Source: George S. Mack of
The Life Sciences Report (4/20/16)
https://www.streetwisereports.com/pub/na/what-andy-grove-and-michael-milken-have-taught-us-about-prostate-cancer
Solid tumors are typically managed with surgical resection, chemotherapy, radiation and biologics, but it's the secondary tumor mass, the metastasis, that kills patients. Dr. Stuart Holden of the UCLA Institute of Urologic Oncology understands the importance of targeting metastatic disease, which is driven by different genetic factors than the primary tumor from which it arose—a fact that oncologists are just now coming to grips with. In this interview with
The Life Sciences Report, Dr. Holden describes an essential target in aggressive prostate cancers, and a drug with the potential to address that target and extend the lives of thousands of men.
The Life Sciences Report: You have had some noteworthy figures as patients in your career. Among your prostate cancer patients are the late Andy Grove, former chairman and CEO of Intel Corp. (INTC:NASDAQ), who passed away in late March at age 79, and former investment banker Michael Milken, who continues to be active as a supporter of prostate cancer research. You've had some very public patients, haven't you?
Stuart Holden: I was involved with Dr. Grove when he was first diagnosed in 1998, and I actually worked with him on the preparation of his now-famous
article in Fortune magazine. As a result of that, I got to know him, and became one of his confidants on issues related to prostate cancer. As a matter of fact, I was instrumental in convincing him to go on the board of the Prostate Cancer Foundation, originally known as CaP CURE, which was started by Michael Milken in 1993.
TLSR: Andy Grove was an engineer, and he approached his disease very differently than most people, didn't he?
SH: Yes, he did. Dr. Grove had an incredibly analytical mind—the mind of an engineer. Those of us who see patients know that when you get to complex subject matter like prostate cancer, different types of people process information in ways you might predict from their backgrounds. As an engineer he was extremely precise on details, and was very quick to understand the nuances of his diagnosis, as well as the vagaries and biases associated with treatment recommendations. He pointed out a lot of the inconsistencies in our knowledge of treatment recommendations at the time, and actually came to an excellent solution for his own disease. It was a successful outcome. In fact, he actually died of complications of Parkinsonism, as I understand it, and not from his prostate cancer, which had been well controlled by the treatment he chose.
TLSR: What about Michael Milken?
SH: Michael is a brilliant guy as well, with a slightly different mind than Andy's, but no less analytical. He came at it from both a financial and philanthropist background. He was diagnosed in 1993 with a very aggressive form of prostate cancer—and, I might add, with a very poor outlook—at the age 46. He had already been active in writing checks to support cancer research when he was diagnosed, but after his diagnosis he decided he needed to get more involved in the culture of the world of prostate cancer, rather than just writing checks and hoping for the best. He instructed me that we were going to start a foundation, now known as the Prostate Cancer Foundation, and we have been working on this together since then.
TLSR: Generally speaking, how did Milken approach the problem? He looked way beyond the immediacy of his own disease, didn't he?
SH: Yes. Michael totally immersed himself into this work. He was quick to understand that there was very little work being done in prostate cancer, and the reason was that very little money was going to support research in the area. When you would ask for funding from agencies like the National Cancer Institute, they would say they didn't support work in this area because there was really no good work to support. Then when you talked to the researchers, they'd say they didn't work in the area because there was no money to support it.
Michael is a pretty smart fellow, and he figured out right away that we needed to formulate a strategy to get more money into the field, and get more talented people focused on this disease, both in his own interest and in the interest of every other man who had prostate cancer or would have it in the future. He reckoned this was a really big disease: the leading cause of cancer death in men, the second leading cause of cancer diagnosis in men. There was virtually nothing going on in the pharmaceutical industry, the biotech industry or even at the academic research level. So we started a process in our foundation of granting money for research. We made it a three-page application, we told people within 30 days whether they were going to get funded, and we funded them. That created a tremendous dynamic in the field.
TLSR: How much money has been granted by the Prostate Cancer Foundation?
SH: In the beginning, people didn't take us that seriously. Some people thought it was a publicity stunt, but it clearly wasn't. We have been in business now for 23 years, and we have funded over $700 million ($700M) in research around the world. I would say there has been almost no development in the treatment of advanced prostate cancer that the Prostate Cancer Foundation hasn't had its fingerprint on at some funding and support level.
TLSR: You've worked on the front lines of prostate cancer for more than 36 years. What is the most dramatic change you've seen?
