Adding Apalutamide Before and After Prostate Surgery Improves Outcomes in High-Risk Prostate Cancer

Table of Contents

• Key Points
• Understanding the Problem: High-Risk Prostate Cancer
• Study Design: A Large, Rigorous Trial
• Who Was in the Study?
• Key Finding 1: Tumor Response at the Time of Surgery
• Key Finding 2: Metastasis-Free Survival
• Secondary Outcomes: Delaying the Next Treatment
• Safety and Side Effects
• What This Means for Patients
• Study Limitations
• Recommendations
• Frequently Asked Questions
• Source Information

Key Points

• In the PROTEUS trial of 2,109 men, adding apalutamide to hormone therapy before and after prostate surgery improved cancer control.
• Apalutamide increased the rate of no or minimal residual cancer at surgery from 1.0% to 8.9%.
• Five-year metastasis-free survival improved from 73.5% with placebo to 78.2% with apalutamide.
• Apalutamide delayed recurrence and the need for additional treatment by about 19 and 33 months, respectively.
• Severe side effects, mainly rash, were more common with apalutamide (39.6% vs. 31.0%).

Understanding the Problem: High-Risk Prostate Cancer

Prostate cancer is not one disease. Some men have slow-growing tumors that may never cause harm. Others have aggressive, high-risk cancer that can return after treatment and spread to other parts of the body. This study focuses on that second group: men with high-risk localized or locally advanced prostate cancer. These men face a much greater risk of recurrence and death than patients with low-risk disease, even when they receive curative-intent treatment with radical prostatectomy (complete surgical removal of the prostate) or radiation therapy combined with androgen-deprivation therapy (ADT, also called hormone therapy).

The numbers are sobering. Despite more than a century of progress in prostatectomy, relapse (the cancer coming back) occurs within 5 years in up to 50% of patients who undergo radical prostatectomy. Up to 20% of these patients die within 10 years, according to prior research cited in the study.

The term "high risk" has a specific definition. The National Comprehensive Cancer Network (NCCN) defines high-risk prostate cancer as having at least one of these features:

• A Gleason score of 8 or higher (scores range from 6 to 10, with higher scores indicating more aggressive disease)
• A prostate-specific antigen (PSA) level of 20 ng per milliliter or higher
• A clinical disease stage of T3 (meaning the tumor has grown beyond the prostate capsule)

For decades, doctors have hoped that giving systemic therapy (drugs that travel through the whole body) before and after surgery — known as perioperative treatment — could improve cure rates, the way it does for many other cancers. However, this approach has not shown benefit in prostate cancer until now. Earlier trials of neoadjuvant therapy (treatment given before surgery) were hampered by the inclusion of patients with low-risk disease and by the use of primary end points such as PSA response, which do not reliably predict long-term outcomes. The results were not practice-changing.

In the past decade, a series of phase 2 randomized trials of neoadjuvant androgen-receptor pathway inhibitors (drugs that block the male hormone signals that fuel prostate cancer growth) showed a favorable safety profile and encouraging prostate tumor response. Cancer disappearance at surgery was measured by two key indicators: pathological complete response (no cancer cells found in the removed tissue) and minimal residual disease (only a tiny amount of cancer left). These findings set the stage for the current trial.

Apalutamide is an oral nonsteroidal androgen-receptor inhibitor. That means it blocks the androgen receptor, the protein on prostate cancer cells that receives signals from male hormones (androgens) such as testosterone. It is already approved for treating two advanced forms of the disease: nonmetastatic castration-resistant prostate cancer (prostate cancer that progresses even when testosterone levels are extremely low) and metastatic castration-sensitive prostate cancer (cancer that has spread and still responds to hormone therapy). These approvals were based on the SPARTAN and TITAN trials, respectively. In patients with metastatic, castration-sensitive prostate cancer, treatment with ADT plus apalutamide led to rapid, deep, and durable declines in PSA levels and better overall survival than ADT plus placebo.

