New drugs and new combinations challenge advanced disease.

By Alice McCarthy

"These days, having advanced prostate cancer does not mean a death sentence,” says 67-year-old Carl Visoky of Staten Island, New York, who was diagnosed with advanced prostate cancer more than 14 years ago and is continuing to live an active life. Each year, 230,000 men in the United States receive a diagnosis of prostate cancer and 30,000 men die from the disease. But since 1992, the death rate has fallen about 3.6 percent every year. Possible reasons for the drop include detection of earlier-stage cancers thanks to widespread use of the prostate-specific antigen (PSA) blood test plus treatment with hormone therapies for both early and advanced prostate cancers.

Almost all patients with prostate cancer will respond to hormonal therapy initially,” says Oliver Sartor, MD, director of the Stanley Scott Cancer Center and chief of the Hematology/Oncology Section at Louisiana State University Health Sciences Center. “However, the duration of the response is highly variable between patients.”

“When I was diagnosed, the doctors told me to go home—that there was nothing they could do because the cancer had already spread,” says Visoky, a father of three. “But doing nothing was not an option for me and obviously that is not the truth for everybody.” After surgery to remove his prostate, Visoky’s cancer was successfully treated with hormones for eight years. “It kept my PSA levels pretty steady and kept me going like normal for a long time.”

Hormone therapies used for prostate cancer aim to reduce testosterone levels either by preventing its production or by blocking its action. Testosterone increases prostate cell growth, including prostate cancer cells if present.

Male hormones, including testosterone, can stimulate the growth of prostate cancer cells. Most testosterone in the body is produced by the testicles. Orchiectomy, or removal of one or both testicles, is an effective and permanent way to reduce testosterone synthesis in men with prostate cancer. But, many men are not willing to have their testicles removed, and thus, a number of drugs have been developed to reduce testosterone secretion. These include drugs known as luteinizing hormone-releasing hormone (LHRH) agonists that reduce the secretion of luteinizing hormone by the pituitary gland. Luteinizing hormone is required by the testicles to produce testosterone, and lack of luteinizing hormone markedly reduces testosterone production. (See illustration to see how testosterone stimulates the growth of prostate cancer and how the drugs work to combat this growth.)

Medications in this group include Lupron®, Eligard® and Viadur® (leuprolide) as well as Zoladex® (goserelin). Initial therapy with these drugs causes testosterone levels to rise, but within two to four weeks, testosterone levels fall to levels equal to or lesser than those seen with testicle removal. Lupron, Zoladex and Eligard are available as long-acting injections given only once every three to four months. Viadur is implanted under the skin and suppresses testosterone for a full year.

Antiandrogen drugs are sometimes given in combination with LHRH agonists to prevent any residual testosterone from binding to its receptors on prostate cells. Eulexin® (flutamide), Casodex® (bicalutamide) and Nilandron® (nilutamide) are three examples. Combining LHRH agonists with antiandrogens is called “total androgen blockade.”

More recently, the FDA approved a new type of hormonal treatment for prostate cancer called Plenaxis™ (abarelix), which binds directly to the luteinizing hormone receptor on testicular cells to block its activity, causing an immediate suppression of testosterone level without a “testosterone surge” seen with Lupron, Zoladex and Eligard. Some patients may have an allergic reaction to Plenaxis, so extra caution is needed during its administration.

Taxotere: The New Standard of Care

Once hormone therapy stops working, the disease is then referred to as hormone-refractory prostate cancer (HRPC). Until very recently, the next treatment step for men with HRPC was limited to drug therapy with Novantrone® (mitoxantrone) and prednisone, a steroid. But two recent phase III studies involving almost 1,800 patient volunteers prove the drug Taxotere® (docetaxel) is the new standard of care for men with advanced HRPC. (Advanced prostate cancer is defined as cancer that has spread beyond the prostate into the lymph nodes or distant sites such as the bones, liver or lungs.)

The studies showed that Taxotere-based treatment reduces the risk of death from metastatic HRPC by 20 to 24 percent when compared to mitoxantrone/prednisone. The Food and Drug Administration (FDA) approved Taxotere in combination with prednisone for use in men with metastatic HRPC in May 2004. “We now have a new foundation to treat men with advanced prostate cancer,” says Daniel Petrylak, MD, director of the Genitourinary Oncology Program at New York-Presbyterian Hospital and a lead investigator for one of the new studies.

The trials compared Taxotere (both with and without another chemotherapy drug, estramustine) with mitoxantrone/prednisone. In both studies, men receiving Taxotere-based therapy lived longer—on average, about three months longer when compared to those receiving mitoxantrone/prednisone.

Three years ago, Visoky’s PSA levels started climbing into the 50s and 60s. “But after two years in the Taxotere trial, my PSA leveled off in the 30s,” he says. “It is important not to concentrate too much on the PSA number itself. The idea is to see leveling off.” While on Taxotere, Visoky experienced weakness and fatigue. “It slowed me down a little, but I stuck with it and did what I loved,” he says, which included a trip to Africa.

Ignacio Asperas, another advanced prostate cancer survivor, was diagnosed 13 years ago. “After my cancer diagnosis, I was treated with Zoladex for nine or 10 years,” says the 70-year-old.

After nearly 10 years of hormone therapy, Asperas’ PSA began climbing quickly into the high 50s. “That is when I decided to do the Taxotere trial,” he says. His PSA levels have mostly leveled off to around 14. “I don’t expect it will fall much lower, but mentally, bringing down the PSA makes me feel much better.”

