The PROTEUS Study: The Era of Apalutamide Before and After Surgery in Prostate Cancer
In this article
Could Apalutamide Before and After Surgery Begin a New Era in High-Risk Localized Prostate Cancer?
Study design
PROTEUS is a randomized, double-blind, placebo-controlled phase 3 study in patients with high-risk localized or locally advanced prostate cancer who were candidates for radical prostatectomy. Patients with distant metastases were not included. All patients were planned for radical prostatectomy and pelvic lymph node dissection.
| Item | Apalutamide + ADT arm | Placebo + ADT arm | Clinical significance |
|---|---|---|---|
| Number of patients | 2109 patients | One of the largest perioperative prostate cancer studies in this field. | |
| Neoadjuvant period | 6 months of apalutamide 240 mg/day + ADT | 6 months of placebo + ADT | Aims to reduce tumor burden and the proportion of viable tumor before surgery. |
| Surgery | Radical prostatectomy + pelvic lymph node dissection | The backbone of local treatment with curative intent is maintained. | |
| Adjuvant period | 6 months of apalutamide + ADT | 6 months of placebo + ADT | Aims to reduce microscopic disease and the risk of recurrence. |
| Primary endpoints | pCR/MRD and MFS | Both a deep response in the surgical specimen and the long-term risk of metastasis were assessed. | |
pCR means pathological complete response, that is, no viable tumor remaining in the surgical specimen. MRD means minimal residual disease, or a very small amount of tumor remaining. In PROTEUS, these were evaluated together as “no or very little cancer remaining at surgery.”
Main efficacy results
Median follow-up was 61,7 months . The study met both primary endpoints. The pCR/MRD rate in the apalutamide + ADT arm was %8,9, compared with %1,0 in the placebo + ADT arm. This result is very strong in relative terms; however, in absolute terms, the proportion of patients with a deep pathological response remains below %10.
A significant benefit was also seen in the long-term clinical outcome. Apalutamide + ADT reduced the risk of metastasis or death by %20 in relative terms . Five-year metastasis-free survival rates were %78,2 and %73,5 ; thus, the absolute difference was approximately %4,7 .
| Outcome | Apalutamide + ADT | Placebo + ADT | Clinical interpretation |
|---|---|---|---|
| pCR/MRD | %8,9 | %1,0 | OR 10,17; the relative increase is large, but the absolute rate remains low. |
| 5-year MFS | %78,2 | %73,5 | HR 0,80; an approximately %4,7 absolute difference. |
| Time to subsequent treatment | 74,2 months | 41,5 months | The need for additional treatment was delayed by approximately 2,7 years. |
| Event-free survival | HR 0,71 | A %29 reduction in the risk of recurrence, progression, or death. | |
| Time to distant metastasis | HR 0,68 | The development of distant metastasis was significantly delayed. | |
| MRD based on residual cancer burden | %30,6 | %11,7 | Additional analysis supporting a deep pathological response. |
Why is delaying the need for additional treatment important?
When recurrence develops after surgery in high-risk prostate cancer, patients may need radiotherapy, hormone therapy, or systemic treatments. In PROTEUS, the time to starting subsequent treatment in patients receiving apalutamide + ADT was 74,2 months, compared with 41,5 months in the control arm. This difference may mean that patients need additional treatments and experience their adverse effects later.
In this patient group, the aim is not merely to lower PSA or see a better response in the surgical specimen. The main goal is to delay or prevent the spread of disease to distant organs. MFS is therefore a highly meaningful endpoint in treatments given with curative intent.
Safety
The safety profile of apalutamide + ADT was consistent with previous studies. The most common adverse effects were hot flashes, urinary incontinence, and erectile dysfunction. Grade 3–4 adverse effects were reported as %39,6in the apalutamide + ADT arm and %31,0 in the control arm. Treatment discontinuation due to adverse effects was reported as %7,4 and %2,7 , respectively.
Critical reading: how should these data be interpreted in a balanced way?
- MFS is positive, but the absolute difference is modest: The difference in 5-year MFS is approximately %4,7. This is statistically significant but should be discussed on a patient-by-patient basis against 12 months of intensive hormonal therapy.
- pCR/MRD increased greatly in relative terms, but the absolute rate is low: %8,9 vs %1,0 is an important difference; however, the overall proportion of patients with a deep pathological response remains below %10.
- The control arm does not represent all real-world options: Early salvage radiotherapy after surgery, primary radiotherapy + long-term ADT, or different systemic intensification strategies are not options directly compared in this study.
- The treatment burden is not small: 12 months of apalutamide + ADT should be considered alongside hot flashes, effects on sexual function, fatigue, metabolic effects, rash, and quality of life.
- Patient selection is critical: “High risk” is a heterogeneous group. The greatest net benefit should be expected in patients whose risk of metastasis is truly high and who can tolerate treatment.
Points to consider
Apalutamide + ADT is not yet a regulatory-approved indication at this early disease stage. Furthermore, the results should not be interpreted as “automatic intensification for every high-risk patient.” Surgery, radiotherapy, ADT duration, systemic intensification, and patient preference should be evaluated together by a multidisciplinary board.
Drozdogan Academic Commentary
PROTEUS is a practice-changing study that challenges the surgery-centered approach to high-risk localized prostate cancer that has remained unchanged for years.
The fact that apalutamide + ADT both improves pathological response and enhances metastasis-free survival shows that systemic treatment should not be reserved only for after recurrence or metastasis.
However, this approach should be viewed not as “automatic intensification for every high-risk patient” but as a multidisciplinary decision that jointly considers metastatic risk, surgery/radiotherapy options, functional outcomes, adverse effects of hormonal treatment, and patient preference.
Conclusion
The PROTEUS phase 3 study showed that adding apalutamide + ADT before and after radical prostatectomy in high-risk localized or locally advanced prostate cancer significantly improved both the deep pathological response at surgery and metastasis-free survival. The pCR/MRD rate was %8,9 versus %1,0, and the 5-year MFS rate was %78,2 versus %73,5.
These data show that perioperative systemic therapy may have a real clinical benefit in high-risk prostate cancer treated with surgery with curative intent. However, when the absolute magnitude of benefit, toxicity burden, and patient selection are considered together, the most appropriate message from PROTEUS is this: surgery remains important in high-risk prostate cancer, but adding the right systemic treatment around surgery in selected patients may reduce the risk of metastasis and delay the need for subsequent treatment.
- ASCO 2026 LBA1. Final analysis of the PROTEUS phase 3 study.
- Taplin ME et al. Perioperative Apalutamide in High-Risk Localized Prostate Cancer. New England Journal of Medicine. 2026.
- Johnson & Johnson. Phase 3 PROTEUS study results. 31 May 2026.
- Reuters. J&J prostate cancer drug reduces risk of cancer spread and death in late-stage study. 31 May 2026.
- ClinicalTrials.gov. PROTEUS / NCT03767244.
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