Mike Toner

Although hormone therapy is the mainstay for treating metastatic prostate cancer, it can only slow the progress of the cancer for so long, a reality that heightens the importance of any new way of manipulating testosterone or its activity. That’s why preliminary results of two new targeted therapies, now in late-stage clinical trials, hold so much promise for men with hormone-refractory, or castration-resistant, prostate cancer.

Abiraterone is an orally administered compound that acts on the “supply side” of the testosterone cycle—inhibiting a key enzyme involved in the final steps of testosterone production. It helps, at least temporarily, to “starve” the prostate cancer cells by blocking the production of testosterone, which they depend on to grow.  

Abiraterone does this by blocking testosterone production, not only in the testes, but also in the adrenal glands, which produce about 5 percent of the hormone.

In phase 2 trials of men whose cancer had spread, abiraterone significantly shrank the tumors and enabled two-thirds of the men to live pain-free for an average of eight months. Phase 3 trials at more than 150 hospitals worldwide are now looking at the effects of the compound in 1,300 men, one of the largest trials ever for advanced prostate cancer. 

Another new targeted therapy, MDV-3100, attacks prostate tumor cells themselves, disrupting the pathway for the uptake of testos- terone. The oral drug not only prevents the hormone from binding to the cell’s androgen receptor, but also helps induce the cellular self-destruction of the tumor cell, a process called apoptosis. In phase 2 trials, the compound stabilized or shrank tumors in 22 to 56 percent of the patients and substantially lowered PSA levels for up to 41 weeks in more than half of all patients. Phase 3 trials are under way in the United States and 14 other countries. 

“In the past, we didn’t have many options once prostate cancer became resistant to hormonal treatments,” says Winston Tan, MD, senior consultant for the Mayo Clinic Florida. “These new drugs—and others that are still in clinical trials&mdash;are going to change the landscape for the treatment of men with metastatic, castrate-resistant prostate cancer.” 

More information on recent results of clinical trials and enrollment in ongoing trials is available at 

Articles

Preliminary results of two new targeted therapies, now in late-stage clinical trials, hold much promise for men with hormone-refractory, or castration-resistant, prostate cancer.

New Options in Androgen Therapy

 Cholesterol-lowering statins, which reduce systemic inflammation, may also play a role in slowing the progression of prostate cancer. A Duke University Medical Center study of 236 men has found that men who took statins prior to prostate surgery had a 69 percent lower risk of intra-tumor inflammation, which is thought to contribute to the recurrence of cancer after surgery. Researchers say more studies are needed before recommending statins to slow post-surgical prostate cancer progression, but they say it is possible that widespread use of statins—by 11 million to 30 million people, according to some estimates&mdash;may account, in part, for the recent decline in the rate of deaths from prostate cancer. 

 Phase 3 clinical trials of a new “antisense” compound designed to wreak genetic havoc on cancer cell defenses are under way this year at 50 cancer centers worldwide. The developer, OncoGenex Pharmaceuticals, says phase 2 trials show that custirsen (OGX-011) inhibits the production of a protein that helps cancer cells develop resistance to chemotherapy. Used in combination with Taxotere (docetaxel), which is the current first-line treatment for hormone-refractory prostate cancer, custirsen reportedly increased patient survival from 16.9 months to 23.8 months. A total of 300 men are being recruited for trial. 

 An injectable treatment to reduce bone loss and injury in patients with solid tumors, including prostate cancer, that have spread to the bone was approved by the U.S. Food and Drug Administration in November. Although initially approved to reduce the risk of fractures from osteoporosis in women, the FDA agreed that Xgeva (denosumab), given at four-week intervals, decreased skeletal-related events when compared to Zometa (zolendronic acid). The FDA approved the drug in June for treatment of osteoporosis in postmenopausal women at high risk for fractures. 

