Latest Evidence Guides Use of ADT with RT in Prostate Cancer

Mack Roach III, MD

Practice-changing trends in the combined use of androgen deprivation therapy (ADT) and radiation therapy (RT) for the treatment of prostate cancer were highlighted recently in a review paper by Mack Roach III, MD, a professor of Radiation Oncology and Urology and chair of the Department of Radiation Oncology at the University of California, San Francisco.

Roach, who is also a member of the National Cancer Advisory Board, focused the paper on how best to use ADT in conjunction with RT in certain patients with localized or locally advanced prostate cancer. He emphasized the importance of using both strategies in order to get the best results for these patients, and highlighted data on a newer ADT drug, degarelix (Firmagon), that can be administered in this population.

The article, titled “Current Trends for the Use of Androgen Deprivation Therapy in Conjunction With Radiotherapy for Patients With Unfavorable Intermediate-Risk, High-Risk, Localized, and Locally Advanced Prostate Cancer,”¹ appeared in the journal Cancer in June.

“A number of new findings had come out that could change the way people practice medicine,” he said. “Talking about who should get hormonal therapy and for how long was an opportunity to make that sort of information readily available. At the same time, a lot of people were not familiar with the antagonists like degarelix, which give a more rapid response to castration.”

In a conversation with Urologists in Cancer Care (UCC), Roach summarized the messages at the heart of the paper.

UCC: Why was this the right time to review practices involving the administration of ADT before, during, and/or after RT for men with unfavorable intermediate-risk, high-risk, localized, and locally advanced prostate cancer? What recent findings did you want urologists to consider?

Roach: First, there was a recent study, RTOG 9910,² presented at a national meeting by Tom Pisansky from the Mayo Clinic. The trial looked at neoadjuvant hormonal therapy either 8 weeks or 28 weeks before radiation. That is a landmark study, because there was already level 1 evidence suggesting that men with intermediate-risk prostate cancer live longer if they receive short-term hormonal therapy, but it was unclear what the optimal duration of hormonal therapy should be. This study demonstrated that these men need hormonal therapy for only 4 months. This is a big change, because it had become a standard of care, in many people’s opinions, to give 6 months of hormonal therapy. Of course, there’s an impact on quality of life for a man to be castrated medically for an additional 2 months beyond what he needs.

A related topic is that we published a paper³ evaluating PSA outcomes in the trial RTOG 94-13, a phase III randomized study of about 1300 patients. One thing we had built into the RTOG 94-13 study design as a secondary endpoint was how low PSA [prostate-specific antigen] went after 4 months of hormonal therapy, and whether that had prognostic significance. And we showed that a man’s PSA level at the period of 4 months was somewhat predictive. If it failed to go below a certain level, a man’s outcome was worse, and you could use that as an early predictor of which patients might need more aggressive treatment.

Building on that finding, I wanted people to be aware that you can use a GnRH antagonist, as opposed to an agonist, to get a more rapid response to hormonal therapy, and that you could then use this potentially lower PSA as a predictor of long-term outcome for your patient.

We also updated the fact that there was a lot of confusion about morbidity associated with hormonal therapy. There had been an idea that survival was being compromised in men taking hormonal therapy, but a meta-analysis has suggested that was overrated.⁴ That was important, because there were patients who were declining to take hormonal therapy because they were afraid they were going to die of a heart attack, when really they would benefit from the treatment with the hormonal therapy and the risk of heart problems was not a real concern. Finally, there are data on using hormonal therapy in the setting of recurrent disease, and I just wanted to update people on preliminary results suggesting that you still need to combine hormonal therapy and radiation, because both together are better than either alone.

In the paper, you gave an overview of current treatment options for men in this population. Please summarize those options.

Basically, for a low-risk patient, we don’t recommend hormonal therapy at all, but rather monotherapy either with active surveillance, surgery alone, or radiation alone. For intermediate- risk prostate cancer, we recommend short-term hormonal therapy with radiation, if the patient is going to have radiation. For high-risk disease, we recommend long-term hormonal therapy if the patient is going to be treated with radiotherapy.

The paper looks in-depth at evidence for how best to sequence or combine ADT with RT, and for how long. What is the bottom line?

