A recognized world leader in the study and practice of urology and a pioneer in developing treatments for bladder, kidney, testicular, and prostate cancers, Dr. Daniel P. Petrylak is currently the head of Prostate Medical Oncology and Professor of Medicine and Urology at Yale University Cancer Center in New Haven, CT. He is also the Co-Leader of the prostate cancer research group and Co-Director of the Signal Transduction Program at Yale and the Smilow Cancer Hospital.
- Dr. Danial P. Petrylak at Yale School of Medicine
- Dr. Petrylak on Twitter: @Danielpetrylak
- Smilow Cancer Hospital
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Cancer Health empowers people living with prostate cancer and other cancers to actively manage and advocate for their care and improve their overall health. Launched in 2017, cancerhealth.com provides accessible information about treatment and quality of life for people with cancer and their loved ones, along with information about cancer prevention and health policy.
Ed Randall: Hi, everybody. I’m Ed Randall, the chief advocacy officer of Fans for the Cure. And welcome back to our Stay in the Game Podcast. Our guest is a recognized world leader in the study and practice of urology and a pioneer in developing treatments for bladder, kidney, testicular, and prostate cancers.
He is currently the head of Prostate Medical Oncology and Professor of Medicine and Urology at Yale University Cancer Center in New Haven, Connecticut. He is also the Co-Leader of the prostate cancer research group and Co-Director of the Signal Transduction Program at Yale and the Smilow Cancer Hospital.
Perhaps his most important credential is that he is a proud graduate of Columbia College in the city of New York. And it is our pleasure to welcome to the Stay in the Game Podcast, Dr. Daniel P. Petrylak.
Doctor, You are the closest thing to being the Shohei Ohtani of the neurology field in that I have seen you described as one of the world’s elite clinicians, teachers, and researchers in the fight to help men and their families deal with prostate cancer. So at this point in your career, from which of these areas do you derive the most satisfaction?
Dr. Petrylak: Wow, that’s a great question. I think I derive my… they all interact. All those are synergistic with each other. First of all, taking care of patients, it’s been an honor and a privilege to take care of so many men over the years and to help them through the disease process, from the initial diagnosis of their disease to the development of spread to other organs. I really have… I would say “enjoy it” is the right word, but it’s really just been an honor to take care of these people.
But that feeds the research and the teaching. So having a patient who has no options, having a patient who maybe would like to spend their retirement, see their grandchildren graduate, like to do things that they’ve earned over their lifetime, and then have it cut short by disease like prostate cancer.
Well, I’ve had a scientific training since I was the age of 16. And my way of trying to help that patient care is developing new drugs, doing the research to bring forth prostate cancer, and find out new treatments for this disease. And then also conveying that information to students, to residents, to fellows, and to other physicians in the cancer field. So I think that they all interact together. I’ve been really, really blessed to have a career like this.
Ed Randall: I have been on prostate cancer panels that quickly veer away from science to the anecdotal. For instance, I too often hear about a world divided into two silos. Number one, men who got screened and saved their lives, and two, those who went to the doctor too late and were left with no options. But it’s not that simple, is it?
Dr. Petrylak: No. As we learn more about prostate cancer, we learn that it is not one disease. It’s a heterogeneous disease. We’ve been able to identify certain genetic signatures that may actually predict for poor outcomes.
I think that it’s so important to communicate with your internist about whether you should have a PSA drawn, and then what are you going to do with that PSA if you find something abnormal. And I think that then from that standpoint, if you are diagnosed with prostate cancer, what’s the treatment that best fits you? Should it be expected to observation? Should it be radiation therapy? Should it be surgery? If it’s more advanced, should chemotherapy or other treatments be employed?
So, as we’ve learned more about how the disease behaves, we understand that there are different subgroups, and these each have their own unique treatments.
Ed Randall: Most of the cases of prostate cancer in your area of specialty are latter stage, metastatic, and often drug-resistant. Of the men that you treat, what’s the mix between cases that had a chance of being detected earlier had they been routinely screened starting at the age of 45 or 50, versus those who were simply too fast-moving and aggressive when detected?
