High-dose androgens may ‘rewrite the textbooks’ on prostate cancer treatment
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One journal reviewer told Donald P. McDonnell, PhD, the research should be “banned from the literature.”
A different reader told him, “This is going to rewrite the textbooks.”
McDonnell — Glaxo-Wellcome distinguished professor of molecular cancer biology at Duke University School of Medicine — said he understands the passionate but polar-opposite opinions about his team’s most recent work.
In a paper published in September in Nature Communications, McDonnell said he and his colleagues have detailed, mechanistically, how high-dose androgens could prevent prostate cancer progression.
This finding contradicts decades of practice and clinical trials that have demonstrated androgen inhibition successfully treats the disease.
McDonnell is convinced prostate cancer’s “paradoxical response” to androgens could open new therapeutic possibilities.
“Somebody wrote to me and said, ‘This can’t be right,’” McDonnell said. “I wrote back and said, ‘I appreciate your comments, but we thought the world was flat for 4 million years, and we know how that turned out.’ I thought I’d won that argument, but then he wrote back and said, ‘Yeah, but they put Galileo under house arrest for the rest of his life.’”
‘Forgot about the excess part’
In the 1940s, surgeon and urologist Charles B. Huggins, MD, discovered removing the testicles could treat prostate cancer. Hormone treatment later became standard of care, and Huggins won a Nobel Prize in 1966 for his findings.
He made an interesting statement in his acceptance speech.
“He actually said there’s two ways you can treat these hormone cancers — one is to block the hormone, and the other is to give an excess,” Samuel R. Denmeade, MD, R. Dale Hughes professor of oncology and urology at Johns Hopkins University School of Medicine, and director of Johns Hopkins Kimmel Cancer Center’s genitourinary oncology division, told Healio. “Well, the pharmaceutical companies and everybody went crazy with the blocking part, but we forgot about the excess part.”
Surgery and radiation are traditional first-line treatment options for early-stage prostate cancer. Some men who receive radiation also get hormonal ablation, Denmeade said.
Androgen-deprivation therapy is the primary approach for individuals with metastatic or recurrent disease.
“At that point it’s dual androgen ablation,” Denmeade said. “You get something that turns off your testicles, and you get a peripheral kind of blocking.”
There are four androgen receptor signaling inhibitors available: abiraterone (Zytiga, Janssen) enzalutamide (Xtandi; Astellas Pharma, Pfizer), apalutamide (Erleada, Janssen) and darolutamide (Nubeqa, Bayer).
Androgen deprivation therapy can produce “deep and long-lasting” response, Andrea Miyahira, PhD — senior director of Global Research and Scientific Communications at Prostate Cancer Foundation, which funded previous and current research by Denmeade and his team — told Healio.
However, “it’s not curative” because the treatment may not remove androgens completely, allowing the cancer to adapt and proliferate with low levels of androgens still in the body.
“There’s several different resistance mechanisms,” Miyahira said.
She cited neuroendocrine prostate cancer — which can affect anywhere from 17% to 30% of patients who have developed resistance to androgen receptor signaling inhibitors — as one example.
“The cells stop having prostate-cell features, and they gain these neuroendocrine features,” Miyahira said. “They no longer rely on the androgen receptor to stay alive. They now rely on other pathways that would keep a neuroendocrine cell alive.
“The most common resistance mechanism to these therapies, though, is mutations that amplify the androgen receptor gene itself, or other types of mutations that amplify the activity of the pathway,” she added. “The androgen receptor is still the primary driver of primary prostate cancer and, in most patients, it is still the driver of resistance.”
Ongoing androgen ablation research is investigating combining androgen receptor signaling inhibitors and moving them into earlier settings, which could extend survival.
Ongoing trials also are investigating androgen receptor degraders, Miyahira said.
