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Laying the Foundation For a Cure

As drug treatments for prostate cancer dominate the news at ASCO, we look back at how abiraterone (Zytiga) made its way onto the A list.

June 2, 2012 -- This week, researchers announced some fairly stunning news: a group of men whose prostate cancer ran a high risk of spreading to other sites in the body and becoming lethal may have cheated death by the simple addition of one FDA-approved drug to their treatment regimen. In fact, in some cases, the prostate tumor that was present before the drug was administered disappeared completely. And while nearly everyone involved in the study says the results need to be confirmed in a larger group of men in gold-standard clinical trials, they also say the results to date point to an upcoming game change in how some men with prostate cancer are treated; indeed, the study’s lead author, Dr. Mary-Ellen Taplin of the Dana-Farber Cancer Institute, titled the abstract to the study, which she presented at the American Society of Clinical Oncology’s (ASCO) annual meeting in Chicago, “New Paradigms for Hormone Therapy for Prostate Cancer.” That’s fancy speak for: it’s a whole new deal now.

One drug added. So simple. But then again, not. Games aren’t changed, paradigms aren’t shifted and men’s lives aren’t saved without the mind-breaking pre-clinical work that costs millions of dollars and a seriously strong appetite for risk. And even now, with these tantalizing results and men waiting with potentially cured prostate cancer, the funding for the gold-standard studies that are needed to convince the government (Medicaid/Medicare) or private insurance companies to pony up and pay to add this very expensive drug to treatment regimens is in jeopardy: the company who owns the patent to the drug will lose that patent long before any long-term gold standard study can be completed.

The drug in question is Johnson & Johnson’s Zytiga (generic abiraterone) but before they took ownership of the drug it was considered a sort of unremarkable stepchild drug, just another system-wide testosterone-inhibitor used against prostate cancer that had little chance of outshining its other brothers and sisters. It was discovered some 20 years ago, by researchers at the Institute of Cancer Research in England but it wasn’t until foundation funding, specifically the Prostate Cancer Foundation, was mounted, that the drugs unique properties became clear: it lowered testosterone levels inside a prostate tumor itself by preventing cancer cells from churning out the hormone, as opposed to simply lowering adrenal-gland produced testosterone circulating in the blood. And because testosterone fuels prostate cancer growth and because lowering blood levels of testosterone is not as effective against the disease as limiting it inside the tumor, abiraterone started to look more like Cinderella in her well-fitting slippers, to drug investigators. It’s doubtful, without that discovery made by Dr. Peter Nelson of the Fred Hutchinson Cancer Research Center and colleagues at the University of Washington along with other groups, that big pharma would have ever taken a shine to abiraterone. (Dr. Nelson was an author of the study presented at ASCO.)

Up until this study, abiraterone was used to treat men with metastatic prostate cancer who had failed to respond to other drugs that limit the androgens, or testosterone, that fuels tumor growth. (It was FDA-approved in April of 2011.) In that group of patients, while overall survival was increased, it didn’t effect cures and at best added years to patient’s life, at worst weeks.  In contrast, in the study presented by Dr. Taplin at this week’s ASCO, the drug was given to men whose prostate cancer had not yet spread, or metastasized, but was likely to do so. (Cancer that has not metastasized is referred to as localized cancer.)   And rather than being given the drug after surgery, they were given it before in what is known as neoadjuvant (prior to the primary treatment) therapy. Also added to their neoadjuvant drug therapy was Lupron, a standard-of-care drug for men with advanced, metastatic prostate cancer that slashes blood levels of testosterone by interrupting signals sent from the brain to the testicles.

Once the men completed their neoadjuvant drug therapy they underwent radical prostatectomy to surgically remove the gland.

Strikingly, at the time of surgery, the researchers found that in one-third of the men given neoadjuvant chemotherapy of abiraterone along with Lupron for six months, their tumors not only did not spread, they shrank to either undetectable levels, or to what researchers call “near pathological resolution,” which means a tumor size of less than 5 millimeters—both of which are deemed a cure.

“These results show that, as opposed to just extending life for two months, there are some men in this study who may have died of prostate cancer, who instead may have been cured because they got this treatment,” says Dr. Taplin.

She credits Johnson & Johnson with funding this study because it won’t do much to increase sales in the near term while still under patent protection, but is equally quick to note that “it was also a bargain for them because the Prostate Cancer Foundation paid for all the science” behind the drug’s early development. 

This is something that is often overlooked in the hoopla that surrounds a big announcement of a drug’s successful completion of a clinical trial; the long, arduous nurturing process that fronts a drug company’s decision to dance with a drug in the first place, let alone pursue it with a glass slipper in hand. Howard Soule, PhD, chief science officer at the Prostate Cancer Foundation (PCF), says donor money to the Foundation is what nurtured abiraterone from a seedling into an FDA-approved drug. It was money granted to teams of researchers by PCF that “nailed the mechanism of action,” said Soule, speaking of Nelson’s work at the University of Washington that determined abiraterone lowered inta-tumor levels of testosterone, which are now known to be so important in halting disease progression.

