Pam Harrison

October 22, 2015

The addition of long-term peripheral androgen blockade during and after salvage radiation therapy in men whose prostate cancer recurs following radical prostatectomy improves overall survival compared with salvage radiation therapy alone, show long-term results from the RTOG 9601 trial.

At 12 years, the rate of death from prostate cancer in the group receiving androgen blockade was 2.5% vs 7.5% in those not receiving such therapy. The number need to treat to prevent one death from prostate cancer was 17, said lead investigator William Shipley, MD, professor of radiation oncology, Massachusetts General Hospital and the Harvard Medical School, Boston.

The study was presented here at the American Society for Radiation Oncology (ASTRO) 57th Annual Meeting.

"Over the last 25 years, many men with intermediate-risk prostate cancer have undergone radical prostatectomy, yet many will face recurrence in 1 to 4 years, with a rising PSA [prostate- specific antigen]," Dr Shipley said in a statement.

"Our results show that salvage radiation therapy plus androgen blockade, when compared to radiation therapy plus placebo, improved long-term overall survival and reduced death from prostate cancer without adding significantly to radiation toxicity," he said.

In this study, which began in 1998, androgen blockade was achieved with bicalutamide (Casodex, AstraZeneca Pharmaceuticals LP), which is not commonly used now because the current standard is to use androgen deprivation therapy with drugs that act as luteinizing hormone–releasing hormone agonists and antagonists, such as leuprolide (multiple brands), goserelin (Zoladex, AstraZeneca Pharmaceuticals LP), triptorelin (Trelstar, Actavis Group), and histrelin (multiple brands).

But the survival benefit seen in this trial with bicalutamide is likely to be similar to that seen with androgen deprivation therapy, commented study discussant Alan Pollack, MD, PhD, University of Miami, Florida.

Study Details

The NRG Oncology/RTOG 9601 study was a phase 3 study conducted in 761 men with prostate cancer (two thirds had pT3pNO disease, and one third had pT2pNO disease) who had either positive margins or whose PSA level was elevated by 0.2 to 4.0 ng/mL following radical prostatectomy.

Patients were randomly assigned to receive radiation therapy at a dose of 64.8 GY delivered in 36 fractions of 1.8 Gy each plus either peripheral androgen blockade with bicalutamide, 150 mg a day, for an additional 24 months or to the same dose of radiation therapy plus placebo.

Following radical prostatectomy, for almost all patients, the nadir PSA level <0.5 ng/mL.

For most patients, after biochemical recurrence, entry PSA value was <1.6 ng/mL; for about 15%, the entry PSA value was 1.6 to 4 ng/mL.

At 10 years, 82% of patients who had received the additional long-term peripheral androgen blockade were still alive, compared with 78% for patients who received salvage radiation therapy alone (P = .036).

At 12 years, the incidence of prostate cancer–specific mortality was 2.3% for the salvage radiation plus bicalutamide group compared with 7.5% for the group receiving salvage radiation alone; 14% of the bicalutamide group had developed distant metastases, compared with 23% of the group receiving radiation alone (for both comparisons, P < .001).

Rates of both gastrointestinal and genitourinary toxicities were low and were similar in the two treatment groups.

On the other hand, 70% of men in the peripheral androgen blockade arm developed gynecomastia, Dr Shipley noted.

"We think this is an important study in men we were able to salvage with radiation therapy, and it gave us the anticipated result, because we knew that hormonal therapy plus radiation therapy was beneficial in other settings," Dr Shipley said in a press briefing.

"And it's also becoming increasingly clear from several other studies, one of which will probably be our own, that you have more success if you radiate the patient before the PSA has a chance to rise much at all — so as low as 0.2 or 0.3 ng/ml — and that makes it even more important to see whether patients [with very low PSA values] are the ones who will benefit from 2 years of peripheral androgen blockade or other forms of androgen deprivation or whether they don't need it at all," he added.

Quality of Life

In his discussion of the study, Dr Pollack said: "These results fill a knowledge gap in men treated for salvage, and results parallel those seen in men treated with androgen deprivation therapy for primary prostate cancer."

He pointed out that there was clearly a difference between the two treatment arms in favor of the arm in which men were given peripheral androgen blockade for 2 years.

"This would also have an impact on patients' quality of life," Dr Pollack suggested.

Although quality of life was not specifically addressed when the trial was initiated in 1998, freedom from disease progression, as reflected by the decreased risk for both prostate-specific mortality and distant metastases, could be fully expected to improve quality of life for men in the additional bicalutamide arm.

True, the majority of men in that arm did develop gynecomastia, Dr Pollack observed.

However, Dr Shipley noted that if this had not been a randomized trial, radiation oncologists could have attenuated painful swelling of the breasts by delivering several days of very-low-dose radiation to the breast prior to initiation of anti‒male hormone therapy to prevent the breast from responding to androgen blockade.

"Bicalutamide is similar to orchidectomy — it reduces bone loss and increases libido and sexual function, although gynecomastia is common," Dr Pollack said.

The RTOG 9601 trial was supported by the National Cancer Institute and AstraZeneca (the manufacturer of bicalutamide). Dr Pollack serves on the advisory board of Medivation.

American Society for Radiation Oncology (ASTRO) 57th Annual Meeting: Abstract LBA5. Presented October 19, 2015.


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