Out of the Box: How PCF Funded the Creation of Enzalutamide

The first targeted therapy for prostate cancer

Enzalutamide (Xtandi^®) has been a game-changer.  The first drug ever developed specifically to treat advanced prostate cancer, it has slowed disease and prolonged survival for tens of thousands of men since its initial approval by the FDA in 2012.  PCF invested more than $14 million to fund its development.

Enzalutamide began in 2002 as simply an idea:  to find a molecular target for metastatic prostate cancer.   Back then, scientists didn’t know nearly as much about the molecular biology of evolving and spreading prostate cancer.  All they really knew was that once cancer escaped the confines of the prostate, it could be subdued – sometimes for many years – with androgen deprivation therapy (ADT), shutting down production of testosterone.  But they knew that ADT, like a beleaguered dam, would eventually fail.  It could not hold back advanced prostate cancer forever.

Less than a decade earlier, philanthropist Michael Milken had started a foundation called CaP CURE (now PCF) to fund the cure for prostate cancer.   A prostate cancer survivor himself, he knew that out-of-the-box thinking was desperately needed, because Federal funding for research works much like Hollywood does.  It bets on sure things, on proven concepts, on sequels to smash hits.  But what if you have a higher-risk proposition– a potential blockbuster – and you don’t have the money to develop it?  How will you ever know if it’s as promising as you think it is?  The seed money provided by PCF awards lets scientists develop superb but riskier ideas to get early results in the lab or from small pilot studies, which they can then leverage into more funding from larger grants.    

Bringing the Right People to the Table

In 1996, Milken and the PCF Board of Directors held a meeting at UCLA.  They invited members of the UCLA faculty including Owen Witte, M.D., a noted physician-scientist with expertise in leukemias, immune disorders, and epithelial cancers, who served as a scientific advisor to the Board.  Also present was Witte’s mentee, an up-and-coming leukemia physician-scientist named Charles Sawyers, M.D.  

That day, Witte and another scientific advisor, the noted Johns Hopkins scientist, Donald S. Coffey, Ph.D., had a watershed suggestion for the Board:  what if you fund scientists who may not be experts in prostate cancer specifically, but who know how next-generation drug discovery works – and how to find molecular targets to stop cancer?  

This was just the kind of innovative idea Milken was looking for.  When the opportunity arose, “PCF bet on it as a first mover,” says Jonathan Simons, M.D., a prostate cancer oncologist-scientist who would later join PCF as CEO.  Sawyers had been doing world-class work in chemotherapy-resistant chronic myeloid leukemia (CML).  After much painstaking effort and several daunting setbacks, he and colleagues developed two compounds – both approved by the FDA – that have made a huge difference in curing patients with CML.  

Witte believed that Sawyers would be an excellent candidate to develop a drug to combat castration-resistant prostate cancer (CRPC, cancer that has progressed on ADT).  In 2002, PCF provided a competitive research award to Witte, Sawyers, and a brilliant organic and pharmaceutical chemist at UCLA named Michael Jung, Ph.D.  More PCF awards would follow, with Sawyers as Principal Investigator. 

The opportunity to work on prostate cancer appealed to Sawyers.  “It’s an incredibly important problem,” he says.  “There are 5,000 new patients a year diagnosed with CML in the U.S. – and there are 33,000 men each year who die of CRPC.”  

Applying Lessons From Leukemia to Prostate Cancer

Sawyers and team went to work, “using the same strategies that we applied with CML.”  In mouse models, they performed a comprehensive analysis of prostate tumors as they evolved from a hormone-sensitive to a hormone-refractory stage (CRPC).  “We found something,” says Sawyers.  “I will never forget that group meeting in which Charlie Chen, the postdoc leading this work, showed a table in which the only gene that was consistently altered was the androgen receptor (AR),” suggesting that evolving prostate cancer cells were somehow using these receptors to survive – even though there were no male hormones to bind to them.

