Radiation/ADT Use in High-Risk Prostate Cancer Can Be Personalized

Paul L. Nguyen, MD

The current standard of care for men with high-risk prostate cancer is 2 years of hormonal therapy plus radiation and a brachytherapy boost, despite ongoing evaluations of the optimal duration of androgen deprivation therapy (ADT), explained Paul L. Nguyen, MD.

“I generally advocate for the ASCENDE-RT regimen, which is radiation to the prostate, possibly the pelvis, anywhere from 46 Gy to 50.4 Gy plus a brachytherapy boost. The combination of radiation plus a brachytherapy boost is the best radiation-based combination for [men with] high-risk prostate cancer,” said Nguyen.

Regarding the optimal duration of ADT, the phase 3 Prostate Cancer Study (PCS) IV trial randomized over 600 patients with high-risk prostate cancer to pelvic and prostate radiation therapy plus 36 months versus 18 months of ADT. The results demonstrated 5-year overall survival (OS) rates of 91% in the long arm versus 86% in the short arm (P = .07). The quality-of-life analysis showed a significant difference (P <.001) in 6 scales and 13 items, favoring the shorter course of ADT. Although the authors concluded that 18 months of ADT is a viable option for men with high-risk disease, Nguyen explained that the trial didn’t sufficiently demonstrate noninferiority.

“Because there was a high dropout in the 36-month arm and the hazard ratio for the Gleason 8 to 10 patients is not reassuring, I would not recommend 18 months as the universal standard for patients with a Gleason score of 8, 9, or 10,” said Nguyen.

In an interview with OncLive® during the 2020 International Perspectives in Cancer on Genitourinary Malignancies, Nguyen, senior physician and professor of radiation oncology, at Harvard Medical School, and director of the Genitourinary Clinical Center for Radiation Oncology, at Dana-Farber Cancer Institute, discussed the role of radiation in high-risk prostate cancer and ongoing research efforts in the space.

OncLive: What is the role of radiation for men with high-risk prostate cancer?

Nguyen: The current use of radiation in this setting is typically a standard 2-year duration of hormonal therapy, although there’s some debate about what the optimal duration should be. Most randomized trials right now are testing a 2-year duration plus some duration of radiation.

Could you elaborate on the important takeaways from the ASCENDE-RT trial?

The ASCENDE-RT trial looked at patients with unfavorable intermediate- or high-risk prostate cancer and found that if you add a brachytherapy boost to standard radiation, you cut the risk of recurrence in half. That is a really profound difference. At 9 years, the rate of biochemical recurrence-free survival (RFS) increased from about 63% to 83%. For high-risk patients, the rate of biochemical RFS increased from about 58% to 78%. Especially for high-risk patients, it’s important to offer the brachytherapy boost.

The downside is there hasn’t yet been an improvement in metastasis-free survival (MFS) or OS. There are also admittedly more adverse effects. Therefore, we do have to pick our patients carefully. For most young and healthy patients, we want to be offering this [approach] to maximize the chance of cure, minimize the psychological distress of [potential] recurrence, and minimize the chance they have to go on lifelong ADT after they recur.

Could you explain the controversy regarding the optimal duration of ADT?

There is a lot of controversy over what the best duration of ADT is for patients with high-risk prostate cancer. The short story is: I still prefer to use approximately 2 years [of ADT], which is what’s currently being used in most randomized national and international trials for high-risk patients.

I see an interest in moving towards 18 months, but I don’t feel that the trial that compared 18 months with 36 months [of therapy] has proven the equivalence of 18 months even though the hazard ratio for death on the most recent update looked pretty reasonable, meaning it was 1.02 with a 95% confidence interval of .18 to 1.29.

There were some problems with the study. One problem is the high dropout rate in the 36-month arm. Immediately after 18 months, 25% of the patients [in the 36-month arm] had already [stopped receiving] ADT. By the time they got to 36 months, only 59% of the patients were still on the drug. A very high dropout rate tends to bias towards equivalence. I [don’t think we can claim] that the 2 treatments are equivalent. Ultimately, it hasn’t been proven that 18 months is equivalent to 36 months.