Dr. Petrylak: Well, you remind me of a quote from the late Willet Whitmore, who was really one of the godfathers of prostate cancer research. And his line was, “In patients who a cure is possible, is it necessary?” And in patients who a cure as necessary, is it possible?” It is very, very difficult to predict who that individual patient is who has that very, very narrow window in which they should receive local therapy, and then should they receive more treatment?
So we’re actually finding a lot of things out about the biology of the disease. And even some men who have advanced disease may actually benefit from local therapy. That’s one of the research questions that’s going on right now. But I think that when you look at the disease in total, we need to understand more about the biology. We would ideally like to… we’ve done this to some extent is to take a biopsy specimen, assess risk, and then learn who should be treated aggressively and who should not be treated aggressively.
And that also comes forth for screening as well. You know, who may have a genetic predisposition to cancer? And we’ve identified some of those genes. And who needs to be screened more intensely versus who perhaps does not need that same amount of screening?
PSA is actually a pretty good guide in that situation. You know, if your PSA is very, very low, then you don’t necessarily need to be screened at a very, very intense rate. But if you’re, you know, 2.5, 3.0, that’s somebody who needs to be watched pretty carefully.
Ed Randall: In 2018, the US Preventive Services Task Force improved its grade for PSA tests to the proverbial gentleman’s C for men 55 to 59 while maintaining a grade of D on PSAs for men 70 and older. Is there testing coming down the pipeline that will, a, eliminate the diagnostic PSA test in favor of saliva or DNA, and most importantly, b, be more precise at distinguishing between aggressive and indolent cases?
Dr. Petrylak: Well, we certainly have come a long way in terms of our biopsy techniques for patients who may have an elevated PSA. You know, the recommendation that was made by the preventive task force was met with a lot of controversy. And there had been some unforeseen consequences of that.
So what happened, I believe, it was when the D recommendation came, and I believe it was somewhere around 2008, 2010, that led a lot of internist to say, “Look, we don’t need to do PSA anymore.” That’s not true. If somebody is symptomatic, they should have a PSA done. This whole D really came for those patients who are asymptomatic.
Then, of course, as time went on, what we’re starting to see is that there are more men who are diagnosed with metastatic disease. Remember in the 1980s, before PSA came about that was the most common way that men were diagnosed with prostate cancer. They had bone pain, they had an elevated acid phosphatase and they were not curable at that particular point.
So as time has gone on, and as we’ve refined our treatments and have begun to understand who should be watched, who should receive local therapy, then PSA is becoming more and more important in terms of detecting disease.
We have now the Artemis biopsies that can line up a biopsy specimen using the MRI and using an ultrasound to more accurately go after lesion we’ve seen on the MRI. We have genetic tests that will help us determine whether a patient should be treated what’s the risk is of having a 5 year and 10-year disease-free survival. So using those techniques, we’ve been able to refine that.
The Preventive Task Force has actually retracted that. It’s gone back to a C where patients should be able to discuss these particular treatments with their doctor. And I think I encourage everybody to have the discussion.
Ed Randall: Teaching students and treating patients isn’t all you get to do at Yale. You also have the opportunity to do cutting-edge research with the top minds in the world. Take us through your partnership with Dr. Craig Crews on ARV-110, a PROTAC designed to end run the drug-resistant component of drug-resistant prostate cancer.
Dr. Petrylak: Well Craig is really a brilliant chemist. He was also responsible for the approval of Carfilzomib for multiple myeloma. He’s done a tremendous amount of work in new drug development.
And one of the more fascinating seminars that we have at Yale, and one of the reasons why I went to Yale is the interaction between basic science and between the clinicians. And we had a monthly chemistry colloquium, where the members of the chemistry department came to… We had a meeting, we had a dinner with this, and they would present what they were working on.
And then each of us from each individual disease, such as lung cancer, prostate cancer, bladder cancer, would present what we thought were the most important clinical questions and the most important biologic questions and where the therapeutic targets were.