This trial — called PROTEUS — was designed to test whether giving apalutamide together with ADT before and after surgery could improve outcomes for men with high-risk localized prostate cancer.

Study Design: A Large, Rigorous Trial

PROTEUS was a phase 3, double-blind, randomized, placebo-controlled trial. This is the gold standard of medical research design. "Double-blind" means neither the patients nor the doctors knew who was receiving the active drug and who was receiving an identical-looking placebo (inactive pill). The trial was conducted at 184 sites in 18 countries.

Patients were randomly assigned in a 1:1 ratio (like a coin flip) to one of two groups:

• ADT plus apalutamide (240 mg taken orally once daily)
• ADT plus placebo (a matched inactive pill once daily)

The treatment schedule was carefully structured. Patients received six cycles of neoadjuvant treatment (each cycle lasting 28 days) before surgery. The study drug (apalutamide or placebo) was stopped from 2 weeks before radical prostatectomy to 4 weeks after prostatectomy. After surgery, patients received six more cycles (28 days each) of adjuvant treatment (treatment given after surgery). ADT was continuous throughout the treatment phase. The ADT used was a gonadotropin-releasing hormone analogue (either an agonist or an antagonist), which works by suppressing the testicles' production of testosterone. All patients also underwent pelvic lymph-node dissection (removal of lymph nodes in the pelvis) as part of their surgery.

The trial had two primary end points (the main outcomes being measured):

1. Pathological complete response or minimal residual disease — a composite end point. This was defined as the presence of a minimal residual tumor of no more than 5 mm (in the greatest dimension of the largest tumor lesion) in prostate-confined disease (stage ypT2 or lower), or no identifiable tumor at all (stage ypT0). The prefix "yp" indicates the stage was determined after neoadjuvant treatment. Pathologists made these assessments using hematoxylin and eosin staining, with immunohistochemical analysis (NKX3.1, CAM5.2, and PIN4 cocktail staining) as needed. All pathology was reviewed by blinded independent central review.
2. Metastasis-free survival — the time from randomization to the first occurrence of distant metastasis (cancer spreading to distant parts of the body) or death from any cause. Distant metastasis was detected on conventional imaging (computed tomography, magnetic resonance imaging, or bone scan) or on prostate-specific membrane antigen positron-emission tomography (PSMA PET, a highly sensitive type of scan). The use of PSMA PET was allowed starting in protocol amendment 7, adopted on April 14, 2022.

Secondary end points, tested in a hierarchical order, included event-free survival (time from randomization to biochemical failure, local or regional recurrence, distant metastasis, or death), time to the first subsequent local or systemic treatment, time to distant metastasis, freedom from disease at 4 years, metastasis-free survival as assessed with conventional imaging alone, and PSA-free survival with recovery of testosterone to at least 200 ng per deciliter.

Exploratory end points included low residual cancer burden (≤0.25 cm³ of residual disease in the prostate in organ-confined tumors without lymph-node involvement and with negative surgical margins), castration-resistant prostate cancer, testosterone recovery, and overall survival.

The trial was designed by the sponsor, Johnson & Johnson, with input from the protocol steering committee and health authorities. An independent data-monitoring committee monitored safety and reviewed efficacy. All patients provided written informed consent, and the trial was conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki.

Statistical planning was rigorous. A sample size of 2,000 was estimated to give the trial 94% power to detect a between-group difference of 5 percentage points in the rate of pathological complete response or minimal residual disease, assuming rates of 10% in the apalutamide group and 5% in the placebo group. For the final metastasis-free survival analysis, 477 end-point events were estimated to provide 85% power to detect a 25% between-group difference in the risk of distant metastasis or death (a hazard ratio of 0.75). Patients were stratified according to region (Europe, North America, or rest of the world), locoregional lymph-node involvement (N0 vs. N1), and Gleason score (7 vs. 8 to 10).

Who Was in the Study?

