By Howard Wolinsky
Would you consider a drug to prevent or suppress prostate cancer in place of the ritual of active surveillance with all the digital exams, PSAs, MRIs, and biopsies?
Would the risk of side effects with current oral drugs in the ARI (androgen receptor inhibitors) category, such as fatigue and breast growth, be acceptable?
What if the drug costs more than $150,000 per year? Could you afford it if your insurance company refused to pay?
The issue of drug therapy for patients with low-risk to favorable intermediate-risk has been cropping up because new research shows that ARIs can suppress and prevent the progression of prostate cancer in patients who otherwise qualify for AS.
(I just wrote about this in Medscape Medical News: https://wb.md/3BcgLkI I expand on the topic here.)
Over the past few years, researchers have been looking at ARIs to prevent the progression of cancers in patients with low-risk to favorable intermediate-risk disease.
Move drugs from high-risk to low-risk patients?
The theory is patients and their doctors should consider transferring these drugs used in patients with prostate cancer to the lower-risk, localized cancer group.
This is not necessarily unusual. Results should be available soon from a study in lower-risk patients of Provenge (sipuleucel-T, Dendreon Pharmaceuticals).
(Provenge is a hormone therapy approved in patients with metastatic castrate-resistant cancer using the patient’s own blood. The vaccine stimulates the patient’s immune system into recognizing and destroying prostate cancer cells.)
We’ll get back to Provenge when the data are published.
Meanwhile, by definition, active surveillance involves close observation—with digital exams, PSAs, MRIs, and biopsies of patients with low-risk (Gleason 6 or Grade Group 1) “prostate cancer” and of patients with favorable intermediate-risk (of Gleason 3+4=7 or Gleason Grade 2) prostate cancer.
Step backward?
Christopher Booth, MD, of the Division of Cancer Care and Epidemiology, Queen's University Cancer Research Institute, Kingston, Ontario, Canada, told me while I was wearing my Medscape hat: “I cannot see how this represents an important advance for patients. I worry we are taking a step backward if clinicians begin to adopt this approach over true active surveillance.
“Uptake of active surveillance over the past two decades has been a huge advance for patients with early-stage prostate cancer, as it allowed us to deescalate care, reduce side effects, and preserve good outcomes.”
But research is moving ahead to see if ARI drugs that help in advanced cancer can work on those of us with early-stage, low-risk prostate cancer.
The widely publicized ENACT study showed that enzalutamide (Xtandi, Astellas Pharma Inc. and Pfizer Oncology)), an ARI drug, is highly effective in lower-risk patients.
Compared with AS alone, “enza” significantly reduced the risk of pathologic or therapeutic progression of prostate cancer by 46%.
(https://jamanetwork.com/journals/jamaoncology/fullarticle/2793567) and
(https://jamanetwork.com/journals/jamaoncology/article-abstract/2793572)
“Results suggest that enzalutamide may offer an alternative short-term treatment option for this patient population, potentially reducing the need for more aggressive treatment approaches,” said Neal Shore, MD, principal investigator of ENACT and medical director for the Carolina Urologic Research Center (Myrtle Beach, S.C.). and colleagues said in JAMA Oncology.
It sounds impressive.
Bogus?
But Laurence Klotz, MD, a University of Toronto researcher, who coined the term “active surveillance,” told me: “Trials like this are bogus in my opinion because they include a decrease in tumor volume as an endpoint, and it is totally predictable that that will occur with a cytoreductive agent.”
In other words, what do you expect from a drug known to shrink prostate cancers?
Along the same line, William Catalona, MD, of the Feinstein School of Medicine at Northwestern University in Chicago, a pioneer urologist, said:
“Of course, any form of ADT (androgen deprivation therapy) would be expected to slow the progression of prostate cancer, and favorable intermediate-risk disease does progress more frequently and more rapidly, so it does deserve consideration.”
So Catalona has an open mind while Klotz is “resolutely” opposed to this use of ARIs.
