Despite level 1 evidence from the Prostate Cancer Prevention Trial (PCPT) and subsequent studies showing that 5-alpha reductase inhibitors (5-ARIs) can meaningfully reduce the risk of prostate cancer and disease progression in men on active surveillance, the drug class remains largely absent from contemporary treatment guidelines and clinical conversations, according to lan M. Thompson Jr., MD.
“5-ARIs reduce the risk of prostate cancer and reduce the risk of progression, specifically in men on active surveillance,” Thompson, a urologist at Christus Health in San Antonio, Texas, said in an interview with OncLive®.
In the interview, Thompson discussed the mechanism of action of 5-ARIs in prostate cancer, data from the PCPT,1 and the future of the agent class in prostate cancer management.
OncLive: What are 5-ARIs and what is their mechanism of action?
Thompson: There are two 5-ARIs available: finasteride [Proscar] and dutasteride [Avodart].2,3 Finasteride was made available first. It's a single, type II 5-ARI, whereas dutasteride is a dual type I and II inhibitor. From a practical, clinical standpoint, their effects are very similar, and they're probably interchangeable. Both were first used for the management of benign prostatic hyperplasia [BPH], for obstructive voiding symptoms, and were later registered with the FDA for the treatment of male pattern baldness.
These drugs inhibit the 5-alpha reductase enzyme, which converts testosterone to dihydrotestosterone [DHT]. DHT has a much greater affinity for the androgen receptor, so although testosterone levels go up a bit when you inhibit the enzyme, the impact on androgen receptor activation is profound. That leads to shrinkage of the prostate, probably because the epithelium involutes.
How did that mechanism first lead researchers to think about 5-ARIs as a potential prostate cancer treatment?
An interesting observation came up when we wrote the original PCPT. The evidence for a prevention effect was sparse at the time, but some of the more interesting data came from individuals born with modifications of the SRD5A2 gene, which encodes 5-alpha reductase. Individuals born with these modifications didn't develop BPH, and because DHT is required for masculinization of the external genitalia, they were phenotypically more akin to females.
Long-term observation found no BPH and no prostate cancer in this population. Given the involution of the prostatic epithelium, the concept emerged of whether 5-ARIs could be used to prevent prostate cancer.
What led to the launch of the PCPT?
This all happened as a confluence of events around the same time. The discovery of 5-ARIs occurred almost exactly when prostate-specific antigen [PSA] became available. If you look at cancer statistics, what jumps out is what happened to incidence rates, not death rates, when PSA became available: an enormous spike. As that spike was happening, finasteride specifically became available.
The Division of Cancer Prevention and Control convened an external advisory board that recognized where things were headed. If you look at autopsy data on older men, almost everybody has prostate cancer; PSA testing was going to find all these cancers. The real concern was that we were going to overwhelm the medical system with prostate cancer detection, so the decision was made to run a prevention trial.
That led to the rollout of the PCPT. I was the principal investigator of that study, and we randomly assigned men to finasteride or placebo. Because there were so many confounders around detection, we built a biopsy into the end of the study, which ended up revolutionizing how prostate cancer is managed.
What did the PCPT ultimately show, including that early signal around high-grade disease?
The short story is there was 24.8% [95% CI, 18.6%-30.6%; P < .001] reduction in the risk of prostate cancer [over a 7-year period].1 More high-grade cancer was detected in the finasteride arm, [and] it turned out that the increased detection of high-grade cancer occurred because a man on finasteride has a better opportunity for prostate cancer detection. A smaller prostate improves sampling on biopsy, improves the performance of the PSA test, and has a small positive impact on the performance of digital rectal examination. The study wasn't powered for mortality, but there were fewer prostate cancer[–related] deaths among men who had taken finasteride. That's the basis for a lot of this [research].
5-ARIs in Prostate Cancer: Key Takeaways
- In the Prostate Cancer Prevention Trial, finasteride reduced the risk of prostate cancer by 24.8% (95% CI, 18.6%-30.6%; P < .001) over 7 years.
- The benefit persisted through 18 to 20 years of follow-up, translating into fewer prostate cancer deaths, despite the trial not being powered for mortality.
- The benefit-risk calculus favors many surveillance candidates, but toxicities need discussion. 5-ARIs carry risks of sexual toxicity and gynecomastia that warrant patient counseling.
How does this connect to the evolution of active surveillance as a management strategy?
Some smaller studies then looked at what happened in men on active surveillance. When PSA testing first rolled out, virtually every man diagnosed with prostate cancer was treated. Then a few urologists recognized the risk of overtreatment.
We know that if 80% of men will have prostate cancer and 2% of men will die from it, there's a severe risk of overtreatment. It's no surprise now that active surveillance is standard of care for low-risk prostate cancer.
With PCPT data reported in 2003, what's driving your interest in revisiting this now?
I practiced urologic oncology for about 46 years, and as you [treat] patients with prostate cancer, what breaks your heart is a patient who dies from the disease; someone who presents with metastatic disease, or [someone] whose cancer is high-grade from the start, no matter what you do, still dies. The other thing that breaks your heart is complications, because we know the majority of patients treated for prostate cancer may not benefit from that treatment. That's very clear from the randomized trials: those patients are either treated for disease that was destined never to cause problems, or they're treated and still die from the disease.
We know that over half of men placed on active surveillance are ultimately treated, and that's when you see complications. Some of those complications can be catastrophic: radiation cystitis, for example. I've had patients this year who needed radical cystectomy for complications of radiation, along with patients left incontinent or with erectile dysfunction that completely changed their lives.
What are the safety concerns with 5-ARIs that should be discussed with patients?
There's a potential risk of sexual toxicity, [including] decreased libido and erectile difficulty. That risk is small but clearly present; for some it happens right away, and in clinical practice you never really know for certain whether it's attributable to the drug. There's a clear potential impact on sexual function, and 5-ARIs reduce ejaculate volume because the prostate shrinks.
There's also a small risk of gynecomastia, because blocking the conversion of testosterone to DHT raises testosterone levels, and testosterone is partly metabolized to estrogen, so estrogen levels rise too, with a small effect on breast tissue that can be substantial in some individuals. Gynecomastia is a fairly common condition in aging men generally, which is reflected in our PCPT data. There's a meaningful background rate of gynecomastia even on placebo, with somewhat more in men on finasteride, but the absolute risk isn't very high.
What benefits may 5-ARIs offer beyond the cancer-related effects?