However, androgen ablation can cause quality-of-life problems for men, too, Miyahira said. These effects can include hot flashes, decreased sexual desire, loss of bone density and increased fracture risk, erectile dysfunction, fatigue, increased risk of diabetes, stroke and heart attacks, weight gain, decreased muscle mass, anemia, mood changes and memory loss.
“We’re at the limit, I think, of what we can accomplish with androgen ablation therapies,” McDonnell said.
‘Holy Grail’ is c-MYC inhibition
McDonnell began his research into high-dose hormones approximately a decade ago, after an andrologist asked him why testosterone affects maturing boys differently depending on the amount in their system.
McDonnell mentioned the question to a trainee, who said researchers evaluating prostate cancer had a similar query.
“If we look at all the animal and cellular models of prostate cancer, what we find is that low doses of androgens drive the prostate cancer — that wasn’t a surprise,” McDonnell said. “But as you increase the levels of androgens, you get a paradoxical response. It doesn't drive the proliferation further. It inhibits the proliferation. It inhibits the tumor growth.
“And now we’re back to the same question: How is it that prostate cancer itself can recognize and respond differently to different doses of hormone?” McDonnell added. “Is it possible, then, that this paradoxical response could be exploited to develop a new therapeutic?”
The “Holy Grail” for prostate cancer researchers is an inhibitor of the c-MYC gene, the primary driver of the disease, McDonnell and Denmeade said.
McDonnell and colleagues discovered in models that high-dose androgens block production of c-MYC.
“Even the most contemporary androgen ablation therapies don’t touch MYC,” McDonnell said. “Why do they work? It’s like a three-legged stool. Androgen ablation therapies kick one of the legs out but, ultimately, what you’re trying to do is get rid of the stool altogether. You can [slow] the growth of a tumor by many ways, by taking away a lot of its needs. MYC wipes the floor. It takes the legs out from under it.”
High-dose androgens in practice
Denmeade was not involved with the research McDonnell and colleagues published in Nature Communications. However, he and fellow investigators have conducted multiple trials involving high-dose androgens and prostate cancer.
Results of the randomized TRANSFORMER trial — published in 2021 in Journal of Clinical Oncology — showed patients who received high-dose androgens had similar response and PFS as those who received androgen ablation with enzalutamide.
The more “interesting” finding came when trial participants crossed over from one therapy to the other, Denmeade said.
Participants who went from high-dose androgens to enzalutamide had a 77.8% response rate, compared with 23.4% for the other group. PFS improved, too (median, 28.2 months vs. 19.6 months; HR = 0.44; 95% CI, 0.22-0.88).
“It looked like we were kind of resetting the cancer,” Denmeade said. “We think the key to this idea with TRANSFORMER is not so much the testosterone alone, but it’s the sequencing. It’s shocking the cancer from one extreme to the next.”
In the BATMAN trial — results of which appeared in The Prostate in 2022 — participants received 6 months of androgen deprivation. They then received alternating 3-month regimens of high-dose androgens and androgen deprivation.
“We guessed about 40% would still be sensitive to hormone therapy at a year and a half, and we were going to declare victory if we hit 60%,” Denmeade said. “At the end of the day, we hit about 70%.”
In the ongoing randomized STEP-UP study, men with prostate cancer whose disease progressed after androgen ablation will either continue to receive enzalutamide or get high-dose testosterone, then enzalutamide, and then continue to cycle between the therapies.
Results are not yet available.
“One of the things we’re trying to do is to keep men in kind of a hormone treatment phase, so we can avoid some of those more toxic treatments or push them down the road,” Denmeade said. “That’s what we think we were able to achieve in the TRANSFORMER trials. Men had this year or more response that was better than we would have expected with another hormone.”
Denmeade said patients’ energy levels could fluctuate between treatments, but most did not have “big emotional swings.” In fact, most participants preferred the high-dose therapy.