Catalona added: “The study reminds me of what Dr. Susan Domchek (of the Basser Center for BRCA studies at the University of Pennsylvania) jokingly calls the “Duh” paper she published in Lancet Oncology years ago showing that among women with BRCA1 and BRCA2 mutations, risk-reducing mastectomy was associated with a lower risk of breast cancer; risk-reducing salpingo-oophorectomy was associated with a lower risk of ovarian cancer, first diagnosis of breast cancer, all-cause mortality, breast cancer-specific mortality, and ovarian cancer-specific mortality https://pubmed.ncbi.nlm.nih.gov/20810374/. “
He added: “Of course they do.
However, Shore, who also honchos the Provenge study, told me the research was necessary you can’t assume that what works in advanced cancer will work in early-stage disease.
Enza has some nasty side effects that should give otherwise healthy men pause about drug therapy for active surveillance.
Side effects the drug had in the ENACT study included fatigue (55.4%), gynecomastia or breast growth in males because of hormone imbalances (36.6%), nipple pain (30.4%), breast tenderness (25.9%), and erectile dysfunction (17.9%). A total of 88.4% of patients experienced drug-related adverse effects, 2.7% of which were serious and 7.1% resulted in treatment discontinuation, per Shore.
Fatigued
In 2011, my UChicago doctor suggested I try finasteride (Proscar, Merck), an anti-BPH drug based on research suggesting finasteride, a hormonal drug ha increases testosterone, might prevent prostate cancer.
(Finasteride is in a class of medications called 5-alpha reductase inhibitors. Finasteride treats BPH by blocking the body's production of a male hormone that causes the prostate to enlarge. Finasteride also treats male pattern hair loss by blocking the body's production of a male hormone in the scalp that stops hair growth.)
This medicine knocked me on my ass.
I was teaching in the graduate school at Northwestern Medill School of Journalism at the time. I usually am the energizer bunny.
By the end of the day on his med, I could barely find the energy to make it to the commuter train station. And then, I felt like I needed a seat belt to keep me up in my seat.
So I quit finasteride.
The “cost” of enza
I interviewed a Florida man with metastatic prostate cancer, who had a similar experience to mine but with enza—only far worse. He took the ARI because he had to.
One of his doctors told me to imagine my experience amplified 50-fold.
This patient, Russ Hoover, of Hudson, who takes enza with Lupron, said some guys don’t have side effects, but enza hit him and others hard: ”We don’t have a life. If you feel like doing anything, you can’t. You just don’t have the strength or energy.”
In the study, low-risk patients were given the same dose of enzalutamide as patients with advanced prostate cancer.
Hoover’s advice about the idea of low-risk patients taking drugs like enza: “My layman advice: DO NOT DO IT based on my side-affects.”
He added that he was told he might have side effects: “They warn you. They give you a piece of paper two pages long saying here are the possible side effects and things all the way down to an ingrown toenail because they’re covering their ass. Everybody is different as far as how their body reacts.”
A leading medical oncologist told me: “Enzalutamide is a great drug. It effectively blocks testosterone. It has helped some men live longer. But it has a cost for some men.”
Quality of life?
Shore conceded: “There is a significant spectrum of side effects associated with androgen deprivation therapy. They include a decrease in energy, in sexual function, libido. There is the quasi-metabolic syndrome. There is visceral abdominal weight gain. There is some suggestion of worsening cardiovascular risks or complications, depression, bone demineralization, and hot flashes. Most patients feel fatigued, which is a problem for all aging men, and most men with prostate cancer tend to be older. Assuredly, these symptoms can have a very negative impact on quality of life and daily activities.”
Catalona said enzalutamide can be a difficult drug for men with advanced prostate cancer let alone those with low-risk cancers.
“Most of my patients on treatment with enzalutamide don’t feel well. Many suffer from extreme fatigue, and some refuse to continue taking this medication. Gynecomastia is also problematic to most men,” he said.
He added: “The other elephant in the room is that ADT selects for more aggressive and difficult-to-treat castrate-resistant cancer cells, so when it stops working, patients are in a far worse place. They would have been better off being cured with definitive treatment in the beginning."
Silver lining in an enza cloud?
Still, some doctors see a silver lining in the enza study.