Between July 15, 2019, and June 30, 2022, the trial enrolled 2,109 men with newly diagnosed high-risk localized or locally advanced prostate cancer who were candidates for radical prostatectomy. Of these, 1,057 were assigned to receive ADT plus apalutamide and 1,052 to receive ADT plus placebo. At the clinical cutoff date (February 2, 2026), the median follow-up was 61.7 months (just over 5 years).

Patient retention was strong. As of the cutoff date, 899 patients (85.1%) in the apalutamide group and 922 (87.6%) in the placebo group remained in the trial. The two groups were well balanced in terms of demographics and disease characteristics. The median age of the patients was 66 years (interquartile range, 61 to 71).

Key characteristics of the study population included:

• Gleason score: 95.8% of patients had a Gleason score of 8 or higher; 57.8% had a Gleason score of 9, and 4.3% had a score of 10. Only 4.2% had a score of 7 (the lowest allowed under the trial's risk criteria for this group).
• Tumor stage: 35.5% had a clinical tumor stage of T3 or T4, meaning the cancer had grown through or beyond the prostate capsule. Most patients (44.3%) had stage T2 disease (confined to the prostate).
• Lymph-node involvement: 12.3% had clinical lymph-node metastases (stage N1), meaning cancer had spread to lymph nodes within the pelvis.
• PSA level: The median PSA level was 14.8 ng per milliliter (interquartile range, 8.1 to 31.5). Forty percent of patients had a PSA of 20 ng/mL or higher at baseline.
• Race and ethnicity: The overall population was 69.4% White, 19.3% Asian, and 3.7% Black, with 6.5% not reported. Among the 431 patients from North America, 44 (10.2%) were Black.
• Performance status: 96.6% of patients had an Eastern Cooperative Oncology Group (ECOG) performance-status score of 0 (fully active), and 3.4% had a score of 1 (restricted in physically strenuous activity but ambulatory).
• Geographic region: 52.9% were enrolled in Europe, 20.4% in North America, and 26.6% in the rest of the world.

All patients who underwent randomization were included in the intention-to-treat population (the standard method of analyzing everyone as assigned, regardless of whether they completed treatment). The safety population included all patients who received at least one dose of apalutamide or placebo — 1,050 patients in each group.

Key Finding 1: Tumor Response at the Time of Surgery

The first major result concerns what pathologists found when they examined the removed prostate tissue. This is the most direct measurement of whether the drug was shrinking and eliminating the cancer before surgery.

The percentage of patients achieving a pathological complete response or minimal residual disease was dramatically higher in the apalutamide group: 8.9% vs. 1.0% in the placebo group. In plain terms, about 9 in 100 men who received apalutamide had no cancer or only a tiny speck of cancer (≤5 mm) remaining in the prostate at the time of surgery, compared with about 1 in 100 men in the placebo group.

The statistical analysis confirmed this was a real effect, not chance. The odds ratio was 10.17 (95% confidence interval [CI], 5.27 to 19.64; P<0.001). Because an odds ratio can overstate the size of an effect, the researchers also provided the unadjusted relative risk: 9.36 (95% CI, 4.90 to 17.86). A P value of less than 0.001 means there is less than a 0.1% probability that this difference occurred by random chance.

Other surgical pathology findings reinforced the benefit. The rate of complete tumor disappearance in the prostate (stage ypT0, meaning no identifiable tumor) was 5.1% in the apalutamide group (54 of 1,057 patients) vs. 0.4% in the placebo group (4 of 1,052 patients).

Positive surgical margins — meaning cancer cells were found at the edge of the removed tissue, a risk factor for recurrence — were present in only 20.9% of the apalutamide group compared with 42.7% of the placebo group. Similarly, disease that had grown beyond the prostate (stage higher than ypT2) was found in 53.1% of the apalutamide group vs. 70.6% of the placebo group. Pathological lymph-node involvement (cancer in the removed pelvic lymph nodes) was similar between groups: 23.3% vs. 24.4%.

