Prostate cancer treatment around surgery is being studied as a way to reduce the risk of recurrence in men with high-risk disease. The PROTEUS trial examined whether adding apalutamide to hormone therapy before and after surgery could improve cancer-control outcomes.
Who this is for
This article is for men with high-risk prostate cancer who are planning to undergo surgery to remove the prostate.
It may be particularly relevant when the cancer has aggressive features that increase the possibility of recurrence after surgery.
The results do not apply to every man with prostate cancer, particularly those with low-risk disease who may be suitable for active surveillance or less intensive treatment.
Clinical observation
One of the most important lessons I have learned during my career as a medical oncologist is that surgery alone is not always enough to control an aggressive cancer.
In breast cancer, treatment is often given before surgery.
In lung cancer, chemotherapy and immunotherapy may now be given before surgery in selected patients.
These approaches are based on a similar principle.
The surgeon removes the cancer that can be seen.
Medical treatment aims to destroy microscopic cancer cells that may already have moved beyond the main tumour but are still too small to appear on a scan.
For many years, I wondered whether prostate cancer would eventually follow a similar path.
The PROTEUS study suggests that treatment before and after surgery may improve outcomes for some men with high-risk prostate cancer. However, careful patient selection and longer follow-up remain important.
What surprised me
For decades, the usual surgical approach to high-risk prostate cancer was relatively straightforward:
Diagnose the cancer.
Remove the prostate.
Monitor the PSA.
Consider further treatment if the PSA later rises.
The PROTEUS study challenges this sequence.
Rather than waiting for recurrence, the researchers asked whether giving more intensive hormone treatment before and after surgery could reduce the risk of the cancer returning or spreading.
This represents an important change in how we may think about surgery for high-risk prostate cancer.
However, it does not yet mean that this treatment should be given to every man planning prostate surgery.
Why the PROTEUS study matters
PROTEUS was a large, international phase 3 clinical trial involving 2,109 men with newly diagnosed high-risk localised or locally advanced prostate cancer.
The results were presented at the 2026 American Society of Clinical Oncology Annual Meeting and simultaneously published in the New England Journal of Medicine.
The study examined whether adding apalutamide to androgen-deprivation therapy before and after radical prostatectomy could improve outcomes.
Apalutamide is a tablet that blocks the androgen receptor. Androgens, including testosterone, can help prostate cancer cells grow.
Importantly, this was not a comparison between the new treatment and surgery alone.
Both groups received hormone therapy before and after surgery:
- One group received androgen-deprivation therapy plus apalutamide.
- The other group received androgen-deprivation therapy plus placebo.
Therefore, the study shows the additional benefit of apalutamide when added to perioperative hormone therapy. It does not directly tell us how this approach compares with immediate surgery alone or radiotherapy combined with hormone treatment.
Understanding the background
Many men with prostate cancer are cured with surgery.
However, men with high-risk disease have a greater risk that microscopic cancer cells may already be present outside the prostate before surgery.
These cells may be too small to appear on MRI, CT or other imaging.
They may also be impossible for the surgeon to see during the operation.
Over time, these microscopic cells may grow and cause a rising PSA, recurrence near the prostate area or metastatic disease elsewhere in the body.
The aim of PROTEUS was to determine whether systemic treatment given both before and after surgery could control more of this invisible disease.
Is this study relevant to me?
PROTEUS included men with newly diagnosed high-risk localised or locally advanced prostate cancer who were considered suitable for radical prostatectomy.
The study population included men with aggressive features such as:
- higher-grade prostate cancer;
- cancer extending beyond the prostate;
- involvement of nearby structures or regional lymph nodes in some patients;
- other features indicating a substantial risk of recurrence.
The exact trial eligibility criteria were more specific than simply having one high-risk feature.
Therefore, a man should not assume that he is suitable for this approach based only on his PSA or Grade Group.
The study does not apply to men with low-risk prostate cancer who may be suitable for active surveillance.