A genetic test that could distinguish between aggressive prostate cancer in need of urgent treatment from less dangerous, slower growing tumors may be a little closer. Researchers at Harvard University Brigham and Women’s Hospital have identified the genetic pathway by which a single enzyme becomes a key driver in the cascade of events called metastasis, by which cancer spreads from the prostate to other parts of the body. The new research has encouraged work at several laboratories on ways to inhibit the gene that regulates production of the enzyme EZH2.

New developments in the treatment and management of prostate cancer.

And What Else Is New

The news that he had prostate cancer hit Don Schnurbusch  with the same force it will strike an estimated 217,000 Americans this year. “It was a jolt, a real jolt,” the 69-year-old former community college teacher recalls. “I didn’t feel like a guy who had cancer. But I did. It was very scary stuff. And then I had to decide what to do.”

Once the shock wore off, Schnurbusch faced one of the most difficult choices of his life. Should he take a wait-and-see approach? Should he have surgery? Radiation?  What about the side effects? And most importantly, would whatever he chose rid his body of the cancer? Like many American men confronted with that choice, Schnurbusch elected to have a radical prostatectomy—the surgical removal of the walnut-sized prostate gland and its surrounding tissue. He was fully aware that because the prostate lies so close to other parts of the male plumbing system&mdash;bladder, rectum, seminal vesicles and nerves&mdash;any intervention might have complications, including incontinence, rectal injury and erectile dysfunction.  

“I told them I wanted to do everything necessary to effect a cure, even if they had to take the nerves,” he says. “I was a lot more interested in staying alive than being able to have an erection.” 

In April, the Food and Drug Administration approved Provenge (sipuleucel-T), the first of an entirely new class of drugs that stimulate a patient’s own immune system to fight cancer. Provenge, an immunotherapy, is already being used to treat men with advanced prostate cancer at 50 U.S. medical centers, and doctors report that the lines of waiting patients are growing. The manufacturer plans to increase production of the drug dramatically in 2011. 

Then in June, the FDA—acting with near record speed even for a drug on the agency’s fast-track approval schedule&mdash;approved Jevtana (cabazitaxel), the first new chemotherapeutic drug for metastatic prostate cancer to come to market since 2004. Approval took less than three months. Jevtana belongs to a powerful and widely used class of cytotoxic drugs called taxanes and gives doctors a new chemotherapy agent for times when cancer cells become resistant to the first-line hormone treatment. 

The reality of prostate cancer is that there are only two ways to cure it—surgery or radiation. To be successful, both must be performed early enough in the course of the disease that cancer cells have not yet escaped from the capsule of the prostate into surrounding tissue or distant sites. But even patients who have no clinical or biochemical evidence of cancer after primary treatment can have relapses. In general, the higher a patient’s Gleason score was at the time of diagnosis, the more likely it is that the cancer will spread. A score of 7 or higher (on a scale of 2 to 10) is a sign that some cancer cells have begun to invade surrounding tissue. 

In most men, a PSA level of less than 4 nanograms per milliliter of blood is not usually considered a cause for concern. After surgery or radiation, however, regular PSA tests, often at six-month intervals, are watched closely for any abrupt or sequential increases in PSA. Although a PSA of zero is the benchmark of a surgical “cure,” treatment with radiation is generally considered successful if the PSA declined to less than 1 ng/ml, reached a nadir and then leveled off. In either case, an abrupt, sequential increase in PSA from any level usually provides the first hint that the primary therapy has failed and the cancer has recurred and possibly metastasized. 

“Once disease has progressed after radiation and surgery, we can no longer talk about a cure,” says Oliver Sartor, MD, medical director of the Tulane Cancer Center in New Orleans. “But prostate cancer progresses very slowly, and hormone therapy can provide prolonged remission, which means that many of these men will die from something other than prostate cancer.”

This has been an extraordinary year and an unprecedented time of hope for men with prostate cancer. We haven’t had any new drugs for the treatment of advanced prostate cancer for over six years, but we are finally beginning to see the fruits of research that was begun years ago.

