Before and After Surgery: The PROTEUS Trial May Rewrite How We Treat High-Risk Prostate Cancer
First Look at PROTEUS Results: Dr. Monty Pal on ASCO26 Plenary Research - YouTube
A landmark Phase 3 study shows that adding a powerful hormone blocker around the time of surgery dramatically reduces the chance of cancer spreading — and may change a treatment paradigm that has stood for more than a century.
- The PROTEUS trial tested adding apalutamide (Erleada®) plus standard hormone therapy for six months before and six months after radical prostatectomy in men with high-risk or locally advanced prostate cancer.
- Men receiving apalutamide were nine times more likely to have little or no cancer remaining in the prostate at surgery.
- The combination reduced the risk of cancer spreading (metastasis) or death by 20% over follow-up.
- Time before needing any further treatment was extended by more than 33 months compared to hormone therapy alone.
- Results were presented May 31, 2026 at the ASCO Annual Meeting and published simultaneously in The New England Journal of Medicine.
- Apalutamide is not yet FDA-approved for this use; regulatory review is expected to follow.
What Is This Study, and Why Does It Matter?
For most men diagnosed with localized prostate cancer — cancer that has not yet spread beyond the prostate — the goal of treatment is cure. Surgery (radical prostatectomy) and radiation therapy with hormone therapy are the two main curative approaches. Both have been used for decades, and each has a strong track record. But for men with high-risk disease — cancers graded Gleason 7 (Grade Group 3) or higher, those with large tumors, or disease that has grown into nearby lymph nodes — surgery alone often is not enough. Studies have shown that roughly half of men with high-risk localized disease experience a return of their cancer after prostatectomy.
That reality has driven researchers to ask a deceptively simple question: what if we used powerful medications to shrink and weaken the cancer before surgery, then kept that pressure on afterward? This strategy, called "perioperative" (meaning around the time of surgery) treatment, has long been standard for some other cancers such as breast and bladder cancer — but prostatectomy has traditionally been done without drug preparation. The PROTEUS trial was designed to find out whether prostate cancer surgery patients could benefit from the same approach.
The Drug: Apalutamide (Erleada®)
Apalutamide is an androgen receptor pathway inhibitor, or ARPI. Prostate cancer cells need the male hormone testosterone — and closely related androgens — to grow. Apalutamide works by directly blocking the androgen receptor, the "lock" inside prostate cancer cells that testosterone fits into. When the lock is blocked, the cancer cell receives no growth signal, even if androgens are still present at low levels. This makes apalutamide substantially more effective than traditional hormone therapy (androgen deprivation therapy, or ADT) alone.
Apalutamide is taken as four 60-mg tablets once daily by mouth. It is already FDA-approved for two other situations: men with non-metastatic castration-resistant prostate cancer (based on the SPARTAN trial) and men with metastatic castration-sensitive prostate cancer (based on the TITAN trial). PROTEUS is the first major trial to test it in men who still have their prostate and are proceeding to surgery.
How the Trial Was Designed
PROTEUS (NCT03767244) is a Phase 3, randomized, double-blind, placebo-controlled trial — the most rigorous type of clinical study. That means neither patients nor their physicians knew who was receiving apalutamide and who was receiving placebo (an inactive pill) until after the data were analyzed.
A total of 2,109 men were enrolled across more than 203 sites in 18 countries. All participants had newly diagnosed high-risk or locally advanced prostate cancer (Gleason/Grade Group 3–5) and were candidates for radical prostatectomy with removal of pelvic lymph nodes (pelvic lymph node dissection, or PLND). Men with confirmed distant metastatic disease on conventional imaging were excluded.
Participants were randomly assigned 1:1 to one of two groups. The first group received apalutamide 240 mg daily plus ADT for six months before surgery, then resumed the same combination for six months after surgery. The second group received placebo plus ADT on the same schedule. All patients then underwent radical prostatectomy with PLND between the two treatment phases.