It also does not establish that surgery with perioperative apalutamide is better than radiotherapy with hormone therapy for every high-risk patient.
What treatment did patients receive?
All 2,109 men were planning to undergo radical prostatectomy with pelvic lymph-node assessment.
Approximately half received:
- androgen-deprivation therapy; and
- apalutamide.
Treatment was given for approximately six months before surgery and approximately six months after surgery.
The other half received:
- androgen-deprivation therapy; and
- placebo.
They followed the same general treatment schedule.
The researchers then compared cancer outcomes between the two groups.
What did the researchers measure?
The study had two main goals.
Did the treatment improve the findings at surgery?
The researchers examined the prostate after removal to determine whether the treatment had produced a complete or near-complete pathological response.
In patient terms, they wanted to know whether very little—or no recognisable—cancer remained in the surgical specimen.
Did it reduce the risk of metastasis or death?
The researchers also measured metastasis-free survival.
This means the length of time patients remained alive without the cancer spreading to distant parts of the body.
The trial also examined:
- recurrence or progression;
- the need for further cancer treatment;
- the time until distant metastasis;
- treatment side effects.
Conventional imaging and PSMA PET could contribute to the assessment of distant metastasis during follow-up. It would be too strong, however, to suggest that every participant underwent PSMA PET at the same points in treatment.
Key results
The PROTEUS study met both of its primary goals.
Risk of metastasis or death
At five years:
- approximately 78 in every 100 men who received apalutamide plus hormone therapy were alive without distant metastasis;
- approximately 74 in every 100 men who received hormone therapy plus placebo were alive without distant metastasis.
This was an absolute difference of approximately 5 men in every 100 at five years.
When the researchers compared the rates over the full follow-up period, adding apalutamide was associated with a 20% relative reduction in the risk of distant metastasis or death.
A 20% relative reduction does not mean that 20 out of every 100 men were prevented from developing metastases. The five-year absolute difference was approximately 4.7 percentage points.
Recurrence or progression
The median event-free survival was:
- 57.1 months with apalutamide plus hormone therapy;
- 38.4 months with hormone therapy plus placebo.
This corresponded to a 29% relative reduction in the risk of an event such as recurrence, progression or death.
Need for additional treatment
The median time before patients required another cancer treatment was:
- 74.2 months in the apalutamide group;
- 41.5 months in the placebo group.
This suggests that adding apalutamide delayed the need for further treatment in the overall study population.
Findings at surgery
Men who received apalutamide were more likely to have a complete or minimal-residual-disease pathological response when the prostate was examined after surgery.
In patient terms, this means that no recognisable cancer, or only a very small amount of cancer, remained in the removed tissue.
This provides evidence that the treatment affected the cancer before the operation. However, pathological response does not by itself prove that an individual patient has been cured.
What about side effects?
The improvement in cancer outcomes came with additional side effects.
Grade 3 or 4 adverse events occurred in:
- 39.6% of men receiving apalutamide plus hormone therapy;
- 31.0% of men receiving hormone therapy plus placebo.
This means that severe or medically significant side effects occurred in approximately 40 out of 100 men in the apalutamide group, compared with approximately 31 out of 100 men in the control group.
Treatment discontinuation because of adverse events was also more frequent with apalutamide: 7.4% compared with 2.7%.
Possible effects of hormone therapy and apalutamide may include:
- hot flushes;
- tiredness;
- loss of sexual function;
- changes in muscle and bone health;
- metabolic effects;
- rash;
- falls or fractures in a smaller proportion of patients.
The potential benefit therefore needs to be balanced against treatment duration, side effects, general health and individual preferences.
What does this mean for patients?
The study does not mean that every man with prostate cancer should receive apalutamide before surgery.
Many men with lower-risk disease do extremely well with active surveillance, surgery or radiotherapy without this additional treatment.
For appropriately selected men with high-risk localised or locally advanced prostate cancer, perioperative apalutamide plus hormone therapy may reduce the risk of recurrence and distant metastasis compared with perioperative hormone therapy alone.