The other concern I have about using 18 months as the standard is that we’re basically applying it to patients with Gleason score of 8 to 10. However, in that trial, the PCS IV trial, about 60% of the patients had a Gleason score of 7. A lot of that equivalence was driven by these Gleason 7 patients. No one would argue that you should go beyond 18 months or even to 18 months [in these patients]. When you look at the Gleason 8 to 10 subgroup, which is the subgroup of patients who we really want to apply these data to, the hazard ratio for death was 1.13, which is a little bit better serving. The upper bound of the 95% confidence interval was about 1.54. That’s not a level we would accept as equivalent.

Instead, I would tend towards what’s being tested as the control arm in most trials, which is 24 months. There will be an NRG Oncology study that’s going to look at the optimal duration of ADT. This is the Predict-RT trial, which will be using genomic markers to try to stratify patients. Very high genomic risk patients are going to get radiation, 2 years of hormones with or without a novel therapy. Slightly lower genomic risk patients will receive radiation and 2 years of hormones versus 12 months of hormones. With a proper noninferiority trial to test different durations [of ADT], we’ll be able to get an answer [regarding the optimal duration of ADT].

How do you approach treatment for high-risk patients in your practice?

The standard for patients with high-risk prostate cancer is standard ADT, which would be something like a gonadotropin-releasing hormone agonist plus an antiandrogen. Certainly, new agents are being tested. Enzalutamide (Xtandi) is being tested in the ENZARAD trial. Apalutamide (Erleada) is being tested in the ATLAS trial. Abiraterone acetate (Zytiga) has been tested in the STAMPEDE trial. Although those results have been published, the patients with nonmetastatic disease still require further follow-up to see whether there will be a benefit, especially in node-negative nonmetastatic disease.

The DASL-HiCaP trial will be evaluating darolutamide (Nubeqa) in this setting. The Predict-RT trial for high genomic risk patients is going to be testing abiraterone and apalutamide as a combination.

Could you shed light on the design of the ATLAS trial?

The results of the ATLAS trial have not been presented yet. However, patients with high-risk prostate cancer were randomized to radiation plus 2 years of standard hormone therapy with or without apalutamide. The end point of that trial is MFS. I do believe the trial is accrued, and we’re waiting for the results.

Where should future research efforts be focused?

Future research for high-risk prostate cancer is going to be about personalizing therapy. Right now, we have pretty much a one-size-fits-all approach with ADT. I do look forward to the Predict-RT trial, which is going to be opening in September 2020. This trial will use genomic information to try to personalize therapy for men with high-risk prostate cancer.

Ultimately, we want to get to the point where, based on a patient’s genomic score, you can tell whether they need 2 years of hormones plus treatment intensification or less hormone therapy, which would minimize the side effects from hormone therapy. I think there’s a lot of enthusiasm for this kind of approach.

What are some of your key take-home points about this prostate cancer subset?

For the high-risk space, give radiation plus a brachytherapy boost plus 2 years of hormones.

For patients who have had a radical prostatectomy and unfavorable features, we discussed the data about adjuvant versus early salvage therapy. For the vast majority of these patients, early salvage therapy is fine, and we do not need to be offering adjuvant therapy.

The last thing we talked about is whether to use hormone therapy with salvage radiation. In my own practice, for the vast majority of patients, I am offering 6 months of hormone therapy with salvage radiation except possibly for the most favorable kind of patient, which would be somebody with pathologic T2 disease, a Gleason 7 score, a positive margin, and a very low prostate specific antigen. In those patients, the benefit of ADT is small, and I feel generally OK treating them with radiation alone.

Reference

Nabid A, Carrier N, Martin AG, et al. Duration of androgen deprivation therapy in high-risk prostate cancer: a randomized phase III trial. Eur Urol. 2018;74(4):432-441. doi:10.1016/j.eururo.2018.06.018