The trial had two co-primary endpoints — the two main questions it was designed to answer. The first was the pathologic complete response rate (pCR): how many men had essentially no cancer visible in the removed prostate under the microscope? The second was metastasis-free survival (MFS): how long until cancer spread to distant sites (such as bones or lymph nodes outside the pelvis) or the patient died? Both endpoints were assessed by a blinded, independent central review committee. The trial also incorporated PSMA-PET imaging — the newest and most sensitive type of prostate cancer scan — as an additional measure of disease status.
What the Results Showed
The trial met both of its primary endpoints, and the results were striking enough to earn the opening slot at the ASCO 2026 plenary session — the most prestigious spot at the world's largest cancer meeting — alongside simultaneous publication in The New England Journal of Medicine.
8.9% of men in the apalutamide group had little to no cancer remaining at the time of surgery, compared with just 1.0% in the placebo group. This translates to an odds ratio of approximately 10, meaning apalutamide-treated patients were roughly nine to ten times more likely to reach this benchmark of near-complete tumor clearance (OR 10.17; 95% CI 5.27–19.64; p<0.0001).
Men receiving apalutamide had a 20% reduction in the risk of developing distant metastases or dying compared to men receiving placebo plus ADT alone (hazard ratio approximately 0.80; statistically significant).
Men receiving apalutamide went more than 33 months longer before needing any additional treatment — a meaningful benefit for quality of life and for delaying exposure to more aggressive therapies.
To put these numbers in human terms: before PROTEUS, a man with high-risk prostate cancer who had a prostatectomy faced roughly a 50% chance of his cancer eventually returning. PROTEUS does not eliminate that risk entirely, but it meaningfully improves the odds — and when it prevents spread to bones and other organs, it is preventing some of the most serious and difficult-to-treat complications of advanced prostate cancer.
Principal investigator Dr. Mary-Ellen Taplin of Dana-Farber Cancer Institute, who has studied neoadjuvant hormone therapy in this setting for more than a decade, led the trial. Senior author Dr. Adam Kibel, Chair of Urology at Mass General Brigham, noted: "As a urologic surgeon who cares for patients with advanced prostate cancer, I am thrilled by the significant improvements in pathology and metastasis-free survival we observed in the PROTEUS trial."
Safety: What Are the Side Effects?
Apalutamide is generally well tolerated, but it does cause distinctive side effects that patients considering this approach should know about. Compared to the placebo group, men receiving apalutamide experienced higher rates of skin rash (approximately 24% vs. 6%), hypothyroidism (low thyroid function, about 8% vs. 2%), and bone fractures (about 12% vs. 6%). Fatigue is also a recognized side effect of the drug class.
Importantly, experience from the SPARTAN, TITAN, and Apa-RP studies has taught investigators that proactive rash management — including patient education about skin care and early use of topical treatments — substantially reduces both the severity and duration of rash. Testosterone recovery after stopping ADT was also a consideration: in the Phase 2 Apa-RP study, 77% of men recovered testosterone to normal levels (≥150 ng/dL) within 12 months of completing treatment, a reassuring finding for men concerned about long-term hormonal side effects.
About 10.6% of patients in the apalutamide group discontinued treatment due to adverse events, compared to 7% in the placebo group. Overall, the safety profile was considered manageable and consistent with what has been seen in prior apalutamide trials.
Context: What Other Trials Are Telling Us
PROTEUS does not stand alone. Several other recent studies paint a complementary picture of how treatment intensification is improving outcomes across the prostate cancer spectrum.
The Phase 2 Apa-RP study (NCT04523207) enrolled men with high-risk localized prostate cancer who received apalutamide plus ADT as adjuvant therapy (after surgery only, not before). Presented at the 2024 American Urological Association Meeting, Apa-RP showed a 100% biochemical recurrence-free survival rate at 24 months — meaning no patient in the study had experienced a PSA rise indicating recurrence at two years. While a small Phase 2 study with shorter follow-up cannot prove the same magnitude of benefit as a 2,100-patient Phase 3 trial, the results provided strong proof of concept that apalutamide plus ADT has durable activity in the post-surgical localized setting.