SH: I don't know if it's the most dramatic, but I would say the most game-changing was the development of the prostate specific antigen (PSA) assay. It was developed academically around 1977, and it was a true early biotechnology story. It took until the mid- or late 1980s before the PSA started creeping into routine clinical practice. It was a huge game changer in the sense that maybe 10% of my patient population was devoted to prostate cancer patients before the PSA assay, but since its introduction, I would say 80% of my patients fall into that category. I specialize in that area as a genitourinary oncologist, so my experience is a little biased, but that's the way it is today.
The PSA has been both heralded and demonized. It's been used properly and misused. But during the PSA era, the death rate from prostate cancer has gone down 40%. The PSA has also led to overdiagnosis and overtreatment—all of that is true. But at the end of the day, PSA is still the best biomarker in clinical utilization. I believe the single greatest reason for that reduction in deaths was the introduction of the PSA assay into routine urology practice.
TLSR: Immunotherapy is the rage right now. Do you see anything interesting in that realm for prostate cancer?
SH: I would say, with some degree of pride, that the first vaccine ever been successfully used to treat cancer of any kind, and approved by the FDA in 2010, is Provenge (sipuleucel-T; developed by Dendreon Corp., which was acquired in bankruptcy by Valeant Pharmaceuticals Intl Inc. [VRX:NYSE]). I use the word pride because the Prostate Cancer Foundation provided critical philanthropic support to UC San Francisco to support this work in its infancy.
It was also the first cell therapy ever approved to treat cancer. The data show that Provenge extended life, compared to a placebo, by about four-odd months. While that's not a huge, grand-slam home run, Provenge has energized lots of companies to start looking into immunological therapies for cancer in many different areas. There is a lot of work going on in that area right now.
In addition to the FDA-approved vaccine Provenge, and we have several others in development. One is GVAX-PCa (Aduro Biotech Inc. [ADRO:NASDAQ]); the other is a viral vector called ProstVac VF (Bavarian Nordic [BAVA:OMX]).
All sorts of work is going on in immunotherapy for prostate cancer using vaccine strategies or checkpoint inhibitor medications in conjunction with radiation and chemotherapy. There are many diseases in which immunotherapy has shown itself to be effective, but I would also say we're in the first inning of a nine-inning game on immuno-oncology. In the next few years, immune therapy will find its way into the armamentaria of those who treat prostate cancer. There is certainly a lot of interest in it.
TLSR: Provenge was not successful financially because it had a very high manufacturing cost burden, which could not be overcome by even the high price tag for patients. On March 28,
Medivation Inc. (MDVN:NASDAQ), which developed the prostate cancer drug enzalutamide (Xtandi; partnered with Japanese big pharma Astellas Pharma Inc. [ALPMF:OTCPK; 4503:TYO]), received a congressional letter signed by six U.S. senators and six U.S. representatives calling for a public hearing to question Medivation about the cost of enzalutamide, which has a selling price of $129,000 ($129K) in the U.S., versus $39K in Japan and Sweden, and $30K in Canada. Do you have any thoughts on this topic, generally?
SH: I'll give you some background first. One of the things we did in our initial work at the Prostate Cancer Foundation was try to attract the best scientists at UCLA to work on prostate cancer. As part of that process, we wound up funding a small project at UCLA headed by Dr. Charles Sawyers and Dr. Michael Chung, who are the inventors and developers of enzalutamide. That charitable donation led to the data they eventually produced, which eventually was licensed and bought by Medivation, and was ultimately approved by the FDA. What's interesting here is that this started with a fairly small research grant of just $150K, and that led to the development of this multibillion-dollar drug. UCLA recently got a fairly sizable royalty on that enzalutamide invention.
As a practicing physician, I'm excited to have played some role in the development of enzalutamide, but when you prescribe it for patients, it becomes very difficult because you immediately start something of a battle with the patient's insurance company to figure out how it's going to get paid for. It usually involves several phone calls, and sometimes peer-to-peer conversations with oncologists at the insurance companies. It's very difficult to get utilization of these new drugs at these cost levels. I'm not an expert, and I wouldn't pretend to give you a cost analysis as to why the drug costs so much in the U.S. But to your point about Japan or Canada, it is obviously disturbing when you see that the drug has become available in other countries at a much lower cost. I think this is a very worrisome thing from the standpoint that lots of new drugs are coming online that will be very expensive to patients in the U.S.
TLSR: You are chair of the
Arno Therapeutics Inc. (ARNI:OTC.MKTS) prostate cancer scientific advisory board (SAB) for onapristone, a progesterone receptor antagonist that is being tested in prostate and breast cancers. By contrast, Medivation's enzalutamide is an androgen receptor inhibitor. Both of these receptors are constitutively activated. Could you tell me about onapristone and why you want to be involved with it?