“They feel like doing more things,” Denmeade said. “They get out of the house more [or] they want to go back to the gym. Some men, over time, feel like they have more muscle strength [or] more endurance. Probably the biggest thing that they notice that comes and goes is their libido. They have strong libido, and then it’s gone. Many times, they get their desire back but they can’t have erections. That’s a little bit frustrating for them. We counsel them that that might happen.”
Denmeade emphasized though that androgen ablation is still an “amazing” treatment.
“Androgen ablation is probably the best single treatment for any cancer,” Denmeade said. “People respond sometimes for 10 years.”
Future of high-dose androgens
McDonnell recently received a call from a researcher who tried to reproduce his study and came up with the same results.
“I said, ‘It looks like you photocopied the figures out of our paper,’” McDonnell said. “It was beautiful. That’s gorgeous. That’s nearly the best comment I got.”
McDonnell said he believes high-dose androgens will be a more mainstream therapy within 5 years.
“I think we will be either starting or already started trials in early-stage disease, and you’re going to see one or more pharmaceutical companies coming up with drugs that exploit this mechanism,” he said.
Denmeade, though optimistic about the future of high-dose treatments, is not convinced it can be used as a first-line treatment alone.
“Our worry is at the very beginning, when the [cells] haven’t adapted yet and you give testosterone, you might actually make them grow better,” he said. “Again, we haven’t done the study to prove that or disprove that.
“[The mechanism outlined by McDonnell and colleagues] would suggest it could work, but that’s the one thing with the paper that I struggle with,” Denmeade added. “It seems like the cancer cells would have this biphasic thing where, initially, patients are kind of stimulated by testosterone and blocked by anti-testosterone. But then, at some point, there’s like a switch, and it goes the other way. Now, they're stimulated by anti-testosterone and blocked by testosterone. What happens at that switch? I don't know.”
“The dance” the cells do when alternating high-dose treatments and ablation could be the key instead, Denmeade said.
More research is necessary for both approaches — particularly for high-dose androgens, Miyahira said.
“It’s not surprising to see another study showing an entirely new function for the androgen receptor,” she said. “It’s cool to see new hypotheses coming out, but we need more studies to confirm these findings.”
Treating men with androgen receptor-targeted therapies creates its own challenges, Miyahira said.
“Once you start treating patients with androgen receptor-targeted therapies, you just start collecting androgen receptor alterations,” Miyahira said. “By the time you end up with late-stage disease, the majority of patients have all kinds of different androgen receptor mutations. Understanding how androgen receptors are functioning in these different contexts under different conditions — for instance, the level that you can knock down androgen receptor activity using current standard-of-care therapies in primary cancer vs. late-stage cancer, refining how androgen receptor is working in all these different contexts — will really help us to know how best to target it.”
More studies of MYC inhibition and targeting PSMA, another prostate cancer biomarker, could push the field ahead further.
“I’m hoping in 5 years somebody who’s working on the immune system will figure [it] out, and we’ll joke that we used to castrate men with prostate cancer,” Denmeade added. “Failing that, our idea is that the cancer starts out under hormonal control. Over time, with the way we treat it right now, we lose that, and the patients eventually die. I think that in 5 years, if we figure this out the right way, we might be able to just keep a [man] under hormonal control. We will have periods of high testosterone and low testosterone. and we’ll just be able to do that their whole life.”
References:
- Denmeade S, et al. Prostate. 2022;doi:10.1002/pros.24426.
- Denmeade SR, et al. J Clin Oncol. 2021;doi:10.1200/JCO.20.02759.
- Hara M, et al. Urol Case Rep. 2022;doi:10.1016/j.eucr.2022.102158.
- Safi R, et al. Nat Commun. 2024;doi:10.1038/s41467-024-52032-y.
For more information:
Samuel R. Denmeade, MD, can be reached at denmesa@jhmi.edu.
Donald P. McDonnell, PhD, can be reached at donald.mcdonnell@duke.edu.
Andrea Miyahira, PhD, can be reached at amiyahira@pcf.org.
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