The side effects—hair loss, fatigue and upset stomach—were annoying but not overwhelming, he says. “I have a vacation home in Vermont and my children live in Europe and I’m able to travel as much as I want. There is nothing I want to do that I can’t.”

Taxotere also lowers the number of circulating white blood cells, which can increase the susceptibility to infections. Other side effects of Taxotere include swelling (edema), nerve damage and nail changes.

Dr. Petrylak says, “These are the first trials to show a survival benefit over standard treatments for men with HRPC. The only remaining question is whether you need the estramustine, and this we do not know yet.”

Drugs on the Horizon

“The question now is what can we do when Taxotere fails?” says Dr. Sartor. One possibility is satraplatin, a type of oral platinum-based chemotherapy. A small earlier European study showed that, compared with prednisone alone, satraplatin slowed the time to disease progression and provided a hint of a survival benefit.

“Satraplatin may offer an alternative for men with HRPC who otherwise have sparse chemotherapy alternatives,” says Dr. Sartor, who is heading the phase III SPARC (SatraPlatin Against Refractory Cancer) trial, a study designed specifically for men whose cancer progresses despite Taxotere treatment.

Another option, Xinlay™ (atrasentan), is a selective endothelin-A receptor antagonist that gets to the endothelin receptor on the cancer cell before endothelin does, explains Michael Carducci, MD, associate professor of oncology and urology and co-director of the Drug Development Program in the Division of Medical Oncology at Johns Hopkins Medical Institutions. “So it blocks the activation of the receptor. By blocking the receptor, the cell stops growing and is more likely to die.”

The idea behind Xinlay is to delay cancer progression, particularly in the bony metastatic sites common to men with advanced prostate cancer. “The trials to date suggest that Xinlay likely alters the bone-tumor interface, making it a more difficult environment for prostate cancer cells to grow or thrive,” says Dr. Carducci, who studied Xinlay in an 809-patient phase III study in men with metastastic HRPC. “With Xinlay there is a delay in time to progression,” he says.

In addition, Xinlay treatment leads to no rise in bone alkaline phosphatase (BAP), a sign of bone infiltration and destruction. “If you have metastasis, it will delay the time before you have pain, symptoms, new lesions,” Dr. Carducci says. “If you have not started on chemotherapy, it may delay its start.”

William Walston from Spencerville, Maryland, was part of that recent phase III Xinlay trial. “I didn’t go in thinking this drug would get rid of the metastatic progression altogether,” says the 67-year-old. Though his PSA levels have not dropped as hoped, he still finds value in the clinical trial experience. “I would do another trial with another new medication,” he says. “Most of the things going on for recurrent prostate cancer—almost all of them I think—are to slow the progress of disease. My expectations are to eventually find something to slow the rate of PSA increase.”

Dr. Carducci explains that since Xinlay makes bone a harsher environment, it may shift the thinking that prostate cancer goes primarily to bone. “If it receives FDA approval, I would suggest using atrasentan in men with bone metastases,” he says. Because Xinlay is a pill with few side effects—Walston complains only of slight nasal congestion—researchers are designing new studies combining it with other drugs, including Taxotere.

The makers of Xinlay plan to submit the drug for FDA approval by early 2005.

Targeting the Cancer

MLN2704 specifically targets prostate cancer cells. “The drug comprises a chemotherapy linked with an antibody that targets a protein on the surface of prostate cancer cells called prostate-specific membrane antigen (PSMA),” says David Schenkein, MD, vice president of oncology clinical development at Millennium Pharmaceuticals, Inc.

PSMA is not found on normal prostate cells or other tissues but is produced in large amounts by prostate cancer cells and in greater amounts as the cancer metastasizes. Once the antibody portion of the drug binds to PSMA, the drug is engulfed by the cell. “Trojan-horse style, once inside the cancer cell, it delivers its payload of chemotherapy,” explains Dr. Schenkein.

In the first human study with the drug, researchers found MLN2704 was well-tolerated with no severe toxicities. “We also saw some patients who stabilized or reduced PSA levels, and two patients had some fairly major responses,” says Dr. Schenkein. A larger study of the drug’s safety and efficacy is currently enrolling patients.

Stimulating Immunity

“Patients like the idea of stimulating their own immune systems to attack their cancer,” says Dr. Carducci. Provenge®, now in phase III study in men with metastatic HRPC, is a vaccine targeted to attack prostatic acid phosphatase, a protein found on 95 percent of prostate cancer cells.

Another vaccine, GVAX® prostate cancer vaccine, enters phase III studies in late 2004 to compare its efficacy with Taxotere. GVAX comprises prostate cancer cells that secrete granulocyte-macrophage colony stimulating factor (GM-CSF), a hormone that plays a key role in stimulating the body’s immune response to vaccines. In one study, six of 19 men had PSA levels drop after repeated vaccinations. “There have not been tremendous responses to the vaccine like we see with Taxotere, but the benefits to activating the immune system and slowing the disease down may still be important,” says Dr. Carducci.

Asperas, Visoky and Walston share a common realistic and optimistic attitude. “I don’t think Taxotere or any drug now is a permanent thing but mostly a delaying tactic for men like me,” says Asperas. “So I am already thinking about the next step and the next trial.” Visoky’s advice: “I am proof that you can live a normal life for many years with advanced prostate cancer. Get the best doctor you can, do not be afraid to try new therapies and just live your life.”