Michael Schweizer, MD, a medical oncologist at the University of Washington in Seattle, conducted a study showing that another ARI, apalutamide (ERLEADA, Janssen Scientific Titusville, N.J.) can suppress cancer in men who otherwise would qualify for AS. [Resetting the Active Surveillance Clock: Apalutamide in Lower Risk Prostate Cancer, Society of Urological Oncology, December 2020. [https://suo-abstracts.secure-platform.com/a/solicitations/4/sessiongallery/30/application/859]
Of the Shore study, he said: “Overall, this study is an important step toward defining novel approaches for managing patients followed on active surveillance. However, larger studies with longer follow-up are needed before we are ready to start using drugs like enzalutamide as part of routine clinical practice.”
Rebound PSA
Controversial podcaster Vinay Prasad MD MPH, is a hematologist-oncologist and Associate Professor in the Department of Epidemiology and Biostatistics at the University of California, San Francisco, came out with scathing criticism of ENACT at “Plenary Session,” a program at the intersection of medicine, oncology and health policy.
He said a concern with ENACT is that once patients leave a year of treatment, they are vulnerable to a PSA rebound: “Everyone has PSA progression right after that, and the curves actually cross because you’ve taken the brakes off the cart, and now it’s hurdling downhill. They call this rebound PSA. This is actually quite noteworthy.”
He said this problem has to be taken into account in future studies--”if you were crazy enough to design a future study in this space.”
Justification for drugs
The authors, including high-profile AS advocates, such as Matthew Cooperberg, MD, MPH, UCSF, in part justified ENACT because AS use was at such a low ebb when the study launched in 2016. Shore told me that he and other researchers were looking for alternatives to active surveillance.
“At the turn of the 21st century in this country, we were practicing a minuscule amount of active surveillance,” he said.
In 2010, when I was diagnosed, only 6-10% of men who were candidates opted for AS.
In 2016, when the ENACT trial began, only 32% of low-risk patients opted for AS, according to the American Urological Association’s AQUA database, which began monitoring the treatment of low-risk patients in 2014.
Researchers saw ARI research as a way to open a new door for these patients, some of whom avoid AS because they want to be treated and some of whom leave AS because of anxiety or because of disease progression as higher-grade Gleason scores are found.
Things have changed since ENACT launched: Now60% of U.S. patients opt for AS in 2021, a near doubling since 2016 as urologist and patient acceptance grew for the close monitoring strategy. (The U.S, still lags behind the 90%+ uptake in Sweden, Holland, and the state of Michigan.)
The idea is to avoid “active treatment,” including radical prostatectomy and radiation, which can have its own side effects, including impotence and incontinence.
Therapy with drugs would open another path for these patients. But one with serious toxicities.
Drug companies making a move on AS?
In 2018, I attended the meeting of the Prostate Cancer Research Institute in Los Angeles. I made the rounds in the exhibition area, where I met representatives of major drug companies. I had ha in hand asking for support for the newly organized Active Surveillance Patients International (ASPI).
There was none to be had.
I made the case that the companies should build bridges to the entire prostate cancer community, not just patients on their drugs. We knew that many AS patients—ASPI’s constituents—would be on active treatment in a few years and customers. Some potenially, if more aggressive cancers developed, would have metastatic disease and would be on their drugs.
Everyone was courteous. But they didn’t buy into my song and dance. They wished me luck and sent me on my way.
As ASbecame an ”overnight success,” in the ensuing years, pharmaceutical companies seemingly took an interest. Some companies sponsor AS webinars these days.
Patients on AS are starting to emerge as a market that caught the eye of pharma.
Are we a market?
The American Cancer Society estimates that nearly 270,000 American men will be diagnosed with prostate cancer in 2022, about 20,000 more than the previous year. More than half (55%) of these patients have low-risk to favorable intermediate-risk prostate cancer, making them eligible for AS.
Our ranks our growing by the tens of thousands a year--a potentially large market that didn’t exist a few short years ago.
Prasad said of enza: “I think the makers of the product might be crazy enough [to pursue this] because they smell a lot of cash. This is a huge market share, and they will make tons of cash, if they can get an approval here. Even if it doesn’t make a lick of sense at all, they’ll be able to persuade some doctors.”
He estimated that the annual wholesale cost for enza is $168,000.
He also noted it will cost a staggering $4.4 million dollars of enzalutamide to avoid one therapeutic progression. He said treatment to prevent “someone’s Gleason score from going a little bit higher and [preventing] some cores from being positive or having a few people have therapeutic progression. That is a very unpalatable dollar amount.”
