ASCO 2026: A Major Prostate Cancer Trial Shows Drug Can Keep High-Risk Disease From Returning For Longer

The results, published simultaneously in the New England Journal of Medicine, showed that adding a hormone-blocking pill called apalutamide to standard hormone therapy, both before and after surgery, significantly reduced the risk of cancer coming back and spreading, potentially setting a new standard of care for men with high-risk prostate cancer who are headed to the operating room.

“This is a landmark study,” Dr. Russell Pachynski, a medical oncologist at Washington University in St. Louis, tells SurvivorNet. “It shows that these clinical metrics can be significantly improved by this combination of hormone therapy and the pill. Their primary endpoint (metastasis-free survival) was statistically significant.”

The journal itself published an accompanying editorial calling it “a watershed moment” for the field of prostate cancer treatment. That is not language the New England Journal of Medicine uses lightly.

Treating High-Risk Prostate Cancer

Not all prostate cancers are the same. Many are slow-growing and may never cause a problem in a man’s lifetime. But some are aggressive and it’s those cancers that keep oncologists up at night.

High-risk prostate cancer is defined by features that suggest the disease is likely to grow quickly, spread beyond the prostate, and return after treatment. That includes tumors with high Gleason scores, cancer that has already grown outside the prostate gland, or cancer that has spread to nearby lymph nodes.

For these patients, the standard approach has been surgery, known as a radical prostatectomy, sometimes combined with radiation or hormone therapy afterward. It works for some men. For roughly half, the cancer comes back.

“In the higher-risk localized patients, we know that a lot of those actually really don’t have localized disease,” Dr. Pachynski says. “They have micrometastatic disease, aggressive cells that are already floating around in the blood, in the lymph and even in the bone. And so those are the patients that are less likely to be cured from surgery alone.”

PROTEUS: The Trial Results

The PROTEUS trial aimed to determine if it’s helpful to treat patients more aggressively, earlier.

Instead of waiting until cancer returned to escalate treatment, the researchers tested whether adding a powerful hormone-blocking drug apalutamide (brand name Erleada), which is already approved for advanced prostate cancer, both before and after surgery could prevent the disease from spreading in the first place.

More than 2,100 men with high-risk prostate cancer enrolled in the trial at 184 sites across 18 countries:

• Half received apalutamide plus standard hormone therapy (called androgen deprivation therapy, or ADT) for six months before surgery and six months after.
• The other half received a placebo plus ADT. Both groups then underwent radical prostatectomy.
• The total treatment period was 12 months.

The primary goals of the trial were to measure two things: how many patients had no detectable cancer left in the prostate at the time of surgery (called a pathological complete response), and how long patients went without their cancer spreading to distant organs (called metastasis-free survival).

The trial met both of its primary goals, and the results were striking.

At the time of surgery, nearly 9% of patients in the apalutamide group had no detectable cancer remaining in the prostate (a pathological complete response) or minimal residual disease. That compared to just 1% in the placebo group. In other words, patients receiving apalutamide were about nine times more likely to have their tumor virtually eliminated before surgery even began.

The longer-term results were equally meaningful.

• At five years, 78.2% of patients who received apalutamide were free from distant metastasis, compared to 73.5% of those who received placebo, a statistically significant difference.
• In practical terms, adding apalutamide reduced the risk of cancer spreading or death by 20%.

The secondary outcomes told the same story across the board. Patients on apalutamide went a median of 57 months before experiencing any disease event (biochemical failure, local recurrence, metastasis, or death) compared to 38 months for patients on placebo.

The time before needing a next treatment was 74 months with apalutamide versus 41 months with placebo. More patients in the apalutamide group were completely free of disease at four years.

What We Know And What We Don’t

The results, while genuinely meaningful, do come with real limitations.

The most important one is that we don’t yet know if apalutamide helps men live longer. The trial was not designed to answer that question at this stage, and the follow-up hasn’t been long enough. The editorial published alongside the study in the New England Journal of Medicine noted that if a survival benefit is eventually confirmed, “that would be a game changer in the field.” It hasn’t been confirmed yet.

The editorial also raised a question about the 9% complete response rate: the percentage of patients who had virtually no cancer left at the time of surgery. That number is meaningful, but it’s actually lower than what we see in some other cancers when treated with similar neoadjuvant approaches.

It suggests that apalutamide works well for some patients and may not work as well for others. The scientific community is actively trying to understand which patients are most likely to benefit and whether genomic features of a tumor might predict the response before treatment even starts.

