), which was approved in 2003 for refractory multiple myeloma. A recent Phase I/II trial of bortezomib and docetaxel in 32 patients showed that of the 25 evaluable patients, six of them had a PSA decline of more than 50 percent and three of 13 with measurable disease showed a partial response. Carducci, who was an author on the emerging therapies chapter in the report, said, "Some of the data have been mixed, so the jury is still out on whether [proteasome inhibitors] will have a role in prostate cancer."

For endothelin-1 inhibitors, the star is atrasentan. Made by Abbott Laboratories and now named Xinlay, the drug has promise. A meta-analysis from two large trials totaling 1,097 patients comparing atrasentan vs. placebo in androgen-independent prostate cancer (AIPC) showed that atrasentan had a median time-to-disease progression of 115 days, as opposed to 86 days for placebo. Patients taking the drug reported bone pain 45 percent of the time, while patients receiving placebo did so 54 percent of the time. And the median time to bone pain was 224 days for those on atrasentan and 127 days for those on placebo, the report said.

"It's an exciting agent for men and it might delay using chemotherapy or radiation," Carducci told BioWorld Financial Watch. "That's a new drug that will really be evaluated by the FDA to see whether or not the data are approvable. It certainly meets an unmet medical need."

Abbott in July said it planned to submit a new drug application for Xinlay by the end of the year in metastatic, hormone-refractory prostate cancer. The drug has fast-track designation.

Moving to angiogenesis inhibitors, Carducci said data show "these agents should have a role in prostate cancer," adding that those in his field believe they "should be successfully incorporated [into treatment]."

A step in that direction was taken in February, when the FDA approved the first anti-angiogenic drug, Genentech Inc.'s Avastin (bevacizumab). While that approval was for metastatic colorectal cancer, the report said a "randomized, double-blinded, placebo-controlled Phase III trial comparing docetaxel and prednisone with and without bevacizumab in patients with AIPC is scheduled to begin this year," so more should be known soon.

The report mentioned several monoclonal antibodies in clinical trials, including MDX-070 and MDX-010, both of which have Phase II data in prostate cancer, both from Medarex Inc. It also mentioned MLN2704, from Millennium, also in Phase II work.

Of the vaccines, there is GVAX, from Cell Genesys Inc. GVAX is a whole-cell vaccine designed to stimulate an immune response against a patient's tumor. It's made of genetically modified tumor cells that secrete granulocyte macrophage colony-stimulating factor, which is thought to play a role in triggering the immune response. Cell Genesys agreed with the FDA on a special protocol assessment (SPA) for an upcoming Phase III trial in hormone-refractory prostate cancer patients, and the vaccine performed well in Phase II.

Carducci said the vaccine does "stimulate an immune response. It [demonstrated] in the Phase II survival rates of 21 to 23 months, some patients for longer."

GVAX also is being tested in Phase I/II and Phase II trials for lung cancer, pancreatic cancer, leukemia and myeloma.

Perhaps the most notable potential product is Dendreon Inc.'s Provenge, an autologous CD54-positive dendritic cell vaccine loaded with a recombinant fusion protein made of a prostatic acid phosphatases and granulocyte macrophage colony-stimulating factor.

The vaccine, like many biotech drugs, has an oscillating history. Early in 2002, the company admitted that an interim analysis suggested the trial (called D9901) would not hit its primary endpoint of time-to-disease progression in hormone-resistant prostate cancer patients. That news dropped the company's stock by nearly 38 percent the day it was released, leaving the shares at $5, down $3.05.

In the spring, the FDA told the company to halt enrollment in its second Phase III trial, D9902, although it did not ask for safety or trial-design issues. Dendreon reported in August 2002 that D9901 did not hit its primary endpoint, as warned, but a subgroup analysis of men with a prostate cancer Gleason score of 7 or less showed the drug provided benefit. A Gleason score is a measure of the tumor's aggressiveness.

The FDA lifted its enrollment halt for D9902 in October 2002, and in December of that year, the company said it was amending the trial to focus on men with a Gleason score of 7 or less. It increased enrollment and the trial has not yet completed.

But there's a buzz around Provenge, and Dendreon now is trading above where it was before the missed endpoint and Gleason score subgroup discovery. It stock (NASDAQ:DNDN) closed Friday at $8.68, up 27 cents.

Provenge: Winding Road Could Lead To 2006 Approval

"I like the drug," said Quynh Pham, biotech analyst with Delafield Hambrecht. "I think it has shown the largest benefit on survival in the hormone-refractory prostate cancer population."

Nothing's ever a slam-dunk in biotechnology, but if results follow the D9901 subgroup analysis, Dendreon should have a marketed product, she said.

"They have an SPA designation with the FDA, so if they hit their goals, it most likely will be a straight course to approval," Pham told BioWorld Financial Watch.

A potential glitch might be Taxotere (docetaxel), made by Aventis SA. It is being used in prostate cancer now, and Dendreon does not have an arm that tests Provenge with Taxotere, nor is it compared against it.

With Taxotere in the mix, "some say the bar has changed," Pham said, but added, "That's speculation, though. I don't necessarily believe it is a hard-and-fast rule yet."

Pham, who does not own the stock, although her firm has a banking relationship with Dendreon, has modeled a maximum of $800 million in sales for Provenge three years out from approval. But that considers only hormone-refractory men with the Gleason score of 7 or less - the vaccine might work "better in patients that are less disease burdened," she said.

The report noted that if the results of the D9902 trial are positive, Provenge "might be clinically available by 2006." That's good news for those afflicted, a group that, like cancer patients in general, still die of the disease, but are living longer before doing so. There's no cure, but slowing the disease provides optimism to caregivers and biotech companies alike, especially against a cancer that at times can seem to be standing still. There's hope that the disease might be pushed back indefinitely.

"I think we've seen some of those advances," Carducci said, adding that for those who get recurrence of prostate cancer after surgery, the median survival from the Johns Hopkins dataset now is "in the range of 14 to 15 years."

"A 50-year-old man living 25 years with the disease is doable," he said. "Clearly, I think we'll see that."

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