SH: The way this came about was through the Dream Teams—Stand Up To Cancer research projects. It's a partnership of the Stand Up To Cancer and Prostate Cancer Foundation to offer support in prostate cancer. There's a West Coast Dream Team and an East Coast Dream Team. Basically, what they're doing is assaying biopsies of metastases in patients with prostate cancer, and doing genetic analyses of the tumors to see what pathways are activated in the metastases compared to what pathways might be active in the primary tumors. That's because it's the metastases that kill you, not the primary tumors.
One of the most remarkable discoveries that came about from the analysis of these biopsies was that 20% of the patients with prostate cancer metastases in the study showed abnormalities in their DNA repair genes. That would involve the whole family of genes that encompasses the tumor suppressor genes, BRCA1 and BRCA2, which can have abnormalities or mutations that lead to breast cancer. Patients with these mutations could be potentially susceptible to PARP inhibitor drugs, the main one being olaparib (AstraZeneca [AZN:NYSE]), which is a PARP-1 inhibitor. PARP-1 is a vital enzyme for repairing breakage in DNA strands, but you don't want them repaired in tumor cells. You want the tumor cells to die. Second, these are also potentially susceptible to platinum-based chemotherapy as well.
This was a startling discovery because now we have clinical trials going on with a drug that was developed originally for ovarian cancer. It's being used primarily in breast cancer, but it turns out to have potential utility in up to 20% of the men who are dying of metastatic prostate cancer. That was totally unforeseen and it was game changing.
When we treat patients who have had heavy targeting of their androgen receptors with drugs like enzalutamide and abiraterone (Zytiga; Johnson & Johnson [JNJ:NYSE]), so that they have started to become resistant to the therapy, the DNA repair genes become upregulated. One of the genes that is upregulated in these biopsies is the progesterone receptor, which is the target of Arno Therapeutics' onapristone. A significant number of patients have elevated progesterone receptors, and in the way that the PARP inhibitor drugs target the other genetic abnormality, the progesterone receptor should be an effective target in the group of patients display this abnormality. This would be a great application of "precision medicine," which everybody talks about.
TLSR: Does the prospect of working on Arno's SAB to study its progesterone receptor inhibitor excite you?
SH: Yes. I became excited, and a number of my colleagues at the Prostate Cancer Foundation and in the field of prostate cancer also see this as a significant potential target that could address patients whose cancers have metastasized and who may exhibit this particular abnormality. There are two Phase 1/2 clinical trials underway now. Both are open-label and in progesterone receptor-expressing tumors. One is a 60-patient dose-escalation trial (
NCT02052128), which is wrapping up soon. The other, a 75-patient trial (
NCT02049190), is in advanced castration-resistant disease, and it will wrap up at the end of 2017.
TLSR: What's the next step?
SH: I have put together what I hope is an all-star team of good-thinking medical oncologists from around the country and internationally to help Arno both design its clinical trials and also try to evaluate the science. We are trying to understand the biology of why and how this disease progresses and metastasizes. We have this drug that is already in clinical trials, and it just required a shift in thinking. I know they have been testing the drug in endometrial and other cancers, but because of the findings from the Dream Teams' analysis of tumor biopsies, prostate cancer has become a significant therapeutic window of opportunity. The SAB that I'm heading up at Arno will attempt to evaluate what this opportunity is, and determine the smartest way to design the clinical trials and evaluate the information to see whether onapristone could be a new therapeutic entity.
TLSR: Many thanks to you. It was a pleasure.
Stuart Holden MD is a Health Sciences Clinical Professor in the Department of Urology at the David Geffen School of Medicine at UCLA and Associate Director of the UCLA Institute of Urologic Oncology. Serving as Prostate Cancer Foundation's medical director since the inception of the foundation in 1993, Holden directs the medical and scientific strategy of PCF and oversees its grant award programs, consortia activities and scientific meetings. An internationally respected urologic oncologist and surgeon who has worked on the frontlines of prostate cancer for more than 36 years, Holden introduced radioactive seed implantation to Los Angeles and was an early adopter of ultrasound-guided prostate biopsy. He completed his medical degree and surgical training at New York Hospital Cornell University Medical College; his urology residency at Emory University; and fellowships in urology and developmental genetics at Memorial-Sloan Kettering Cancer Center. He also was awarded a clinical fellowship from the American Cancer Society.
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