So Craig stopped me after one of these meetings, came up to my office, and he said, “I had a friend of mine who died from metastatic prostate cancer and I was frustrated that there was nothing else that we could do for him. Do you see the role of another hormonal agent?” And I just sort of looked at him with these… I said, “This is great, Craig.” I said, “This is exactly why I came here. What do you have in mind?”
Well, Craig has been working with something called a PROTAC. So as we know, our body is in constant flux. For example, you turn your skeletal system over pretty regularly by remodeling the bone. Well, within proteins themselves or at least within the cell, we have a garbage disposal mechanism in which a protein gets old, it gets tagged by the cell, and then the cell chews it up and puts it back into amino acids where it can make new proteins again.
Well, what Craig has done is found a process that can accelerate that. So he’s got something called a PROTAC, which can tag an individual protein. And then this ubiquitin ligase system and a proteasome recognize that and chews it up. Well, he’s developed one for the androgen receptor. And it’s called PROTAC. It’s called ARV-110.
And this PROTAC specifically binds to certain mutations of the androgen receptor. So we just finished up our phase one study with that. We’ve been working on this for several years. And we found that there are specific mutations that this can target in patients who failed… Actually, it shouldn’t be ‘who failed’. Whose cancer has worsened on drugs such as Ertiga, or Abiraterone, or Enzalutamide. And we’ve gotten some pretty good responses out of this. So we’re moving forward with further designs and trials.
But this is where I find one of the most exciting areas where we can take bench research, apply it, and move it into the patient. So that patients who may not have had other options could potentially benefit from that.
Craig’s working on other ways of targeting cancer cells. So he’s got a PROTAC for the estrogen receptor, which is now being evaluated in breast cancer. So this is not just for prostate cancer itself, but it could be for any abnormal protein in a number of different diseases. And that’s really an exciting field.
Ed Randall: So while hormone-sensitive prostate cancer is typically treated by androgen deprivation treatments, most patients eventually become resistant to it. And that’s what makes ARV-110 which is being developed by Arvinas and other projects such an exciting development in the fight against metastatic castration-resistant cancer.
Dr. Petrylak: Absolutely. And we are about to go into a phase one trial of a second-generation PROTAC, which, at least in the laboratory may have more activity and a broader range of activity against different androgen receptor mutations. So it’s a very, very exciting time. And this may add another modality of therapeutics to our armamentarium.
Ed Randall: Can the same qualities that PROTAC brought to the phase one in two clinical trials for prostate cancer be applied to certain types and stages of lung, breast, and colorectal cancers that had previously be considered to be untreatable?
Dr. Petrylak: That is a terrific question. And yes, absolutely. So you could target… for example, there is an estrogen receptor PROTAC that is now in clinical trials for breast cancer. So you could target the estrogen receptor with the PROTAC. You could target other targets in lung cancer and colon cancer with this PROTAC as well.
Anytime there’s a protein that’s abnormal, that may be mutated, and have dysfunction based upon that, gain of function, for example, like we see with the androgen receptor, then PROTAC could certainly be used. So this is one way of potentially going after what we call undruggable targets.
There are two targets that we’ve really tried very hard to go after: one is P53 and the other one is RAS. And now we’re beginning to start to develop treatments that go after those particular targets as well. So, again, I think that we’re beginning to broaden our portfolio in taking care of not only prostate cancer patients but all patients with cancer.
Ed Randall: I’ve seen estimates in the tens of millions when it comes to cancer screenings that have been skipped or deferred by men during COVID. My first question, have you detected a rise in the percentage of latter stage cases of prostate cancer due to the missed 2020 screenings? Or will those numbers take years to play out?
Dr. Petrylak: I think we’re going to see something similar to what we saw with the task force as I mentioned before. That’s going to take a little time. Where I’ve seen the biggest differences are in the aggressive cancers, such as… for example, I can give you a specific example. It’s anecdotal, but a gentleman who was diagnosed with localized bladder cancer in early 2020 and then was afraid to come in to talk to the physician about treatment because of COVID.