The NEAR trial (NCT03124433) tested a shorter course of neoadjuvant apalutamide without ADT (apalutamide monotherapy for 12 weeks before surgery) in men with intermediate- and high-risk disease. That approach did not achieve pathologic complete response as a primary endpoint, suggesting that the combination of apalutamide with ADT — rather than apalutamide alone — and a longer treatment duration are important elements of the PROTEUS regimen's success.
Also presented at ASCO 2026, the Phase 3 TALAPRO-3 trial (NCT04821622) targeted a different, later-stage population: men with metastatic castration-sensitive prostate cancer (mCSPC) who carry mutations in homologous recombination repair (HRR) genes such as BRCA1/2. TALAPRO-3 evaluated the combination of talazoparib (a PARP inhibitor, brand name Talzenna®) with enzalutamide (another ARPI, brand name Xtandi®). Results showed a 52% reduction in the risk of radiographic progression or death compared to enzalutamide alone (HR 0.48; 95% CI, statistically significant), with an estimated 77% of men on the combination remaining progression-free at three years. Men with BRCA mutations saw an even larger benefit (63% risk reduction). These results build on the earlier TALAPRO-2 trial, which showed similar gains in the castration-resistant setting and led to FDA approval of the combination in 2023. TALAPRO-3 data were simultaneously published in The New England Journal of Medicine. This study is particularly relevant to IPCSG members who have undergone germline genetic testing and carry HRR mutations — a topic our newsletter has covered extensively.
What This Means for Treatment Decisions
Today, the standard of care for most high-risk localized prostate cancer is either: (1) radical prostatectomy, often followed by radiation if cancer is found at the surgical margins or if PSA rises; or (2) radiation therapy combined with ADT and sometimes an ARPI such as apalutamide or enzalutamide, based on trials like STAMPEDE and others. PROTEUS offers the prospect of a third, more effective surgical pathway — one where surgery remains central but is now supported by a pharmacological "softening" of the tumor before the knife is wielded, followed by a period of consolidation afterward.
It is worth noting that the PROTEUS results are likely to prompt comparisons with the best outcomes from radiation plus ADT/ARPI — a debate among prostate cancer specialists that will play out in coming months and years. However, for men who strongly prefer surgery, or for whom radiation is not the best choice, PROTEUS provides compelling evidence that perioperative apalutamide plus ADT should now be considered.
Before this treatment becomes routinely available, it must receive FDA approval for this new indication. Johnson & Johnson has indicated it intends to pursue regulatory submission based on the PROTEUS final analysis. Given that the trial met both primary endpoints convincingly and the data were published in The New England Journal of Medicine, the regulatory path looks promising — but formal approval is not yet in place as of this writing (May 31, 2026).
Questions to Discuss With Your Doctor
If you have been newly diagnosed with high-risk or locally advanced prostate cancer and are considering surgery, or if you have a family member in this situation, these PROTEUS results are directly relevant to your conversation with your urologist and/or medical oncologist:
Am I a candidate for the PROTEUS approach? The trial enrolled men with Grade Group 3–5 disease, N0 or N1 pelvic nodes on conventional imaging, and no distant metastases. If your diagnosis fits these parameters, ask specifically about perioperative apalutamide.
How does perioperative apalutamide compare to radiation plus hormone therapy for my specific case? Both approaches now have strong evidence in high-risk disease, and the choice depends on tumor anatomy, patient preference, age, baseline function, and other factors.
What about my testosterone? ADT temporarily lowers testosterone to very low levels. Ask your doctor what recovery looks like over time and whether your individual health profile affects that timeline.
Do I need genetic testing first? The TALAPRO-3 results reinforce that knowing whether you carry HRR gene mutations (BRCA1/2, ATM, CDK12, and others) changes treatment options at multiple stages of disease. If you have not had germline genetic testing, ask about it.
Is PROTEUS-based treatment available to me today? Until FDA approval is granted, access outside of clinical trials may be limited. Your oncologist may be able to help identify whether compassionate use, expanded access, or related clinical trials are available in your area.