This was not the big breakthrough Sawyers had been hoping for.  “We were actually pretty disappointed with this result,” he recalls.  “It just didn’t make sense that the AR would be the driver of this disease.”   But Derek Welsbie, an M.D.-Ph.D. student in Sawyers’ lab, said: “’We have to do the functional studies’” – basically, this was a trail that needed to be followed.  “He developed what was brand-new technology at that time and showed that overexpression [inappropriate “switching on”] of the AR was sufficient to cause resistance.”  This evidence was so compelling, Sawyers believed, that “I could not let this go.  We had to do something about it.”  He approached the drug companies he had worked with in developing the CML drugs – but found zero interest in initiating a drug discovery program to develop a next-generation anti-androgen.

Not Giving Up

“So, we formed an academic team,” Sawyers says. First on board was Michael Jung.   Next came Samedy Ouk, a postdoc in Jung’s lab “who had spent a year in a pharmaceutical company in France – where he learned some medicinal chemistry, which was critical.  And Charlie Chen and Derek Welsbie were the biologists in my lab.  We set about looking for a compound that would work – that would inhibit the growth of prostate cancer cells when they expressed high levels of the AR and were resistant to bicalutamide” (an ADT drug).

The UCLA team, notes Simons, “attacked the AR protein with chemistry and molecular biology experiments in an entirely different way. They applied the ‘state of all current AR knowledge” towards finding a vulnerability in the target.  They understood that it’s not just about shutting down testosterone supply; that was achieved with ADT.  You can’t make zero testosterone any less.”  Sawyers showed that “you can make drugs against the AR that stopped it even when there’s no testosterone left.  Cancers were still addicted to the AR; they found another way to use the AR even without testosterone – that wasn’t even known, until they proved it at UCLA.  The more you understand how the pathway works, the sooner and better you can make drugs against it.”

Jung made two similar compounds, which Sawyers’ lab then studied.  In 2005, says Sawyers, “we knew we had something.  [It] shrank tumors in all the mice we tested.”  One of them was licensed to Medivation, and the company initiated a clinical development plan. 

Results of clinical trials in patients were, recalls Simons, astounding.  “PSAs plummeted downwards in men with CRPC.  No one had ever seen PSAs go down in CRPC.  With PCF funding, the UCLA team took the cancer that men were dying of, created it in a mouse, developed a drug to fight it and took it to the clinic.”

The results of the of the Phase 3 trial of this novel compound were so strong that the NIH decided to end it early.  Enzalutamide was approved by the FDA in 2012 for metastatic CRPC, and since then has been approved for use earlier in the course of prostate cancer.  Six years later, a next-generation drug similar to enzalutamide, called apalutamide – also developed with help from PCF – was FDA-approved.

Supporting Innovative Ideas Yields Benefits for Patients

The lesson in both drugs:  “PCF believed that people who are brilliant could make a drug that pharmaceutical companies couldn’t even think of,” says Simons.  “That just wasn’t happening in cancer research.  Then it happened in leukemia.  The UCLA team proved you could do it.  PCF was one of the first organizations to fund young scientists innovative enough to think they themselves could just do these things – and they could, and they can, because the chemistry and molecular biology tools are getting easier for any university laboratory.  When the science of cancer research allows brilliant, driven, and passionate young people who see a new scientific way forward to make a research drug, you should fund them – even though major drug companies are going to wait and see what happens, because radically innovative drug development often is too risky for their management and shareholders.”

Enzalutamide was one of the first cancer drugs given accelerated approval,” Simons continues.  “It became the poster child for identifying a molecular vulnerability in prostate cancer, and figuring out how to target it.  “I can’t emphasize this enough: It was radical to think you could go after prostate cancer like it was a blood cancer (like CML).  You would have been laughed out of the room – in fact, some prominent scientists said at the time, ‘There is no such thing as a magic bullet!’  But the UCLA team Sawyers led proved that if you have the right target, the right human capital, and generous donors, there could be something close.”