Researchers still aren’t sure why some prostate cancers, such as Elalouf’s are more aggressive than others. But they do know that, because testosterone fuels the growth of all prostate cancer cells, it is possible to slow cancer’s progress by disrupting the supply or the action of the male hormone. A leutenizing hormone-releasing hormone (LHRH) analogue,  like Lupron (leuprolide) or Zoladex (goserelin) suppresses testicular production of testosterone. This “chemical castration” can reduce testosterone production by 95 percent. But some men, like Schnurbusch, find the hot flashes, rashes and other side effects of such drugs so onerous that they opt for surgical castration. Other drugs, called anti-androgens, which include Eulexin (flutamide), Casodex (bicalutamide) and Nilandron (nilutamide), block the effects of testosterone on cancer cells. Sometimes the drugs are alternated; sometimes they are used in combinations. In the end, however, cancer lodged in the lymph nodes or distant bone tissue adapts to the chemical assault. It then progresses. 

“Surgical or hormonal castration will work for a while, but all prostate cancer eventually becomes resistant to hormone manipulations, and then, the normal progress of treatment proceeds to chemotherapy,” says Thomas Hutson, DO, PharmD, director of genitourinary oncology at Baylor University’s Charles Sammons Cancer Center in Dallas. 

That was the reality Schnurbusch was facing this year until Hutson informed him that FDA approval of Provenge was opening a brand new front in the war on advanced prostate cancer, and he had a chance to be Baylor’s first patient. Hutson explained to him that Provenge itself would not kill cancer cells, but it would stimulate his own immune system to attack them. There would be three treatments at two-week intervals.

“I would show up at a local blood center around 8:30 a.m. and be out by noon,” Schnurbusch recalls. There, using a process called leukapheresis, blood was withdrawn from one arm, the white blood cells separated and the whole blood returned through the other arm. He says the process, while sometimes boring, wasn’t painful. “They had a courier standing by to pick up the white cells as soon as they were collected.” While Schnurbusch drove home, his infection-fighting white blood cells were on the way to a lab in New Jersey, where they were exposed to a prostate cancer protein, in effect “training” them for combat. A few days later, back at Baylor, the cells were re-infused into Schnurbusch’s bloodstream. Other than a brief bout of night chills and sweats after the second treatment, he had no unpleasant side effects. “I feel great,” he says three months later. “And I really like the idea of having my own immune system fighting this stuff.”

I think virtually everyone who has advanced prostate cancer should be considered for Provenge … Prostate cancer does not progress rapidly in most men, so anything we can do to slow it down will be helpful.

By mid-2011, the manufacturers of Provenge are hoping to have treated 2,000 patients. But those numbers could grow swiftly. The company is expanding the New Jersey laboratory where white blood cells are processed and is building two new labs, one in Georgia and one in California, to handle the expected demand. Under the current FDA label, Provenge is limited to use in “asymptomatic or minimally symptomatic” patients in whom hormone therapy has failed. But researchers say the benefits may be even greater for men with less advanced disease.

“I think virtually everyone who has advanced prostate cancer should be considered for Provenge,” says Hutson. “Prostate cancer does not progress rapidly in most men, so anything we can do to slow it down will be helpful.”

Clinical trials in progress, in fact, are looking at the potential for even wider use of Provenge in men diagnosed with prostate cancer who receive the treatment before surgery, in effect turning the body’s defenses on the cancer while it is still confined to the prostate gland.

Wider use, however, could encounter an obstacle in the national effort to contain medical care costs. Treating a single patient with Provenge costs $93,000. Because it is an FDA-approved therapy, that cost is covered by most major private insurers, but approval is still on a patient-by-patient basis. Fourteen of the country’s 15 regional Medicare contractors also cover Provenge, and in November the Centers for Medicare and Medicaid Services (CMS) advisory panel recommended the agency consider a nationwide coverage policy for Provenge. If CMS implements such a policy, the decision would apply to regional centers as well. Because the average age of men with advanced prostate cancer is 66 and they are Medicare-eligible, the impact could be far-reaching.