And he delayed, he delayed, he delayed and finally came in in August, and he had metastatic disease. We treated him but there was… you know, he took a potentially curable situation to a non-curable situation. What also concerns me is if you look at the statistics, from the beginning portion of the first quarter of the pandemic, and you adjust this based upon deaths that you expect from COVID, all-cause mortality has gone up. But it’s not specifically only driven by COVID. There are other causes too, unrelated to COVID which are now increasing.
Drug abuse, for example, people not going to the physician because they may have chest pain, and they’re afraid to go into the emergency room because the fact that they’re afraid of being exposed. So this is not only a health problem in terms of cancer, but it’s going to be a health problem in terms of all screening: cardiovascular, high blood pressure, anything else that patients really should be seeing the physicians for. So we’re going to see, you know, an issue with health in our aging population because of this.
Ed Randall: Second question. I don’t have to tell you this. Men have complicated relationships with their doctors in their own health. That said, how do we as a charity, and how do you in Yale as health care providers do a better job in getting men to own their health?
Dr. Petrylak: I think you have to do that through the family. That’s the way I’ve approached it. The patients, of course, who are the most diligent about follow-up and about discussing the issues, have a partner who cares, and a partner who really is willing to help that individual.
We have to take the stigma away that goes along with sexual dysfunction, with mortality as well. A lot of people don’t want to discuss these issues until they absolutely are forced to. And then by that time, it’s too late—you’ve lost your window of opportunity.
What I think it’s important to emphasize is that all patients at any stage, we have treatments to offer. That they can both improve quality of life and prolong life. And I think that message has to come out clearly from the physician.
We also have to talk to the primary care doctors as well. Let them know that screening should be done or at least they should discuss screening with their patients, and talk about the pros and cons. Because open discussions are important to patient education, making patients feel comfortable.
Patients will often ask me, “You know, they preface something, “I’ve got this stupid question that I’m going to ask you…” Like, “No, stop there for a second. No question is stupid. No issue is stupid. We’re here to help you. We’re here to discuss these issues with you in terms of your side effects, in terms of your treatments.”
So being open, being able to relate to somebody as well is really, really important. If you’re going to spend the time with somebody and sit down and talk to them, that’s going to make a big difference in whether they’re going to be treated or not or whether they’re going to seek active treatment.
Ed Randall: As those of us who watch baseball on TV can confirm statistics work best when they are the catalysts for larger discussions. The stats for prostate cancer are a 99% five-year relative survivability and the primary cause of death for about 35,000 US men in 2022. So what should be the message? Don’t worry? The M103 bus in Manhattan has a better chance of killing you? Or please don’t be one of the 35,000 empty seats at Thanksgiving?
Dr. Petrylak: Message is don’t be one of the 35,000. Basically, it translates to about 1 in 11 patients who are diagnosed with prostate cancer who eventually die from their disease. That’s second to lung cancer. Lung cancer is the most common cause of death in men with cancer. So we want to make sure that you’re not part of that group. We want to try our best way possible to prevent that from happening.
Of course, there are no guarantees. But certainly, the early detection is a way, as I mentioned before, we’re seeing more metastatic disease after PSA screening was diminished. So we want to be sure that people know that they should be checked. That if they are diagnosed, that even if they have metastatic disease, that we can control the disease for long periods of time. It’s not curable at this stage, maybe in the future we will, but we can control it for long periods of time with good quality of life and being able to be active. So the earlier you detect it, the better off you are.
Ed Randall: I’m in support group that’s turned out to be a valuable community for men who were dealing with prostate cancer at all phases, from diagnosis to recurrence to the challenges of survivorship. But one of the across-the-board complaints is that their urologists, surgeons, and radiologists as a group have soft-pedaled the often life-changing and long term side effects of their treatments. Impotence and incontinence aren’t for the meek. What can we all do to improve the channels of communication among those of us involved in these important dialogues about our lives?
