In the final analysis of the phase III PROTEUS trial, perioperative apalutamide + androgen deprivation therapy (APA+ADT) improves the curative success of radical prostatectomy (RP) in men with high-risk localized or locally advanced prostate cancer (HR LPC/LAPC).
“PROTEUS is the first to demonstrate significant improvements in major pathological complete response (pCR), metastasis-free survival (MFS), event-free survival (EFS), and time to subsequent therapy (TTST) after 1 year of perioperative APA+ADT in [this patient setting],” said Dr Mary-Ellen Taplin from the Dana-Farber Cancer Institute, Boston, Massachusetts, US, at ASCO 2026.
After a median follow-up of 61.7 months, the co-primary endpoint of pCR/MRD* (ypT0 or ≤ypT2; ≤5 mm tumour) was markedly higher in the APA+ADT than the placebo group (8.9 percent vs 1 percent; odds ratio [OR], 10.17; p<0.0001). [ASCO 2026, abstract LBA1]
This was supported by the greater proportion of participants with residual cancer burden ≤0.25 cm3 (≤ypT2, N0; 30.6 percent vs 11.7 percent; OR, 3.36; p<0.0001) and with no tumour identified (ypT0; 5.1 percent vs 0.4 percent) with APA+ADT vs placebo+ADT.
MFS was also better with the investigational vs control regimen, be it by conventional or PSMA–PET** imaging (hazard ratio [HR], 0.80; p=0.02) or by investigator assessment (HR, 0.74; p=0.0004). The same held true for EFS (57.1 vs 38.4 months; HR, 0.71; p<0.0001) and TTST (74.2 vs 41.5 months; HR, 0.65; p<0.0001).
The APA+ADT group had lower rates of subsequent systemic therapy (26.7 percent vs 36.4 percent) and postoperative radiotherapy (13 percent vs 18.4 percent) than the placebo group.
The APA+ADT regimen also reduced the risk of distant metastasis by 32 percent (HR, 0.68; p=0.0002), with more participants having no distant metastasis at 5 years (82.8 percent vs 76.2 percent).
There was also a trend toward better MFS by conventional imaging with APA+ADT vs control (87.1 percent vs 83.9 percent; HR, 0.84; p=0.15). “The use of PSMA–PET with potential early detection of metastasis and subsequent therapy may impact MFS by conventional imaging,” Taplin noted.
Eighty-two percent of the overall cohort recovered their testosterone to ≥200 ng/dL, with no significant differences in testosterone value (median 270 vs 290 ng/dL) and time to testosterone recovery (median 8.1 vs 6.6 months) between the experimental and placebo groups.
Compared with the control group, the APA+ADT group had higher rates of grade 3/4 treatment-related adverse events (TRAEs; 27.5 percent vs 18.9 percent) and TRAEs leading to dose reduction (11.2 percent vs 2.3 percent) and interruption (12 percent vs 4.4 percent).
The most common grade ≥3 TRAE of special interest with APA+ADT was skin rash (5.9 percent). “Nonetheless, treatment algorithms of APA-related skin rash allowed the vast majority of patients to continue on the drug,” Taplin said.
Important novel endpoints
Despite refinements in RP, more than half of PC patients will relapse. [Transl Androl Urol 2025;14:493-495; J Clin Oncol 2024;42:5027; BJU Int 2024;134:96-102] Moreover, metastasis is associated with poor prognosis, Taplin noted.
In PROTEUS, 2,109 men (median age 66 years) were randomized 1:1 to ADT plus apalutamide 240 mg QD or placebo as neoadjuvant treatment for 6 months, with a 2-week break before and a 4-week break after RP + ADT, followed by 6 months of the assigned regimen in the adjuvant phase.
Approximately 96 percent of participants had a Gleason score ≥8 at initial diagnosis, 40 percent had a baseline PSA ≥20 ng/mL, 35 percent had ≥T3 disease, and 12 percent had evidence of nodal disease on conventional imaging.
According to Taplin, PROTEUS had an unprecedented design, the largest trial size to date, and novel endpoints. “In this study, APA+ADT enhanced disease control of RP and delivered significant benefits, including a ninefold improvement in pCR/MRD, a 20-percent lower risk of metastasis or death, a 29-percent lower risk of oncologic event or death, and a nearly 3-year delay in TFST.”
“The positive MFS, pathological, and treatment-free interval endpoints represent clinically meaningful gains for appropriately selected patients,” said discussant Dr Declan Murphy from the Peter MacCallum Cancer Center, Melbourne, Australia, at ASCO 2026. “Delaying subsequent therapy is an important patient-focused endpoint, as it translates to years of reduced treatment burden for many patients.”
A better journey?
Murphy pointed out similarities between PROTEUS and the recent lunar flyby mission by Artemis II. “Apollo 8 showed we could get [to the moon]; Artemis II asked if we could go a little further and if we could travel a little better—PROTEUS asked similar questions.”
“RP already takes us a very long distance, but progress is not only about the destination—it is also about the journey,” he emphasized.
“In PROTEUS, patients receiving APA were less likely to receive systemic treatment or radiotherapy, and less likely to spend years living with recurrent disease. If PROTEUS can deliver on that, then perhaps we have not just built a bigger rocket ship—we might have built a better journey for these high-risk patients,” Murphy concluded.