From a statistical point of view, documented benefits of the treatments might appear modest. The study of 601 patients that led to FDA approval of the treatment found that, compared to patients on placebo, Provenge extended median survival from 21.7 months to 25.8 months, or about four months. But Hutson and other doctors say this means that half of all the patients lived longer. In fact, he says, one-third lived at least three years.

Schnurbusch uses a different kind of calculus: “Four more months of life?” he asks. “I fully intend to live longer than the median,” he says. “But if that’s all I get, it will be four more months in which I get to hold my newest granddaughter. Four more months that I can enjoy my three sons, my daughter and my other grandchildren. Four more months of everything I enjoy—gardening, hunting and fishing on my favorite lake. And four more months to watch the Dallas Cowboys, sing in the church choir and work on projects around the house that I have put off for years.

“Body scans show that I have cancer in my right pelvic bone, my left hip and in my second lumbar vertebrae,” he says. “Not a day goes by that I don’t think about it. But if I die tomorrow, I will still feel I’ve had a good life. Four months? That is a lifetime.”

Six years later, Schnurbusch is alive and outwardly healthy. He mows his own lawn. He gardens, fishes, hunts and still finds time for volunteer work at a Habitat for Humanity store in his hometown of McKinney, Texas. But he still has prostate cancer, too—just like the rest of the estimated 2.3 million men living with one of the most commonly diagnosed cancers in American men. For all of them, and especially for the 60,000 to 70,000 men a year who develop metastatic, hormone-resistant prostate cancer such as Schnurbusch, a recent flurry of medical milestones provide new reasons for hope.

Deaths from prostate cancer have, in fact, declined by more than 4 percent in the last five-year period studied by the National Cancer Institute. Even so, 27,000 men in the United States are likely to die of the disease this year. Sartor estimates that Jevtana alone could benefit as many as 20,000 of them. “It gives us a new treatment for patients with the most advanced stage of prostate cancer, for whom there have been few options.”

Jevtana is a semi-synthetic derivative of a natural substance found in the Pacific yew tree. Administered intravenously, it disrupts the microtubule formation required for cancer cells to reproduce. 

At the Winship Cancer Institute of Emory University in Atlanta, 56-year-old René Elalouf, only months after having two cancerous tumors removed from his spine, was one of the first patients to get Jevtana, a choice doctors made after he developed resistance to first-line chemotherapy and his PSA level soared to more than 1,500 ng/ml. 

“He’ll be getting Provenge soon, too,” says Omer Kucuk, MD, chief of genitourinary medical oncology at the institute. “Even though he had metastatic disease, he was in very good shape, so we do whatever we can to keep the disease under control.”

As a former seal in the Israeli Navy, Elalouf, who lives in Acworth, Georgia, says the new drugs have not only buoyed his spirits but also made him feel better physically. “I’m using crutches this week, but I’ll be able to get by with a cane next week,” he says. “And I’ve told Dr. Kucuk that when I get better, I’m going to take him on a trip to the Red Sea to go scuba diving.”

In addition, two other new drugs currently in the final stages of clinical testing—abiraterone and MDV-3100&mdash;could soon be ready for review by the FDA, perhaps as early as 2011. Both drugs have demonstrated success in reducing the amount and activity of testosterone, the male hormone that fuels the growth of prostate cancer. 

“This has been an extraordinary year and an unprecedented time of hope for men with prostate cancer,” says Howard Soule, PhD, chief scientific officer for the Prostate Cancer Foundation. “We haven’t had any new drugs for the treatment of advanced prostate cancer for over six years, but we are finally beginning to see the fruits of research that was begun years ago.”

New options for advanced prostate cancer mean prolonged remission.

Mike Toner

New Options in Androgen Therapy

And What Else Is New

Promise for Prostate

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