Overturning Dogma -- Using Testosterone in Prostate Cancer

In Subset of Hypogonadal Men

Neil Osterweil

March 20, 2019

BARCELONA, Spain — Conventional wisdom got a swift kick in the pants from a study showing that testosterone replacement therapy (TRT) significantly improved outcomes for some men who underwent robot-assisted radical prostatectomy (RARP).

The finding comes from a study in 824 patients who underwent RARP for the primary treatment of prostate cancer. A subset of patients (n = 152, 18%) who had low preoperative levels of free testosterone were given TRT for postoperative recovery of sexual function.

As a surprise to the researchers, the results showed that this group of patients had significantly fewer biochemical recurrences within a year of surgery. Moreover, TRT use was associated with longer time to recurrence and delayed disease progression compared with standard management, reported Maxwell Towe, BS, a clinical research fellow at the University of California (UC), Irvine.

The findings are in direct contradiction to a dogma, dating to the 1940s, that states, "Thou shalt not give testosterone to men with prostate cancer."

The concern has been that testosterone will accelerate the growth of prostate cancer cells, and indeed, usual treatment aims to lower testosterone levels with "chemical castration" using androgen deprivation therapy.

"It's very hard to overturn guidelines and black box warnings on drugs, but I think this research is important for doing just that. We need to expand the growing body of evidence that testosterone replacement is safe and possibly beneficial for these patients," Towe said in an interview with Medscape Medical News.

Approached for comment, Francesco Montorsi, MD, director of the urology unit at San Raffaele Hospital in Milan, Italy, who was not involved in the study, said these new results "emphasize the importance of checking testosterone levels as a part of the management of patients with sexual disorders following radical prostatectomy.

"Obviously, selection of the right patients is vital, but if confirmed, this may have immediate benefits on quality of life," Montorsi told Medscape Medical News. "The possibility of reducing mortality would be an unexpected bonus."

The new data were presented here at the European Association of Urology (EAU) 2019 Congress.

In an interview conducted prior to the meeting, senior author Thomas Ahlering, MD, professor and vice chair of urology at UC Irvine, explained the rationale for the study to Medscape Medical News.

"The whole thing actually started because, of the men that I was seeing, enough of them were not having recovery of sexual function. I did the same operation — why were these guys not doing as well? That's what prompted me to start measuring total and free testosterone back in 2009 on everybody," he said.

Ahlering explained that free testosterone is the bioactive form of the hormone. He and his colleagues found that a low level of free testosterone is an independent risk factor for high-grade prostate cancer.

"We saw this really clear situation where, as the testosterone levels continued to drop, the grade — grade group in particular — started to go up, so the lower your testosterone, the more aggressive your cancer was," he said.

Hold the Testosterone?

Fears that giving testosterone to men with prostate cancer is like pouring gasoline on a raging fire date back to the work of Charles B. Huggins, MD, a pioneer of hormonal therapy for prostate cancer and co-winner of the 1941 Nobel Prize for physiology or medicine.

However, in recent years, Ahlering and his team, as well as other investigators, have found evidence to suggest that for some men, especially those who are hypogonadal at the time of surgery and who have low-risk disease, TRT may be both safe and beneficial, because it promotes muscle mass, improves lipid profiles, and increases libido and sexual performance.

"This seems to be a win-win," Ahlering said.

Study Details

The UC Irvine investigators followed 824 patients who underwent RARP as primary treatment of prostate cancer. For all patients, preoperative testosterone and sex hormone binding globulin levels were determined; free testosterone levels were calculated in a prospective fashion.

For nearly one fifth of these men (n = 152,18%), preoperative levels of free testosterone were low. These patients were placed on TRT to improve postoperative recovery of sexual function. Patients remained on TRT throughout follow-up or until the time of biochemical recurrence.

The patients who received TRT were proportionately matched to 419 control patients from the same study by pathologic Gleason grade group and stage.

After a median follow-up of 3.1 years, TRT was associated with a 53% relative reduction in risk for biochemical recurrence, which Ahlering acknowledged was "a big surprise."

In addition, in a secondary analysis of time to biochemical recurrence, TRT prolonged the time to recurrence by a median of 1.5 years (P = .005).

In a multivariate analysis that controlled for pathologic grade, stage, preoperative prostate-specific antigen (PSA) level, and free testosterone level, the investigators found that TRT was an independent predictor of reduced risk for biochemical recurrence (odds ratio, 0.54; P = .049).

"Our hope is to get this to a randomized clinical trial so that we can efficiently test this hypothesis that testosterone replacement therapy will help these men who have prostate cancer," Towe told Medscape Medical News.

In a separate study also presented at EAU 2019, Towe and colleagues reported that patients whose free testosterone levels were in the lowest quartile, ≤4.42 ng/dL, had a higher proportion of Gleason grade group 5 disease (15.6%) than patients in the highest quartile, ≥6.96 ng/dL (6.2%, P = .002).

In a multivariate analysis that adjusted for age and PSA level, lower free testosterone level was a significant predictor of a high-risk score (9–10).

A urologic surgeon who was not involved in the study said told Medscape Medical News that the findings echo those seen in his patients.

"We also observed that patients with hypogonadal status have worse cancer prognosis because they have high-grade cancers, and also prospectively we showed that patients who have worse prognosis have more biochemical recurrence," said Yann Neuzillet, MD, from the Hôpital Foch in Suresnes, France.

Neuzillet told Medscape Medical News that when his group planned a study of TRT similar to that of Ahlering's group, the monitoring committee objected on ethical grounds.

The study was internally funded. Towe, Ahlering, Neuzillet, and Montorsi have disclosed no relevant financial relationships.

European Association of Urology (EAU) 2019 Congress: Abstract 646. Presented March 17, 2019.


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