Key Finding 2: Metastasis-Free Survival

The second primary end point was metastasis-free survival, which measures two things: whether the cancer spreads to distant parts of the body, and whether the patient dies from any cause. This is a clinically meaningful end point because preventing metastasis is the ultimate goal of curative treatment.

The final analysis was performed after 472 end-point events had occurred (99.0% of the 477 expected events). An event occurred in 215 patients (20.3%) in the apalutamide group and in 257 patients (24.4%) in the placebo group.

The probability of metastasis-free survival at 5 years was 78.2% (95% CI, 75.3 to 80.8) in the apalutamide group, compared with 73.5% (95% CI, 70.4 to 76.3) in the placebo group. In other words, about 78 in 100 men treated with apalutamide were alive and free of distant metastasis at 5 years, vs. about 74 in 100 men in the placebo group. The difference was statistically significant, with a hazard ratio for distant metastasis or death of 0.80 (95% CI, 0.67 to 0.96; P = 0.02). A hazard ratio of 0.80 means that, at any given time point, patients in the apalutamide group were 20% less likely to experience metastasis or death compared with the placebo group.

Most distant metastases were detected by the highly sensitive PSMA PET scan: 53.0% of the metastatic events in the apalutamide group and 60.7% in the placebo group were first identified this way. A post hoc analysis showed that 686 patients (64.9%) in the apalutamide group and 755 patients (71.8%) in the placebo group underwent PSMA PET at least once during the trial.

Secondary Outcomes: Delaying the Next Treatment

The benefits of apalutamide extended beyond the two primary end points. All three key time-to-event secondary end points significantly favored ADT plus apalutamide over ADT plus placebo (P<0.001 for all comparisons):

• Event-free survival: The median event-free survival was 57.1 months in the apalutamide group vs. 38.4 months in the placebo group (hazard ratio, 0.71; 95% CI, 0.63 to 0.80). This means the apalutamide group went about 19 months longer, on average, before experiencing biochemical failure (a rising PSA), recurrence, metastasis, or death.
• Time to first subsequent treatment: The median time was 74.2 months in the apalutamide group vs. 41.5 months in the placebo group (hazard ratio, 0.65; 95% CI, 0.57 to 0.73). Patients in the apalutamide group went nearly 33 months longer before needing additional therapy such as radiation or systemic treatment.
• Time to distant metastasis: This also significantly favored apalutamide (P<0.001), meaning the cancer spread to distant sites later in the apalutamide group.

The study also measured other secondary end points including freedom from disease at 4 years, metastasis-free survival as assessed with conventional imaging alone, and PSA-free survival with testosterone recovery. For patients who develop a biochemical failure after surgery, a rising PSA triggers discussion of subsequent therapy, including adjuvant or salvage radiation therapy, at the discretion of the treating physician.

Safety and Side Effects

Every treatment has risks, and apalutamide is no exception. Adverse events were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Importantly, the trial was double-blind, meaning neither patients nor doctors knew who was receiving the active drug when side effects were being recorded.

Grade 3 or 4 adverse events (severe or life-threatening side effects) occurred in 39.6% of patients in the apalutamide group and in 31.0% of those in the placebo group. In absolute terms, about 40 in 100 apalutamide patients experienced a severe side effect, vs. about 31 in 100 placebo patients. The difference between the groups was driven primarily by a higher incidence of rash in the apalutamide group. Rash is a known side effect of apalutamide and other drugs in its class.

In addition to standard adverse-event monitoring, the trial protocol included specific safety measures:

• Cardiovascular risk was assessed during screening and before surgery, because ADT is known to affect cardiovascular health.
• Thromboprophylaxis (medication to prevent blood clots) was administered on the basis of risk factors and local guidelines, per protocol amendment 4.

The safety population included all 1,050 patients in each group who received at least one dose of the study medication. These findings emphasize that the decision to use apalutamide should weigh the clear oncologic benefits against the increased risk of side effects, particularly rash.