“It’s not just looking at the biopsy and the Gleason grade,” Dr. Pachynski explains. “Now we have genomic classifiers, advanced diagnostic technology, PSMA PET scans. It’s looking at all of those things and saying, is this pretty aggressive? Let’s throw the book at it or might this not be worth the squeeze?”

There is also a sequencing question that both the editorial and Dr. Pachynski flagged independently. As effective drugs get moved earlier in treatment — before surgery, rather than reserved for later — some patients will have already been exposed to those drugs if their cancer returns.

“Now you’re going to have patients who have seen these drugs very early, and there are going to be some of these cancers that have become resistant. And now what do you do later? Because that’s where these drugs have been initially developed,” Dr. Pachynski  explains.

This is not a reason to refuse treatment, but is a reason to have a thoughtful conversation about your individual situation before deciding.

What To Know About Side Effects

Dr. Pachynski was careful to point out that the results need to be understood alongside the real burden of treatment.

“The current standard of care is no drugs around the surgery,” Dr. Pachynski explains. “If this ends up getting widely adopted, now you may be talking to a patient and saying, instead of just having a surgery, you’re going to be on a year of treatment — a shot and an additional pill. And we know that’s going to help, but you also have to realize that this therapy has toxicity: hot flashes, muscle loss, fatigue. And then there’s also financial toxicity.”

The trial data confirm this. Grade 3 or 4 adverse events (or more serious side effects) occurred in 39.6% of patients taking apalutamide, compared to 31% in the placebo group. The most common side effects were hot flashes, urinary incontinence, and erectile dysfunction, which were largely similar in both groups since all patients received hormone therapy. The key difference driven by apalutamide specifically was rash, which occurred in about 21% of patients on apalutamide versus 10% on placebo, though this was manageable in most cases.

Importantly, overall survival at five years of follow-up showed no detrimental effect from apalutamide. The drug does not appear to shorten lives. The trial’s mortality rate of 8.5% was consistent across both groups in patients under 75.

Dr. Pachynski also points to a mental health impact.

“I’ve had patients go on ADT and apalutamide and get suicidally depressed,” he says. “So imagine you would have had a surgery… yes, you’re high risk, but if cancer came back, we probably would have caught it and we have treatments. These are conversations that have to be thoughtfully had with patients.”

What Does This Mean For Patients?

Not every man with prostate cancer needs or benefits from this approach. PROTEUS enrolled a specifically high-risk population: 95.8% had a Gleason score of 8 or higher, meaning very aggressive disease. For men with lower-risk prostate cancer, active surveillance or surgery alone may still be the right path.

“Those would be the kind of select patients where you sit down and say, even though there will be some toxicity, and you might have to pay out of pocket for the therapy, and it’s a year — we think it’s worth it because your prostate cancer looks more aggressive,” Dr. Pachynski explains.

Modern diagnostic tools should factor into the conversation as well, Dr. Pachynski adds.

Apalutamide is already FDA-approved for men with advanced prostate cancer: both metastatic disease and a form called non-metastatic castration-resistant prostate cancer. But it has not yet been approved specifically for the perioperative setting, which is use before and after surgery in men with localized disease.

The PROTEUS results are expected to form the basis of a new FDA submission.

In the meantime, if you or someone you love has been diagnosed with high-risk prostate cancer and surgery is being considered, the PROTEUS data add real weight to a conversation that was already starting to happen in oncology, about whether treating more intensively from the beginning, rather than waiting for recurrence, leads to better long-term outcomes. The early data suggest it does.

It’s also worth knowing that apalutamide, like all hormone-blocking therapies, comes with side effects. Hot flashes, fatigue, and bone density loss are common with ADT. Apalutamide adds its own risks, including rash, falls, and a small increase in cardiovascular events. These are manageable in most patients, but they are part of the conversation any man should have with his doctor before starting treatment.

For men with high-risk prostate cancer, this is a trial that could fundamentally change what treatment looks like before they ever get to the operating room.

Questions To Ask Your Doctor

• Is my prostate cancer considered high-risk? What makes it so?
• Would I be a candidate for treatment with apalutamide before and after surgery?
• What are the side effects of adding hormone therapy to my treatment plan, and how would they be managed?
• How does this approach compare to surgery alone, or surgery followed by radiation?
• Are there clinical trials I should consider?
• Should I get a second opinion at a major cancer center?

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