10-Year PROTECT Data Underscore Significance of Precision Medicine in Prostate Cancer

Malcolm Mason, MD

Prostate cancer survival was not significantly different among active monitoring, surgery, and radiotherapy for patients with prostate cancer, according to 10-year follow-up findings of the PROTECT study.

In the study, a total of 1643 men were randomized to the 3 treatment arms with no meaningful differences among the 3 groups at baseline. The primary endpoint of prostate cancer-specific mortality was approximately 1% in each group.¹

“Although the prostate cancer-specific mortality was only 1%, the overall mortality was 10% at a median of 10 years,” explained Malcolm Mason, MD.

The rate of disease progression among men assigned to surgery or radiotherapy was less than half the rate among men assigned to active monitoring, but did not translate into significant differences.

OncLive: Please provide an overview of the PROTECT study for patients with prostate cancer.

In an interview with OncLive, Mason, a professor at the Institute of Cancer and Genetics, Cardiff University, discusses the significance of the 10-year follow-up of the PROTECT study for patients with prostate cancer and what it means for the field going forward.Mason: The purpose of the PROTECT study was to directly test 3 major modalities of treatment for localized prostate cancer. The 3 modalities were external beam radiotherapy, radical prostatectomy, or deferred local treatment. Around the time this was set up 15 years ago, the terminology around deferred treatment was not settled. We now understand what active surveillance means. The term that was previously used was “active monitoring,” which was not the same since our protocols were different.

The idea of this study was to invite healthy men for prostate-specific antigen (PSA) screening. The unique thing about this study was that men were counselled about the uncertainties of treating early prostate cancer and were informed about the randomized trial before they even had a diagnosis. That’s important because that meant that men could consider the trial and the uncertainties without the overwhelming thoughts that they would receive if they had just had a diagnosis of cancer. That made all the difference.

What were the results from the 10-year follow-up?

Around 1600 men with localized prostate cancer were identified and were randomized 3 ways between surgery, radiotherapy, or active monitoring. That was a unique achievement in this field.Astonishingly, after a median follow-up of 10 years, the primary endpoint of prostate cancer-specific mortality was only 1%. We did not expect those results when the trial was set up. That tells us about the natural history of this type of prostate cancer. Keeping in mind how it was diagnosed, we took men who were otherwise healthy and were offered a PSA test, so these were not men who had already presented to their urologist with symptoms. That says something about the natural history of localized prostate cancer when it is detected in that way. It was quite a healthy population, but if you look at clinical disease progression, which was defined in several ways, there was a difference.

Radical and curative treatments, either surgery or radiotherapy, manifestly do reduce the likelihood of disease progression by about half. That is a big result; however, it is still only a phenomenon that affects a minority of men.

It is wrong to use PROTECT as an argument to say that we just should not be treating men with differed treatment and they should all be treated immediately. That is not the case because most men do not need treatment. However, whether deferred treatment is right for an individual man depends on the patient's perception of the risks of disease progression and how much that means to them—versus the side effects they would certainly receive if they had immediate treatment with surgery or radiotherapy.

The study showed that if you look at patient-reported outcomes, both radiotherapy and surgery can have detrimental effects in terms of toxicity. The effects after surgery are urinary, whereas there are bowel side effects after radiotherapy. Both treatments can also cause sexual dysfunction.

If we are counselling patients, is it wrong to offer differed treatment? I believe the answer to that is, “no,” but it would be wrong to offer it without explaining to patients the increased risk of disease progression on deferred treatment. If patients are having treatment, is there a best option in terms of efficacy of whether surgery is better than radiotherapy? The answer is, “no.” They appear to be the same. There has been a perception that results of surgery are better than those with radiotherapy. This randomized trial says that is not the case and if you have patients randomized both ways, the outcomes are the same.

How can these findings inform a clinician’s treatment decision?

I do not believe that there is a better option in terms of toxicity for patients who receive surgery versus radiotherapy. Both treatments cause measurable side effects to patients. They both have a detectable impact on quality of life, but the nature of those side effects is different. It is a matter of judgement for the patient as to which side effects bother them the most.If a clinician has a patient who has been diagnosed with early localized prostate cancer based on a PSA and the patient is otherwise well, that patient would seem to have a very good outcome and their likelihood of dying from prostate cancer is very low.

The next question is, “Should this patient have immediate treatment or should they have active surveillance?” Certainly, for patients with low-risk disease the data from this study just adds weight to the argument that those patients should be offered active surveillance in preference to immediate treatment. That is not to say that it is wrong to treat them, but the patient should be adequately informed about the data and the consequences. There is a trade-off to be had between the side effects of immediate surgery or radiotherapy versus the increased likelihood of disease progression if they have deferred treatment. There is no right or wrong answer.

The outlook for men with early localized prostate cancer detected by PSA is extremely good. There is a very low likelihood of those men dying of their disease overall.

Are there any next steps following this study?

I would like them to take away that the effectiveness of anticancer treatments as curative treatments, appear to be equivalent. Additionally, neither one is free of side effects but the side effect profile is different. I don't think we can offer a simple, best option in terms of surgery versus radiotherapy based on toxicity. They both cause side effects and this is where we need a discussion between the physician and the patient to decide what is best for the individual.This is a study of our median 10-year follow-up. We need to know what happens to these patients at 15 and 20 years. Further follow-up is essential for this group of patients. Also, patients have an excellent prognosis on this study. There were prostate cancer deaths in this study, but we have to find a better way of identifying those patients and finding the optimal treatment for them.

Using the same treatment as a blanket therapy for all men with prostate cancer is going to turn out to be the wrong approach. We need a more targeted approach in the future.

Hamdy FC, Donovan JL, Lane JA, et al. 10-Year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer. N Engl J Med. 2016;375:1415-1424. doi: 10.1056/NEJMoa1606220.