Years ago, there were concerns that maybe hormonal therapy was sufficient and we didn’t need the radiation. Since then, two large studies in patients with prostate cancer, randomized between hormonal therapy alone or hormonal therapy plus radiation, both showed that adding radiation improves survival, and established that as the standard of care.^5,6 Before that, there were studies with radiation alone versus radiation and hormonal therapy that suggested that radiation alone was not as good as radiation plus hormonal therapy.

What urologists should know is that we have level 1 evidence in people with intermediate- to high-risk prostate cancer— especially in high-risk disease—that hormonal therapy plus radiation is better than either alone, and is the optimal treatment. In some ways, this argues strongly for radiation having a role in prostate cancer, because many of these highrisk men would not be candidates for radical prostatectomy.

Even in men over the age of 65 years with advanced disease, adding radiation to hormonal therapy prolongs survival over hormonal therapy alone.

You mentioned GnRH antagonists, including degarelix, a newer drug class in the hormonal therapy arena with a different mechanism of action than LHRH agonists. What are the takeaway points about this treatment strategy?

Until recently, LHRH agonists were the only nonsurgical option, but they induce pituitary overstimulation, producing an initial surge in testosterone for 1 to 2 weeks, which delays castration. GnRH antagonists produce faster testosterone suppression without a surge, mini-surges, or clinical flare and lower PSA more quickly; the most extensively studied is degarelix.

Some men will have worsening urinary symptoms, like urgency and frequency, if they experience a surge in testosterone, and there are patients who have a more rapid resolution of their urinary symptoms on degarelix compared with conventional hormonal therapies.

In addition, there are a couple of theories about other benefits that a drug like degarelix might offer.

One is that a GnRH antagonist could be beneficial for people with metastatic disease by allowing them to avoid a testosterone surge, since that could potentially worsen their metastasis. In addition, if PSA reaches a lower level at 4 months on a GnRH antagonist than it would have on an LHRH agonist—and if that PSA level has prognostic significance—that might ultimately be associated with a better outcome.

The only real downside to a drug like degarelix is a worse local injection-site reaction, with swelling, soreness, and tenderness, but that tends to be only on first injection.

You have left your readers with four open questions about the combination of ADT and RT. Please discuss these unresolved issues that you believe should be addressed in future research.

In offering men with prostate cancer the best possible outcomes and an optimal level of physical comfort, there are factors we’ll need to better understand.

First, we’d like to know whether anti-androgens can be omitted when patients are managed with a GnRH antagonist, rather than with an LHRH agonist.

Second, it seems there may be a therapeutic benefit to the suppression of FSH—which occurs when patients take a GnRH antagonist—in addition to the benefit of testosterone suppression associated with these drugs. We’d like to know if FSH suppression provides an additional health benefit to men with prostate cancer.

We also must determine the optimal duration of long-term ADT for patients with unfavorable intermediate-risk and high-risk disease when it is used with radiation therapy.

Finally, should neoadjuvant hormonal therapy be added in men undergoing adjuvant or salvage radiotherapy after a radical prostatectomy?

References

1. Roach M III. Current trends for the use of androgen deprivation therapy in conjunction with radiotherapy for patients with unfavorable intermediate-risk, high-risk, localized, and locally advanced prostate cancer. Cancer. 2014;120(11):1620-1629.
2. Pisansky TM, Hunt D, Gomella LG, et al. Radiation Therapy Oncology Group 9910: phase 3 trial to evaluate the duration of neoadjuvant total androgen suppression and radiation therapy (RT) in intermediate-risk prostate cancer. Int J Radiat Oncol Biol Phys. 2013;87(2; suppl):S1.
3. Cury FL, Hunt D, Roach M 3d, et al. Prostate-specific antigen response after shortterm hormone therapy plus external-beam radiotherapy and outcome in patients treated on Radiation Therapy Oncology Group study 9413. Cancer. 2013;119(11):1999- 2004.
4. Nguyen PL, Je Y, Schutz FA, et al. Association of androgen deprivation therapy with cardiovascular death in patients with prostate cancer: a meta-analysis of randomized trials. JAMA. 2011;306:2359-2366.
5. Widmark A, Klepp O, Solberg A, et al. Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-7/SFUO-3): an open randomised phase III trial. Lancet. 2009;373:301-308.
6. Warde P, Mason M, Ding K, et al. Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial. Lancet. 2011;378(9809):2104-2111.