The companies aren’t showing their hands.
Marjorie Moeling, a spokesperson for ASTELLAS [Northbrook, Illinois], which collaborated with Pfizer Oncology on ENACT, said: “There are currently no plans for additional research in this early stage of the disease, and there are no plans to submit this data to global regulatory authorities. We are committed to the ongoing clinical development of XTANDI, and we continue to evaluate its potential clinical benefit.”
Take that as you will.
There were rumors coming out of the June meeting of the American Society of Clinical Oncology that Nubeqa (dalutamide, Bayer Healthcare, Berlin, Germany), which has lower profile for adverse effects since it doesn’t cross the blood-brain barrier, will be tested on candidates for AS. The rumors can’t be confirmed. But sorta of talk reveal researchers’ state of mind about drugs for low-risk patients,
Could Nubeqa be the right drug at the right time to penetrate the “AS market”?
This ARI drug is already seen as a blockbuster. Bayer recently increased its peak sales estimate for darolutamide from $1.1 billion to $3.4 billion.
Doreen Schroeder, spokeswoman for Bayer said, “Bayer is not a sponsor of any study that investigates darolutamide in men with low or intermediate-risk localized prostate cancer. Bayer supports an independently conducted trial called “INTREPId” (ClinicalTrials.gov Identifier: NCT04025372), whose sponsor is the Dana-Farber Cancer Institute. This trial is conducted in men with intermediate-risk localized prostate cancer.”
Take that as you will.
Another angle for ARIs
There is another treatment angle that might make meds more palatable in these patients.
Pamela Munster, MD, a medical oncologist at the University of California, San Francisco, started Alessa Therapeutics, which has been developing Biolen, a silicon-based seed that releases medications directly into the prostate with the goal of avoiding systemic effects of ARI drugs.
(Pamela Munster, MD)
She said many men, often younger men or those with a strong family history of prostate cancer are torn between the choice of AS versus a prostatectomy or prostate radiation.
“The fact that there are still a lot of surgeries and radiation done on men with low-risk prostate cancer, suggests that both the patients and the doctors struggle with the uncertainty that a patient may progress and become metastatic,” she said. “We strive to offer an additional option that may have the benefits like the ENACT study but not its systemic side effects.”
She said the ENACT study of enzalutamide on lower-risk men is “crucial” and an important step in determining what the benefits and risks of ARI in early-stage prostate cancer are, and she commends the ENACT study group “for establishing this data in a well-controlled and randomized trial. The ENACT results also provide strong support that an ARI seed implant may provide benefits.
“What we’re trying to do is take the same exact approach but now only give the drug to the prostate so there are no drug effects elsewhere in the body,” she said.
She said she is conducting two proof of principle studies at the National Cancer Institute with implants of bicalutamide (Casodex, AstraZeneca, the British-Swedish company). Bicalutamide is a nonsteroidal antiandrogen, which blocks the effect of androgen (a male hormone), to stop the growth and spread of cancer cells.
Munster said: One is a window trial to see whether it affects PSA in high-risk men who are scheduled to undergo prostatectomies. A second study determines whether a bicalutamide implant could be used instead of systemic ADT in men undergoing radiation therapy.
She hopes to next study this approach with apalutamide, darolutamide, or enzalutamide.
Shore said: “The novel innovation of Dr. Munster’s strategy is that via a transperineal approach, similar to a transperineal biopsy, the urologist can implant ARI pellets that can affect local prostate cancer cells and avoid systemic absorption with the attendant toxicity seen with oral ARIs. Her drug delivery technology may also allow therapeutic effect for up to two years.”
I’ll give the last word to Bill Catalona.
“Before the development of these secondary oral ADT agents, for the 10-15 percent of patients with advanced prostate cancer, after surgical castration or LHRH agonists, the next step was chemotherapy or (faux) immunotherapy with Provenge.
“Certainly, the development of flutamide, bicalutamide, abiraterone/prednisone, enzalutamide, darolutamide, and apalutamide have provided a genuine secondary response for some patients, but usually, it has been of a relatively short duration and with little or no additional benefit from crossing over from one of these agents to another.
“Therefore, why wouldn’t pharma be interested in their application to not only the substantially increasing number of patients adopting AS but also the increasing number adopting focal therapy.
