PROTEUS Trial Results Support Apalutamide Plus ADT as New Standard of Care in High-Risk Localized Prostate Cancer

For patients with high-risk localized or locally advanced prostate cancer (HR LPC/LAPC), radical prostatectomy (RP) offers the possibility of cure, but nearly half of patients will relapse. Data from the PROTEUS trial (NCT03767244), presented at the 2026 American Society of Clinical Oncology Annual Meeting, now offer a compelling answer to that persistent gap: Adding apalutamide (Erleada; Janssen Pharmaceuticals) to androgen deprivation therapy (ADT) in the perioperative setting significantly improves both pathologic response rates and long-term metastasis-free survival (MFS).¹

“PROTEUS is just the beginning,” Mary-Ellen Taplin, MD, a medical oncologist at Dana-Farber Cancer Institute and a principal investigator on the trial, said in an Interview with Pharmacy Times. “With the power of 2109 patients, we should be able to prove that a major pathologic response correlates with metastasis-free survival.”¹

Prostate Cancer and Treatment Across the Spectrum

Prostate cancer represents a significant burden for American men, with an estimated 333,000 cases and 400,000 deaths in 2026 alone. Most men with prostate cancer are diagnosed with localized or regional disease, which is generally highly curable with survival rates exceeding 99%. However, patients with metastatic disease have significantly lower 5-year survival outcomes. Improvements have been made over time with the advent of novel therapeutic approaches from approximately 55% in the mid-2000s to approximately 66% by 2020.^2,3

Locally advanced pancreatic cancer accounts for roughly 30% of newly diagnosed cases and is defined by its surgical unresectability due to involvement of adjacent vasculature. For patients with good performance status, current guidelines recommend a nonoperative, multidisciplinary treatment approach, though no prospective randomized trial has established a preferred chemotherapy regimen. Leucovorin calcium (folinic acid), fluorouracil, irinotecan hydrochloride, and oxaliplatin—known as FOLFIRINOX—has demonstrated improved survival in patients with metastatic pancreatic ductal adenocarcinoma but is highly potent with severe toxicities, cumulative adverse effects (AEs), and a strict patient eligibility criteria.⁴

ADT has been the standard of care in prostate cancer since the 1940s, when Huggins and Hodges first demonstrated the androgen dependence of prostate tumor growth.⁵ By suppressing testosterone levels to below 50 ng/dL, ADT slows or halts cancer progression, though its role varies depending on stage, risk category, and patient performance status. Although ADT is initially effective, almost all men will develop castration-resistant disease.³

Building on the hormonal foundation of ADT, a class of agents known as androgen receptor pathway inhibitors (ARPIs) has significantly expanded the prostate cancer treatment tool kit. These include enzalutamide (Xtandi; Astellas Pharma US, Inc), apalutamide, darolutamide (Nubeqa; Bayer HealthCare Pharmaceuticals Inc), and abiraterone (Zytiga; Janssen Biotech, Inc), each targeting the androgen receptor pathway at different points to further limit the signals that drive tumor growth. Apalutamide’s path to PROTEUS was built on more than a decade of investigational work in high-risk localized disease.³

“We did a series of small phase 2 trials starting in 2009, with 50 to 120 patients, and kept exploring various hypotheses around androgen deprivation therapy intensification using androgen receptor pathway inhibitors,” said Taplin. “Each trial looked more and more positive.”¹

Over a 14-year period, that accumulating evidence—including retrospective data showing that patients who achieved a major pathologic response were not relapsing—provided investigators and, ultimately, Janssen with the foundation to commit to a large phase 3 trial. Notably, PROTEUS was the first phase 3 trial in localized high-risk prostate cancer in 13 years, filling a considerable gap for a patient population with high relapse rates and significant unmet need.¹

Apalutamide as a Therapeutic Option for LAPC

Apalutamide is a nonsteroidal androgen receptor inhibitor that binds directly to the AR ligand-binding domain, blocking nuclear translocation, DNA binding, and AR-mediated transcription. Used in combination with GnRH antagonists to suppress testosterone production, apalutamide’s downstream effects include decreased tumor cell proliferation and increased apoptosis, ultimately reducing tumor volume. Its major metabolite, N-desmethyl apalutamide, retains AR inhibitory activity but with reduced potency.⁶

