When and How Much: A Deep Dive into the RADICALS Trial's Questions on Radiotherapy and Hormone Therapy - Nicholas James

October 11, 2022

Alicia Morgans interviews Nicholas James about the RADICALS trial, a complex study aiming to determine the optimal timing for radiotherapy after surgery and the amount of hormone therapy needed. The first question's data showed that waiting was safe and adjuvant therapy unnecessary. The second question, presented at ESMO, involved pragmatic randomization between zero, six, and 24 months of ADT, revealing no survival difference, although the survival data was immature. Dr. James emphasizes the dilemma between benefitting some on certain endpoints but not survival versus giving less treatment to reduce upfront side effects. He also discusses the need for further analysis to identify high-risk patients and avoid overtreatment. Future efforts include using biomarker and molecular data to direct patient treatment, which Dr. James regards as a high priority.


Professor Nicholas James, MBBS, FRCP, FRCR, Ph.D., Professor of Clinical Oncology at the Institute of Cancer Research at Royal Marsden Hospital, London

Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts

Read the Full Video Transcript

Alicia Morgans: Hi, I'm so excited to be here at ESMO 2022, where I have the opportunity to speak with Professor Nick James about the RADICALS trial that was presented. Thank you so much for being here.

Nicholas James: A pleasure.

Alicia Morgans: So can you remind us, Dr. James, that the RADICALS is a bit of a complex study design? Can you clarify?

Nicholas James: It's a pragmatic exercise trying to answer two questions. One is when should you give radiotherapy after surgery, and the second is if you give radiotherapy, how much hormone therapy should you give? Chris Parker had already presented the data from the timing randomization, which essentially showed that it was safe to wait. You didn't need to give adjuvant therapy. You could give salvage therapy on PSA relapse and get the same survival outcomes.

The second question, which has been presented at ESMO today, was how much hormone therapy should you give? And this, again, was a pragmatic randomization, three ways between zero, six, and 24 months of ADT. And clinicians could choose to randomize between any of the pairs, so zero versus six, six versus 24, or all three. But unfortunately, in fact, only a minority got randomized three ways. So the bottom line with it is that there's no survival difference, but the survival data was immature whichever way you did it.

And in a nutshell, the naught versus six was mostly patients with low-risk disease, and there was no metastasis-free survival difference in that subgroup either, suggesting that you didn't get much benefit from hormone therapy on hard endpoints. But you did get a benefit from upfront therapy in terms of lower risk of getting hormone therapy later. But most patients didn't relapse. So you've got a dilemma between adding treatment in to benefit some on some endpoints, but not on survival versus giving everybody less treatment, so fewer side effects upfront.

For the second group, the six versus 24, these were a higher risk group on their baseline characteristics, and the 24 comes out better on metastasis-free survival than the six. But again, most patients are not relapsing. So you've still got this overtreatment issue, and there's no survival difference.

My feeling about the trial, I'm not an author on the paper, but I was an investigator, is that actually, we need to do further analyses trying to tease out who exactly is at highest risk of metastasis and therefore benefits from more treatment. And working at ways of not treating patients who are not that likely to relapse and therefore are going to get harm from hormone therapy if you add hormone therapy.

Alicia Morgans: Oh, and I think that's such a wonderful way to think it through because two years of hormone therapy is quite a long time. It's a lot. And to over treat a large portion to potentially delay metastasis in a small portion may not be the right way to go and certainly is an individualized decision by a patient at a minimum. So thank you for talking that through. Any other closing thoughts on that particular study? And congratulations to the team, and thank you for participating in it.

Nicholas James: Yes. Well, I think a very high priority now that we've got these data is to get the tissue blocks in. So the same team that's done all of the STAMPEDE profiling is being lined up to do that. And I think that's going to be very important and informative work.

Alicia Morgans: Absolutely. So we can really use biomarker data and molecular data to help direct which patients are going to benefit.

Nicholas James: I hope so.

Alicia Morgans: That will be very exciting.

Nicholas James: Yes.

Alicia Morgans: Well, thank you for doing that quick review and quick summary of the RADICALS trial. I really appreciate your time.

Nicholas James: A pleasure.