However, several questions remain:
- How does this approach compare directly with surgery alone?
- How does it compare with radiotherapy plus long-term hormone therapy?
- Which patients obtain the greatest absolute benefit?
- Do the improvements eventually translate into longer overall survival?
- What are the longer-term effects on quality of life?
These issues are important before describing the treatment as improving the chance of cure.
My perspective
Treating patients with breast and lung cancers has influenced how I think about high-risk prostate cancer.
In these diseases, treatment before surgery can help control both the visible tumour and microscopic disease elsewhere in the body.
PROTEUS provides strong evidence that a similar perioperative approach can improve several important outcomes in selected men with high-risk prostate cancer.
What often determines a patient’s future is not only the tumour still sitting inside the prostate.
It may also be microscopic cancer cells that could already exist outside the prostate but remain too small to detect.
Modern pathology, MRI, PSMA PET and clinical risk factors may help identify men at greatest risk.
However, the results should be interpreted carefully.
PROTEUS did not prove that every man should receive treatment before surgery, and it did not compare this approach directly with surgery alone or with modern radiotherapy-based treatment.
I believe this is an important advance and may influence future practice, but treatment should remain individualised while guidelines, regulatory approvals and longer-term results develop.
Key takeaways
- PROTEUS included 2,109 men with high-risk localised or locally advanced prostate cancer who were planning surgery.
- At five years, approximately 78% of men receiving apalutamide plus hormone therapy were alive without distant metastasis, compared with approximately 74% receiving hormone therapy plus placebo.
- The treatment improved cancer-control outcomes but also caused more serious adverse events, and it has not yet definitively proven a higher cure rate or longer overall survival.
References
- Taplin ME, Gleave M, Shore ND, et al. Perioperative apalutamide in high-risk localized prostate cancer. N Engl J Med. Published online May 31, 2026. doi:10.1056/NEJMoa2603878
- American Society of Clinical Oncology. Potential new targeted treatment option for people with localized, high-risk prostate cancer. Published May 31, 2026. Accessed July 30, 2026.
- American Society of Clinical Oncology. Final analysis of the PROTEUS phase 3 study. 2026 ASCO Annual Meeting. Abstract LBA1. Presented May 31, 2026.
Frequently asked questions (FAQs)
- Does this apply to everyone with prostate cancer?
No.
It is most relevant to selected men with high-risk localised or locally advanced prostate cancer who are planning radical prostatectomy.
It does not apply to most men with low-risk disease or those suitable for active surveillance.
- What is ISUP Grade Group?
Grade Group describes how abnormal the prostate cancer cells look under the microscope and gives doctors information about how the cancer may behave.
Grade Groups range from 1 to 5.
In general, a higher Grade Group indicates a greater likelihood that the cancer may grow or spread, although treatment decisions are not based on the grade alone.
- Why give treatment before surgery?
Treatment before surgery aims to shrink or control the known cancer and target microscopic cancer cells that may already exist outside the prostate.
Treatment after surgery aims to continue controlling any cancer cells that may remain.
- Does the study prove that this treatment improves the chance of cure?
Not yet.
The study showed improvements in metastasis-free survival, event-free survival and pathological response.
These are important outcomes, but longer follow-up is needed to determine the effect on overall survival and the likelihood of permanent cure.
- Is this now the standard treatment?
The results may influence future clinical guidelines and specialist discussions as the evidence is reviewed.
However, recommendations, regulatory approvals and access may differ between countries and may change as the results are reviewed.
At present, this approach should be discussed by a multidisciplinary team and considered in the context of alternative treatments, expected benefits and possible side effects.
Dr Dilanka De Silva
MBBS, MRCP(UK), MRCP(UK SCE Oncology), FRACP, PhD
Medical Oncologist & Cancer Genetics Physician
Memorial Sloan Kettering Cancer Center Fellow (New York, USA)