In 2018, apalutamide earned the title of the first FDA-approved treatment for non-metastatic castration-resistant prostate cancer, representing a major shift in treatment. By 2019, it had received a second approval for the treatment of patients with metastatic castration-sensitive disease.⁷

PROTEUS Trial Design and Outcomes

PROTEUS enrolled 2109 patients with newly diagnosed HR LPC/LAPC and randomly assigned them 1:1 to apalutamide (240 mg/day) plus ADT or placebo plus ADT. Treatment began 6 months before RP with pelvic lymph node dissection and continued for 6 months afterward, with brief breaks around the surgical window. The trial had 2 co–primary end points: pathologic complete response or minimal residual disease (pCR/MRD), defined as the pathologic tumor stage assessed after neoadjuvant therapy (≤ ypT2) with a 5-mm or larger tumor diameter, and MFS, assessed by blinded independent central review using both conventional and PSMA PET imaging.⁸

The patient population was high risk by design: the median prostate-specific antigen level at baseline was 14.8 ng/mL, 95.8% of patients had a Gleason score of 8 or higher, and 12% had node-positive disease on imaging. Median follow-up was 61.7 months.⁸

“The eligibility criteria in PROTEUS were more than just simple high-risk disease,” Taplin noted. “These are very high-risk patients.”¹

Both primary end points were met. The pCR/MRD rate was 8.9% in the apalutamide arm vs 1.0% in the placebo arm—a more than 10-fold difference (OR, 10.17; 95% CI, 5.27-19.64; P < .0001). MFS by blinded central review was also significantly improved, with a 20% reduction in the risk of distant metastasis or death (HR, 0.80; 95% CI, 0.67-0.96; P = .0169). The 5-year MFS rate was 78.2% with apalutamide plus ADT compared with 73.5% with placebo, and the median MFS had not yet been reached in either arm.⁸

The benefit extended across all secondary end points. Event-free survival, time to first subsequent therapy, and time to distant metastasis all favored the apalutamide arm. A more stringent measure of pathologic response—residual cancer burden/MRD (≤ ypT2, ≤ 0.25 cm³)—showed a rate of 30.6% with apalutamide vs 11.7% with placebo (OR, 3.36; P < .0001), underscoring the depth of response achievable with perioperative intensification.⁸

Grade 3 and 4 treatment-emergent adverse events occurred in 39.6% of patients in the apalutamide arm vs 31.0% in the placebo arm. Discontinuation due to adverse events was 7.4% vs 2.7%, respectively. No unexpected safety signals emerged.⁸

“Ninety percent [of patients] had testosterone levels over 100 [ng/dL], suggesting they were in the recovery phase,” Taplin noted—a reassuring finding for patients and clinicians weighing the long-term implications of androgen suppression.¹

Apalutamide Dosing and Administration

Apalutamide is administered orally at a recommended dose of 240 mg—four 60-mg tablets—once daily, with or without food. Tablets should be swallowed whole. Concurrent use of a gonadotropin-releasing hormone analogue is required unless the patient has undergone bilateral orchiectomy. If a patient experiences a grade 3 or higher toxicity or an intolerable adverse effect, dosing should be held until symptoms resolve to grade 1 or baseline, at which point treatment may resume at the same dose or a reduced dose of 180 mg or 120 mg as clinically warranted. Apalutamide has no contraindications.⁹

The package insert for apalutamide includes multiple warnings and precautions. Ischemic cardiovascular events leading to death require close monitoring and optimization of management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinuing treatment should be considered in the case of grade 3 or 4 toxicities. In elderly patients, fractures and falls are particularly common and high-risk individuals should be identified. Apalutamide may also cause seizures, which require immediate discontinuation of therapy. Lastly, there is a risk of embryo-fetal toxicities. Pharmacists should counsel patients with female partners of reproductive potential to use contraception during treatment and for 3 months after the last dose of apalutamide to prevent fetal harm or loss of pregnancy.⁹

Clinical Implications and Pharmacist Impact

PROTEUS establishes a new benchmark for how high-risk LAPC should be treated. By integrating apalutamide into the perioperative window—before and after surgery—clinicians can meaningfully increase the odds of curative success, reduce the risk of metastasis, and delay the need for subsequent therapy. For a disease where relapse has long been accepted as near-inevitable in a substantial proportion of patients, these results mark a significant shift in what curative-intent treatment can achieve.