“However, to gain ‘on-label’ FDA approval (and reimbursement !) as well as physician and patient buy-in, level-1 evidence is required from prospective-randomized trials published by well-known authors in prestigious journals. Stay tuned.”
This just in….Sign up because your life may depend on this. Just maybe.
AnCan’s Virtual Support Group for Patients on Active Surveillance is holding a program, “Prostate Cancer Biopsies...The Great Debate,” on a hot topic for patients on Active Surveillance for Low-risk and Favorable Intermediate-Risk Prostate Cancer.
Which is better for patients? Like many things in medicine, it’s debatable.
The program will be 8-9:30 p.m. Eastern on August 29. Register here: https://attendee.gotowebinar.com/register/1375984251183869452
(I will be moderating and want a HUGE crowd. So please register while we have seats.)
The program is on transrectal vs. transperineal biopsies.
If you aren’t already into the pros and cons, read my article in Salon for background: https://www.salon.com/2021/08/11/a-common-biopsy-is-putting-lives-at-risk-its-time-to-retire-it_partner/
The European Association of Urologists last year selected the transperineal approach as the preferred one. The issue heated up in Europe when an otherwise healthy Norwegian man died following a biopsy. It was national news. Men in Norway voted with their prostates and feet. (https://howardwolinsky.medium.com/death-by-prostate-biopsy-5b5bb9c0bf5a)
European and Asian doctors are migrating to transperineal biopsies as a safety measure and also to try to avoid the use of powerful antibiotics that are resulting in drug-resistant microbes.
Many American doctors are standing by transrectal biopsies, which they feel can be as safe as transperineal biopsies and also cause less pain.
Read more here: https://howardwolinsky.medium.com/death-by-prostate-biopsy-5b5bb9c0bf5a
The American Urological Association will be coming out with guidelines on this in 2023. The AnCan debate will be a ramp-up to the AUA’s debate.
The debaters will be:
(Dr. Deborah Kaye)
Deborah Kaye, MD, Assistant Professor Duke UniversityDivision of Urology and Duke Clinical Research Institute Margolis Policy Center, will argue for transrectal biopsies
(Dr. Arvin George)
Arvin George, MD is a Urologic Surgeon specializing in the diagnosis and management of genitourinary cancers at University of Michigan Health, will argue for transperineal procedures.
Please submit questions in advance to moderator Joe Gallo at joeg@ancan.org
(Chicago area cartoonist and marketing executive Ira Lieb drew the cartoon.)
The Prostate Forum of Orange County is holding a webinar “Making Peace with Anxiety” (Perspectives from a cancer survivor) at 7:00-8:30 p.m. Pacific July 28.
Sarah Fenlon-Falk, LCSW, of Sarah Falk Coaching and Consulting, a therapist and cancer patient, will be speaking about how to identify stressors and soothers and rethinking anxiety so it won’t stop us.
Click on: https://us02web.zoom.us/j/85477749453
Join the ASPI program on diet: “Eat to Beat Prostate Cancer,” at 12-1:30 p.m. Eastern July 30, featuring Dr. William Li, a famed TED talker on diet and cancer.
Free Registration: www.aspatients.org or go direct to: https://bit.ly/3t5lFLx
Free prostate-healthy recipes for all registrants.
More info: info@aspatients.org; or DrDavidKingKeller@gmail.com
Join a ZERO webinar, Prostate Cancer and the Unique Needs of the LGBTQIA+ Community featuring Anne Katz, PhD, RN, FAAN, of CancerCare Manitoba, Winnipeg. It will July 27, 2022 at 06:30 PM Eastern.
Register here: https://us06web.zoom.us/webinar/register/WN_eUvLX0yNSAmRe5b-ST7zeg.
Thanks, Steve I think. Howard.
Not sure whether you are more angry given treatment accorded you in the beginning by some of America's best minds or me having read this edition of, "The Active Surveillor." The "feeling" left is desire to dismantle all PCa support groups founded and promoted by medical centers in this country convinced audience wants theater over substance, evening grooming writing skills over contemporaneous state and projected direction of hard science. You deserve a big smooch on the cheek from all of us, Howard, all at the same moment; what a photo!