What This Means for Patients

This trial provides strong evidence that a short course of treatment before and after surgery can meaningfully improve outcomes for men with high-risk localized prostate cancer. The two primary end points — pathological response and metastasis-free survival — both improved, and the secondary end points consistently reinforced the benefit. The size of the effect is notable for a field where previous neoadjuvant trials had failed to change practice.

Several practical points stand out:

• The treatment is time-limited. Patients took apalutamide for a total of 12 cycles (about 11 months of active drug, with a pause around surgery). This is not lifelong therapy; it is a defined perioperative course.
• The benefit is measurable. The absolute improvement in 5-year metastasis-free survival was 4.7 percentage points (78.2% vs. 73.5%). The improvement in pathological response was even more dramatic: an 8-fold increase in the odds of having no or minimal residual cancer at surgery.
• The treatment delays recurrence and additional therapy. On average, patients in the apalutamide group went about 19 months longer without a cancer event and about 33 months longer before needing their next cancer treatment. That delay matters for quality of life.
• Side effects are manageable but real. The increased rate of grade 3 or 4 adverse events (39.6% vs. 31.0%) was driven largely by rash. Patients considering this approach should discuss rash management strategies with their care team.

These results may change the standard of care for high-risk localized prostate cancer. Radical prostatectomy alone has historically left many patients with high-risk disease at substantial risk of relapse — up to 50% within 5 years. Adding apalutamide around the time of surgery appears to reduce that risk meaningfully.

Study Limitations

Like all clinical trials, PROTEUS has limitations that patients and doctors should understand:

• Not a cure for everyone. Even with apalutamide, about 20 in 100 patients still experienced metastasis or death within 5 years, and the pathological response rate of 8.9%, while dramatically better than placebo, means that most patients still had substantial residual cancer at surgery.
• Follow-up duration. The median follow-up was 61.7 months (about 5 years). Overall survival, a key exploratory end point, requires longer follow-up to mature. The trial is ongoing, and longer-term data will be important.
• Odds ratio interpretation. The odds ratio of 10.17 for pathological response overstates the magnitude of the effect compared with the relative risk of 9.36. The researchers explicitly noted this, and the absolute rates (8.9% vs. 1.0%) are the most meaningful numbers for patients.
• PSMA PET evolution. The use of PSMA PET was introduced midway through the trial (amendment 7, adopted April 14, 2022). Most distant metastases in both groups were detected by PSMA PET rather than conventional imaging. This means metastasis detection was more sensitive in the later phase of the trial, which could affect how events were captured over time.
• Assumptions vs. observed rates. The trial's sample size assumed a pathological response rate of 10% in the apalutamide group and 5% in the placebo group. The actual rates were 8.9% and 1.0%. The difference between groups was larger than assumed, but the absolute rate in the apalutamide arm was slightly lower than the trial designers had predicted.
• Patient selection. Trial participants had to be candidates for surgery and able to receive ADT for at least 13 months based on cardiovascular risk. Results may not apply to patients with significant cardiovascular disease or those who are not surgical candidates.
• Racial diversity. Overall, 3.7% of participants were Black. Among North American patients, the proportion was 10.2% (44 of 431). This is a lower representation than in the general U.S. prostate cancer population, where Black men have the highest incidence and mortality rates.

Recommendations

For patients with newly diagnosed high-risk localized or locally advanced prostate cancer who are considering radical prostatectomy, this trial offers a new option. Here are practical steps to consider when discussing treatment with your care team:

1. Ask about perioperative therapy. The PROTEUS regimen — 6 cycles of ADT plus apalutamide before surgery, a pause around the operation, then 6 cycles after — is now supported by phase 3 evidence. Ask your urologist and oncologist whether this approach is appropriate for your specific situation.
2. Know your risk category. Ask your doctor to confirm your Gleason score, PSA level, and clinical tumor stage. These three factors determine whether you fall into the NCCN high-risk category, which is the group that benefited in this trial.
3. Discuss the side-effect trade-off. The benefit is real but not guaranteed. About 9 in 100 men had no or minimal residual cancer at surgery, vs. 1 in 100 with placebo. The 5-year metastasis-free survival was 78.2% vs. 73.5%. Weigh these numbers against the increased risk of rash and other grade 3 or 4 side effects (39.6% vs. 31.0%).
4. Plan for rash management. Rash was the main driver of increased side effects in the apalutamide group. Ask your doctor about skincare routines, when to report a rash, and what treatments (such as topical steroids or dose adjustments) are available.
5. Consider cardiovascular health. The protocol required that patients be deemed able to receive ADT for at least 13 months based on cardiovascular risk. If you have heart disease or risk factors, a cardiology assessment before starting treatment may be advisable.
6. Keep the long-term picture in mind. Median follow-up is about 5 years. Overall survival data are not yet mature. This treatment improves pathological response and metastasis-free survival, but its ultimate effect on how long patients live is still being tracked.
7. Ask about clinical trials. The PROTEUS trial was sponsored by Johnson & Johnson (ClinicalTrials.gov number, NCT03767244). If this regimen is not yet available in your region, or if you are interested in other investigational approaches, ask your doctor about clinical trial options or whether this therapy has been incorporated into local guidelines.

The decision to add apalutamide to surgery for high-risk prostate cancer is personal. It requires balancing the clear improvements in cancer control against the real risk of side effects. The PROTEUS trial gives patients and doctors the data they need to make that decision together.

Frequently Asked Questions

What is the PROTEUS trial and who was eligible?

The PROTEUS trial was a large phase 3 study of 2,109 men with high-risk localized or locally advanced prostate cancer who were candidates for radical prostatectomy. High-risk was defined by a Gleason score of 8 or higher, a PSA of 20 ng/mL or higher, or clinical stage T3 or higher.

What treatment did patients receive in the PROTEUS trial?

Patients were randomly assigned to receive either apalutamide (240 mg daily) plus hormone therapy (ADT) or placebo plus ADT. They received six 28-day cycles before surgery, paused around the operation, then six more cycles after surgery. ADT was given continuously throughout the treatment phase.

What should I ask my doctor about this treatment?

Ask if you are in the high-risk category that benefited in this trial, and whether perioperative apalutamide is appropriate for you. Discuss the trade-off between improved cancer control and increased side effects, especially rash. Also ask about cardiovascular assessment, since ADT affects heart health.

Should I get a second opinion before starting apalutamide plus hormone therapy before prostate surgery for high-risk prostate cancer?

A second opinion can help you weigh the benefits and risks of adding apalutamide to hormone therapy before and after prostate surgery. In the PROTEUS trial, this approach improved 5-year metastasis-free survival from 73.5% to 78.2% and increased the chance of no or minimal residual cancer at surgery from 1.0% to 8.9%. However, severe side effects, especially rash, were more common. A second opinion can confirm your high-risk status and help you decide if this treatment is right for you. Diagnostic Detectives Network provides independent expert second opinions.

Source Information

Original article title: Perioperative Apalutamide in High-Risk Localized Prostate Cancer

Authors: M.-E. Taplin, M. Gleave, N.D. Shore, A. Lopez-Gitlitz, A. Kretschmer, E. Efstathiou, P.L. Nguyen, R. Damião, T. Kamoto, A. Ross, A. Briganti, B.A. Hadaschik, A. Heidenreich, Á. Juárez Soto, H. Ye, G. Gotto, B. Rooney, S.K. Tian, L. Wetherhold, B. Miladinovic, S.A. McCarthy, C.P. Evans, and A.S. Kibel, for the PROTEUS Investigators

Journal: The New England Journal of Medicine, 2026; volume 395, pages 546-560

Publication date: Published May 31, 2026; print issue August 6, 2026

DOI: 10.1056/NEJMoa2603878

Funding: Johnson & Johnson

Trial registration: PROTEUS ClinicalTrials.gov number, NCT03767244

This patient-friendly article is based on peer-reviewed research. The original article contains additional data, tables, and supplementary appendices available at NEJM.org.