As care standards evolve, pharmacists play a crucial role in the effective implementation of new therapies, education for specialists and patients, and interdisciplinary collaboration—driving forward a new era of patient outcomes. In the context of PROTEUS, that role is multifaceted. Pharmacists are uniquely positioned to counsel patients on apalutamide’s tolerability profile, including cardiovascular, metabolic, and fall-related risks associated with ADT in the perioperative setting. Medication reconciliation is especially critical here, as apalutamide is a potent inducer of CYP3A4 and CYP2C19 and carries significant drug interaction potential that must be evaluated prior to and throughout the treatment course.

Beyond the individual patient, pharmacists embedded in multidisciplinary surgical oncology teams can support protocol adherence across the neoadjuvant and adjuvant phases, ensuring that the precise sequencing that made PROTEUS work is translated faithfully into practice. ADT has been the backbone of prostate cancer treatment for more than 8 decades, and PROTEUS represents the latest and most definitive attempt to build on that foundation in the perioperative setting.

“PROTEUS started in 2019; it’s now 2026—that’s 7 years and longer if you count protocol development,” explained Taplin. “We only got there in that time because of the shift in standard of care around PSMA PET for staging. Looking back in 10 years, I hope PROTEUS will have changed the field on all of those fronts: more rational development of new therapies, faster development of new therapies, and ultimately a future where a patient walks in, gets their testing done, and receives recommendations based on clinical trials that bring the cure rate for these patients to 98%.”¹

REFERENCES

1. Taplin ME, Gerlach A. The future of localized prostate cancer treatment: Mary-Ellen Taplin, MD, and the PROTEUS Trial. Pharmacy Times. May 31, 2026. Accessed May 31, 2026. https://www.pharmacytimes.com/view/the-future-of-localized-prostate-cancer-treatment-mary-ellen-taplin-md-and-the-proteus-trial

2. Key statistics for prostate cancer. American Cancer Society. January 13, 2026. Accessed April 29, 2026. https://www.cancer.org/cancer/types/prostate-cancer/about/key-statistics.html

3. Vogt S, Ewing J. Communication in action: empowering community oncology pharmacists to optimize prostate cancer care across urology & oncology. Presented at: 2026 Community Oncology Alliance Annual Meeting; April 28-29, 2026; Orlando, FL.

4. Gemenetzis G, Groot VP, Blair AB, et al. Survival in locally advanced pancreatic cancer after neoadjuvant therapy and surgical resection. Ann Surg. 2019;270(2):340-347. doi:10.1097/SLA.0000000000002753

5. Huggins C, Hodges CV. Studies on prostatic cancer: I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. 1941. J Urol. 2002;168(1):9-12. doi:10.1016/s0022-5347(05)64820-3

6. Patel UJ, Caulfield S. Apalutamide for the treatment of nonmetastatic castration-resistant prostate cancer. J Adv Pract Oncol. 2019;10(5):501-507. doi:10.6004/jadpro.2019.10.5.8

7. Erleada FDA approval history. Drugs.com. Updated September 19, 2019. Accessed June 9, 2026. https://www.drugs.com/history/erleada.html

8. Taplin ME, Gleave M, Shore ND, et al. Perioperative (neoadjuvant and adjuvant) apalutamide (APA) + androgen deprivation therapy (ADT) vs placebo (PBO) + ADT with radical prostatectomy (RP) in high-risk localized or locally advanced prostate cancer (HR LPC/LAPC): final analysis of the PROTEUS phase 3 study. Presented at: 2026 American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2026; Chicago, IL. Abstract LBA1.

9. Erleada. Prescribing information. Janssen Products, LP; 2019. Accessed June 9, 2026. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/210951s001lbl.pdf