Revolutionizing the Standard of Care for Men on Hormone Therapy
PCF-funded research changed the landscape of survivorship.
Hormone therapy has been a cornerstone of treatment for prostate cancer for decades, extending the lives of patients who previously had no options or hope. But 25 years ago, the situation was very different: the complications of hormone therapy were not well understood. The field of prostate cancer survivorship – with the goal of improving patients’ quality of life, in addition to the quantity – didn’t exist. At the time, the Prostate Cancer Foundation (PCF), too, focused on cancer survival, supporting desperately needed research at a time when the prognosis for men with advanced prostate cancer was bleak compared to today.
But PCF has always been in the vanguard, helping researchers with innovative, even outside-the-box, ideas get the initial support they need to pursue them. It takes seed money to prove the merits of a good idea that could help patients. It takes funding to do the research to identify the need and to find a target of drug development.
One noteworthy example of how this vision is put into practice is Harvard physician-scientist Matthew Smith, M.D., Ph.D. Today, he is a world-class expert in prostate cancer survivorship – particularly, in identifying, studying and treating the adverse effects of hormone therapy (also known as androgen deprivation therapy, or ADT). But in 1998, 25 years ago, he was a young researcher who took a chance applying for research funding, and PCF took a chance on him. Were they both right? Had Smith identified problems at his patients’ bedside that could be helped by a new area of research? For PCF’s part, did Smith have the right stuff? Was he asking the right questions, and did he have the acumen to pursue them? The answer to all these questions turned out to be yes.
The New Field of Survivorship
Howard Soule, Ph.D., PCF’s Executive Vice President and Chief Science Officer, first met Smith in 1998, when he was an oncology fellow at Dana Farber. Smith’s mentor, oncologist Philip Kantoff, M.D., introduced them.
“The three of us sat down and talked,” recalls Soule. “Matthew was on his way to treat a prostate cancer patient with one of the really early bisphosphonates [a medicine to help strengthen bones], just before the man was going to get his first dose of Lupron.® He had this hypothesis that medical castration caused bone fractures, and he set out to prove it.” That initial visit, he adds, “was really the first time I had ever thought about cancer survivorship. Survivorship measures quality of life, not just quantity.”
PCF (itself a young foundation then, only five years old) awarded Smith a grant for a clinical trial he designed: to study the effects of ADT on bone density, and to see whether a drug called pamidronate, a bisphosphonate (used to treat osteoporosis in women), could help prevent treatment-related fractures in men.
Sounds like a reasonable thing to study, right? In fact, it was risky, Smith recalls. “At the time, I was the early investigator studying issues that might be described as unpopular, looking at side effects of the most important class of drug used to treat metastatic prostate cancer. PCF took a chance and funded my work when other funding agencies were unwilling to do so. They were forward-thinking in that they were willing to support this sort of high-risk, high-reward research – and that’s the outstanding judgment of PCF, of Howard Soule, in particular. It’s that kind of deep appreciation of what matters to patients with the disease, and the willingness to support work that’s high-risk.”
What is this talk of high-risk? What could possibly be high-risk about studying the effects of ADT on bones? “At the time,” says Smith, “there were so many naysayers. People said, ‘This isn’t important. Men don’t get fractures.’ ” Osteoporosis was viewed as something that only happened to post-menopausal women. “There was a kind of resistance” in the medical establishment. “It was almost like people didn’t want to believe it. There was a naïve view that, other than causing sexual side effects and some hot flashes, ADT wasn’t really hurting anybody.”
But Smith’s work not only helped disprove this; it led to new guidelines for men on ADT. “It was that crucial support from PCF that helped launch my career and, in fact, really helped establish this entire area of survivorship in prostate cancer,” he says, “particularly as it relates to side effects of ADT – not just bone loss and fractures, but metabolic changes and effects on body composition. “Now, it’s just sort of accepted as a routine part of the field and is included in national and international guidelines, but this was all new at the time.”
Bold Steps Towards New Therapies and Research
After that first PCF-funded clinical trial, Soule convened a meeting, with Smith, in Massachusetts: “We brought together academic bone experts, endocrinologists, and oncologists, and people from industry who were developing drugs. We put on a full-court press on survivorship and bone health,” says Soule, “and it set the field on fire!” After this meeting, the pharmaceutical company Novartis conducted a large, randomized trial for zoledronic acid (Zometa®). “If you look at the Zometa® label,” says Soule, “its intended use is for prostate cancer in bone, and other malignancies in bone. We were the first to the table.”
The meeting also proved a landmark for PCF, says Soule. “It was really what opened up the era of prostate cancer survivorship research, which we have funded a lot:” studies by investigators including Charles Ryan, M.D., and Alicia Morgans, M.D., M.P.H. on ADT and cognitive changes; Nancy Keating, M.D., on ADT and cardiovascular disease; and Christina Dieli-Conwright, Ph.D., on preventing loss of lean muscle mass in men on ADT. The effects of ADT on bone, Soule adds, turned out to be “just one tip of one iceberg.”