Dr. Petrylak: I think that one of the things that I do is I do a lot of patients who come to me with localized disease, talk to me about “what I feel is the quote-unquote, ‘unbiased second opinion.'” And right now, at least as far as we can tell, because there’ll never be a randomized trial comparing radiation therapy to surgery. Both of these probably have a very similar anti-cancer effect. And so a frank discussion about the possibilities of losing potency, and the effects of some of the other treatments as well as incontinence needs to be done.
One of the things that I like also to do with our patients in terms of if they’re getting hormones with the radiation therapy is give them some control, way of trying to counteract what side effects we can affect. And that includes waking, loss of muscle mass, thinning of the bones. Those are the ones that I think are very important, in addition to the sexual dysfunction.
So often men who are on hormone therapy can put a lot of weight on. I always discuss exercise, diet, as well as weightlifting, particularly to maintain muscle mass. There’s a great book that a friend of mine wrote. His name is Fred Bartlit. And the book is called “The Strong Path.” And Fred is I think 87 right now, and he looks like he’s 60. And Fred basically has come up with a program of weightlifting and pumping iron, because he feels that that has been important.
As people get older, they lose muscle mass naturally, they become frailer. So if you can delay that process, both naturally, as well as those patients who are on hormone therapy, that’s important. Calcium and Vitamin D important to bone health. People develop fractures over time if they’re on deprivation therapy.
So again, we talk about these things. And we try to give patients a roadmap how they can empower themselves and take control of these particular issues. There are also ways after surgery that you can potentially counteract impotence issues and incontinence issues. All those patients should have preoperative counseling as to how they can manage their own destiny in that situation.
Ed Randall: Before we go, you wanted to make an important point about genetics.
Dr. Petrylak: Yeah. I think we’ve talked a lot about patient empowerment during this really fun… I really enjoyed talking with you, and I always do. But we’ve talked a lot about patient empowerment. And one of the things that all patients should be asking their physicians are, “Am I getting the earliest treatments? And is there anything genetically that is important to my cancer that can make a difference in terms of how I’m being treated, and my family?”
So it’s been demonstrated over the last several years that BRCA which is a mutation seen in breast cancer, ovarian cancer, and pancreatic cancer. BRCA is also present in prostate cancer. And that gene can be passed down to sisters, to children. And so if a prostate cancer patient has BRCA, not only is the cancer patient being treated, but the whole family has to have a discussion about genetics and should be counseled.
In addition, if a patient becomes metastatic, BRCA is important to the response of a drug called Olaparib, also, there’s a drug called Rucaparib, both of which are approved by the FDA. But these are drugs that interfere with one of the targets that BRCA affects, DNA repair. And there can be some pretty dramatic responses in patients who have prostate cancer to these particular drugs. It’s about 1 in 10 metastatic patients who has this.
Also, most importantly, there’s a condition called microsatellite instability, which is also a genetic marker. It’s less prevalent. It’s only in 3% of patients with metastatic prostate cancer. But it marks for response to immune therapy to drugs such as Pembrolizumab. Pembrolizumab is Keytruda. You probably have seen that advertised on television.
Pembrolizumab is FDA approved in patients who have this mutation. And so every patient should discuss with their physician whether they should have markers done. “Am I getting all of my treatments at the right time?” Because some of these treatments now being moved earlier into hormone-sensitive disease. And we’re seeing great benefits with the drugs that are being used late in cancer treatment when they’re moved up earlier. So you should ask these questions to your urologist as well as to your oncologist.
Ed Randall: Such great advice from you. Our guest has been one of the world’s most renowned medical oncologist, Professor of Medical Oncology and Urology at Yale University Cancer Center, Dr. Dan Petrylak. Dan, thanks for all you do for your students, your patients, for all those who benefit from your research and collaboration, and for the support and encouragement you’ve always extended to our charity from the very beginning.
As the late great Joe Franklin said after he wrapped up his interview with Bing Crosby, “Next time we need to do two hours.” Thanks for being with us. Happy holidays.
Dr. Petrylak: Thank you, Ed. It was fun.
Ed Randall: I’m Ed Randall, and thanks for being with us on our Stay in the Game Podcast.
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