A Note on PSMA-PET Imaging
One of the forward-looking elements of PROTEUS is that investigators tracked disease status using PSMA-PET imaging — the highly sensitive nuclear medicine scan that can detect prostate cancer spread at PSA levels far below what conventional CT and bone scans can see. PROTEUS pre-specified metastasis-free survival based on both conventional imaging and PSMA-PET as a separate outcome measure. As PSMA-PET becomes standard of care for initial staging of high-risk prostate cancer (it received FDA approval for this purpose in 2021 and is now widely available), the insights from PROTEUS on how PSMA-PET findings correlate with long-term outcomes will be valuable for future treatment planning.
The Bottom Line
PROTEUS is a genuinely important study. The combination of a nine-fold improvement in pathologic complete response and a statistically significant 20% reduction in metastasis or death represents the kind of result that changes clinical practice. The trial's principal investigators describe it as a potential "paradigm shift" for how high-risk localized prostate cancer is treated surgically — and that description is well justified by the data.
For IPCSG members and their families navigating a high-risk prostate cancer diagnosis, the message is: the landscape is changing, and rapidly. Perioperative apalutamide is a real and evidence-based option that deserves a place in your conversation with your treatment team. We encourage all members facing surgery for high-risk disease to bring the PROTEUS results to their next appointment and ask whether this approach is right for them.
Glossary of Terms
- ADT (Androgen Deprivation Therapy)
- Medical treatment that reduces the body's production of testosterone, depriving prostate cancer cells of their main growth signal. Also called hormone therapy or chemical castration.
- ARPI (Androgen Receptor Pathway Inhibitor)
- A class of drugs (including apalutamide, enzalutamide, darolutamide) that block the androgen receptor more powerfully than older anti-androgen drugs, preventing cancer cells from responding to any residual testosterone even during ADT.
- Hazard Ratio (HR)
- A statistical measure comparing rates of events (such as metastasis or death) between two groups over time. An HR of 0.80 means the treated group has 80% of the risk of the control group — a 20% reduction in risk.
- HRR Gene Mutations
- Inherited or acquired changes in genes responsible for repairing certain types of DNA damage (homologous recombination repair), including BRCA1, BRCA2, ATM, and CDK12. Tumors with these mutations are often more aggressive but also more sensitive to PARP inhibitors.
- Metastasis-Free Survival (MFS)
- The length of time from the start of a study until a patient develops cancer spread to distant sites (metastasis) or dies. A primary endpoint in PROTEUS.
- Pathologic Complete Response (pCR)
- When a pathologist examining the removed prostate under a microscope finds little or no remaining cancer. A primary endpoint in PROTEUS.
- PARP Inhibitor
- A class of drugs that block enzymes cells use to repair certain DNA damage. When cells with HRR gene mutations encounter a PARP inhibitor, they cannot repair DNA breaks and die. Examples: talazoparib, olaparib, rucaparib.
- Perioperative
- The period around the time of surgery, including both the pre-operative (before surgery) and post-operative (after surgery) phases.
- Pelvic Lymph Node Dissection (PLND)
- Surgical removal of lymph nodes in the pelvis at the time of prostatectomy, to check for microscopic cancer spread and potentially remove involved nodes.
- PSMA-PET
- Prostate-Specific Membrane Antigen Positron Emission Tomography — a highly sensitive nuclear imaging scan that detects prostate cancer spread at very low PSA levels by targeting a protein expressed on prostate cancer cell surfaces.
- Radical Prostatectomy
- Surgical removal of the entire prostate gland, often with surrounding tissue and seminal vesicles, performed with curative intent.
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This article is prepared for educational purposes by and for members of the Informed Prostate Cancer Support Group (IPCSG). It is not intended as medical advice. Treatment decisions should always be made in consultation with your oncologist, urologist, and other members of your healthcare team. Clinical trial results reflect outcomes in study populations and may not apply to every individual. Drug availability and FDA approval status may change after the date of publication.
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