Landmark Publication Leads to Changes in Practice Guidelines
Smith’s next PCF grant was to characterize the mechanism of bone loss during ADT and to develop strategies to prevent treatment-related osteoporosis. This work led to a landmark 2001 paper in the prestigious New England Journal of Medicine, reporting that ADT (with leuprolide) “decreases bone mineral density and increases the risk of fracture in men with prostate cancer,” and that “pamidronate prevents bone loss in the hip and lumbar spine in men receiving treatment for prostate cancer” with leuprolide. Smith’s hypothesis was correct: ADT does weaken bones, and treatment with pamidronate can help. This research also led to a significant career development award from the NIH, which helped Smith develop as an independent clinical investigator.
It was Smith’s identification of osteoporosis and fractures as adverse effects of ADT that led the National Comprehensive Cancer Network (NCCN), in its 2009 Practice Guidelines for Prostate Cancer, to recommend screening for osteoporosis as a standard of care for men on ADT. His findings also resulted in global randomized controlled trials to prevent treatment-related fractures in men with prostate cancer.
Smith’s PCF-supported work changed the NCCN Practice Guidelines again in 2010, after his research group demonstrated that ADT “increases fat mass, decreases insulin sensitivity, increases serum lipoproteins, and is associated with greater risk for diabetes and coronary heart disease.” In other words, ADT causes weight gain, problems with blood sugar, higher cholesterol, and increases risk for chronic diseases.
Again, looking at this now, it seems like common knowledge. But at the time, this information was something of a revelation for doctors. “These observations shed light on previously unrecognized harms,” says Smith, and they changed clinical decisions about timing and duration of ADT. “It really was a whole sea change in the field in terms of recognition of these issues. It wasn’t that the problems didn’t exist,” but that doctors didn’t make the connection to ADT.
Another reason the changes that happen on ADT went unrecognized was that “the side effects almost completely overlap what is perceived as a normal result of aging,” says Smith. “And so, older men who were on ADT and said to their doctors, ‘I’m fatigued,’ or ‘I’m not as strong as I used to be,’ the doctors would think it was just because they were getting older, or blame the cancer itself.”
With Patients Living Longer, Quality of Life is Paramount
The legacy of Smith’s work is that all drugs being developed to treat advanced prostate cancer are now studied for their effects on bone density, muscle loss, and metabolism. “Subsequent improvements in the field have led to extended survival, including the development of androgen receptor (AR) pathway inhibitors (drugs such as enzalutamide),” says Smith. “And guess what? While the AR pathway inhibitors are very important drugs, there’s pretty consistent data showing that most of them increase the risk for falls and fractures and probably worsen the metabolic side effects of ADT. So while they’re helping men live longer and preventing men from dying of prostate cancer, there are more side effects of treatment.” Developing strategies to help men on long-term hormonal therapy to have a better quality of life while on these drugs is a major focus of the field of survivorship in prostate cancer.
In 2010, the FDA notified manufacturers of ADT medications such as leuprolide that they needed to add new safety information to the “Warnings and Precautions” section of the drug labels. “This information warned about increased risk of diabetes and certain cardiovascular diseases (heart attack, sudden cardiac death, stroke) in men receiving these medications for the treatment of prostate cancer. “ The FDA based this decision on a review of seven published studies; three of them were published by Smith and his research group.
Smith led the pivotal clinical trial that was the basis for the European Commission’s 2010 decision to grant marketing authorization for denosumab for the treatment of bone loss associated with ADT in men with prostate cancer at increased risk of fractures, and in 2011, the results of a PCF-supported clinical trial led by Smith led to FDA approval of denosumab (Prolia™) in the U.S.
In other work, Smith and colleagues showed that the effects of ADT happen fairly quickly – again, something doctors didn’t realize. “It turns out that bone changes are detectable within a few months. When we first started studying insulin resistance with ADT, we thought, ‘Well, men gain weight, they increase their abdominal fat, and then over time they become insulin resistant.’ But that’s not what happens. You give ADT and within 12 weeks, you can see the changes in insulin sensitivity. It’s a very rapid effect.”
Inspired by One Patient; Helping Millions
It was a patient who inspired Smith to look into other side effects of ADT. “Over time, he came back and said, ‘One of my favorite things to do is to garden, and I can’t carry a bag of mulch from my driveway to the backyard anymore. I used to be able to do that easily, before I started treatment.’ It’s just one of those very tangible things: what does it mean to lose strength? That moved us, when we were looking at bone loss, to look at changes in muscle size and strength, as well. It was a really meaningful change for him.” Smith has gone on to publish dozens of prestigious papers and to receive many grants over the years, from PCF and elsewhere. He has made many other major contributions to the field, including designing the trials that have led to approval of other new AR-blocking drugs, including apalutamide and darolutamide. His research has made life significantly better for millions of men by drawing awareness to, and developing strategies to help prevent, treatment-related problems such as bone fractures, insulin resistance, loss of strength and muscle mass. As Smith says: “Recognizing these burdens ultimately paves the way toward finding solutions.”