And measuring intra-tumor levels of testosterone was a main objective of the ASCO study. “Looking at tumor tissue samples taken after treatment, we have a beautiful demonstration of how much more abiraterone starved prostate tumor cells of testosterone and other androgens compared to Lupron alone,” says Taplin.

Mixing the perfect cocktail and predicting who will benefit

“This is the first study that uses androgen deprivation drug cocktail to treat hormone-sensitive prostate cancer,” says Dr. Philip Kantoff, also of the Dana-Farber Cancer Institute and the study’s senior author, “and it has given us a sub-set of men who could conceivably benefit from early institution of hormone therapy, who could conceivable be cured, who otherwise would not be.”

There are many next steps says Dr. Kantoff. The clinical one, of course is to bring this to a Phase III trial. But more basic science--the sort that drug companies are not inclined or really set up to do—will be needed to determine, pre-treatment, which men will be the third of high-risk prostate cancer patients that are super-responders to the neoadjuvant drug cocktail of Lupron and abiraterone.

Kantoff and Taplin plan to sequence the genomes of the 70 percent of the trial’s patients who did not respond. “This will give us a window into resistance mechanisms these men have to the extreme androgen deprivation drug cocktail therapy used in the trial,” says Kantoff.  But doing such molecular detective work as RNA profiling and exome sequencing to find genetic changes that may be the root cause of resistance to the drug cocktail is the tedious, painstaking work that Kantoff says often has its roots in foundation funding, and that he will likely need to tap the Prostate Cancer Foundation again to get his answers.

On the horizon

The potential for payoff is huge. Not only could 30 percent of high-risk prostate cancer patients be cured, the additional basic science research could uncover what is needed to convert the 70 percent of non-responders. And eventually, when predictions of those men who are extremely likely to be cured by extreme androgen deprivation therapy chemo cocktails become an exact science, those men may be able to forgo radical prostatectomy surgery. 

As they wait for funding for the large, Phase III trial of the Lupron and abiraterone drug cocktail to materialize, Taplin and Kantoff are moving ahead with other early phase trials. “We want to push this envelope forward, for instance, by adding  a third drug to the cocktail—one that, rather than blocking androgen from being made, blocks receptors to androgen,” says Kantoff, referring to MDV3100 that works by cancelling out the negative effects of any testosterone hanging around in a tumor.

That drug was also a pet project of foundation funding—it was discovered by Dr. Michael Jung after working with a PCF-funded physician at UCLA to understand how androgen deprivation therapy worked to halt prostate cancer progression.

Another PCF-funded researcher, Dr. Johann de Bono at The Royal Marsden in the U.K., who led some of the initial clinical studies of abiraterone, says he’s very encouraged by the results presented at ASCO on this drug. He’s a researcher on the STAMPEDE trial, which is a randomized Phase III study being conducted in the United Kingdom and Switzerland that is assessing if men with advanced prostate cancer fare better when given certain drugs earlier in the course of their disease. One group of men in that study will be given abiraterone, along with Lupron to suppress testosterone levels; the study is in its recruitment phase and is both publically and privately funded. Dr. de Bono expects that trial to show that giving abiraterone at the time men are diagnosed with either metastatic prostate cancer or cancer that has not yet spread to distant sites in the body but shows signs of aggressive disease will improve their chances of survival.  

And of course, says, Dr. Nelson, researchers will continue to follow the third of men from the ASCO trial whose tumors shrank down to nothing or almost nothing to check for any recurrence. “In the high-risk population of men treated in our study with neoadjuvant abiraterone and Lupron, if they’d been given only surgery without prior chemotherapy, approximately 50 percent would relapse,” says Nelson. “But if in three years, only 10 percent of the men [given these drugs before surgery] relapse, then that will be pretty interesting,” says Nelson.

Building a community to spur development

Despite the seemingly long slog from the discovery of abiraterone in  the early 90s  to its approval by the FDA in 2011, compared to other drugs this went from lab to beside in an astoundingly short time. “This drug was the fastest Phase III program with overall survival endpoints in the history of drug development,” says Dr. Soule. The speed was in large measure orchestrated by a biomedical research foundation that funded the right blend of clinical science with basic science while assuring constant crosstalk during the discovery process. Foundations can act as matchmaker, (bringing the right mates together to make the right science) marriage counselor, (ensuring fruitful communication during the process of discovery) and philanthropist (seeding money when and where it’s needed) in order to lay the foundation for a cure in the most efficient way possible. 

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