Introduction

Four developments from this year's ASCO meeting reshape decision-making across the prostate cancer spectrum, from the operating room to the metastatic setting. Two are new biomarker-driven combinations, one changes how perioperative therapy is approached before radical prostatectomy, and one gives clinicians real data to support something many have wanted to do for years: giving well-selected patients with metastatic disease a genuine break from treatment.

PROTEUS: Perioperative Apalutamide Becomes a New Standard Before Radical Prostatectomy

For decades, perioperative systemic therapy has failed to move the needle in high-risk localized prostate cancer undergoing radical prostatectomy. The phase 3 PROTEUS trial may be the first to break that pattern. The trial randomized 2,109 patients with high-risk localized or locally advanced prostate cancer to apalutamide plus androgen deprivation therapy or placebo plus androgen deprivation therapy, given as six cycles before radical prostatectomy and six cycles after.

Neoadjuvant apalutamide produced a roughly nine-fold improvement in pathologic complete response or minimal residual disease at the time of surgery: 8.9 percent versus 1.0 percent with placebo. The trial also showed significant improvement in metastasis-free survival and event-free survival. This is a genuinely high-risk population, over half of whom would otherwise be expected to relapse after surgery and require additional therapy, so an intervention that meaningfully delays or prevents that is significant. The investigators and independent discussants both described this as poised to become a new standard of care for men undergoing radical prostatectomy for high-risk disease.

Biomarker-Driven Options Continue to Expand in Metastatic Disease

Two separate developments reinforce the same message: next-generation sequencing should now be routine at diagnosis of metastatic prostate cancer, because it is increasingly opening doors to specific, more effective combinations.

Capivasertib plus abiraterone for PTEN-deficient disease. The phase 3 CAPItello-281 trial tested capivasertib, an AKT inhibitor, added to abiraterone and prednisone in newly diagnosed, PTEN-deficient metastatic hormone-sensitive prostate cancer (about 1,000 patients), using a companion diagnostic test to identify PTEN deficiency. Median radiographic progression-free survival was 33.2 months with capivasertib versus 25.7 months with placebo, a statistically significant improvement. This combination received FDA approval in June 2026, alongside its companion diagnostic, giving PTEN-deficient patients, whose disease has historically progressed faster and carried a worse prognosis, their first dedicated targeted option in the hormone-sensitive setting.

Niraparib plus abiraterone for HRR-deficient disease. The phase 3 AMPLITUDE trial tested niraparib, a PARP inhibitor, added to abiraterone acetate and prednisone in metastatic castration-sensitive prostate cancer with homologous recombination repair (HRR) gene alterations. The combination significantly prolonged progression-free survival compared with abiraterone alone, with particular benefit concentrated in patients with BRCA1 or BRCA2 alterations specifically, reinforcing that within the broader HRR-deficient category, BRCA status still carries the strongest predictive signal.

Both developments point the same direction: metastatic prostate cancer at diagnosis should now routinely include testing for both PTEN status and HRR gene alterations, since either result now changes the standard first-line regimen.

Darolutamide Shows a Cognitive Advantage Over Enzalutamide, But It Hasn't Changed Practice Yet

Darolutamide and enzalutamide are both commonly used androgen receptor inhibitors, and until recently there was little data to help choose between them. A head-to-head cognitive assessment found darolutamide associated with fewer cognitive side effects than enzalutamide, plausibly related to differences in the two drugs' chemical structure and blood-brain barrier penetration. Despite this finding, when asked directly at the ASCO presentation whether this data was changing practice, the investigators said no. It is a useful data point to have in a discussion with patients concerned about cognitive side effects, but not yet enough on its own to drive drug selection.

A Treatment Holiday for Metastatic Prostate Cancer: A Genuinely Practice-Relevant Trial

Metastatic prostate cancer has traditionally meant indefinite androgen deprivation therapy. A trial examined whether well-selected patients doing well on treatment (PSA under 0.2, stable disease, at least 12 months of therapy) could safely stop treatment and be monitored, restarting only if needed.

The results are worth sitting with: 41 percent of patients who stopped treatment remained off it and doing well at 18 months, with a median treatment-free duration of 24 months. Only one in four deaths in this population were attributable to prostate cancer at all, most patients with metastatic prostate cancer are dying of something else entirely, which is itself a meaningful finding about how far treatment has come. This adds to a long history of intermittent therapy already used selectively in prostate cancer, but the design here, with a fairly high bar required before considering retreatment, adds real reassurance that this approach is safe and feasible for the right patient: good prognosis, stable disease, PSA at or near undetectable, and a full year of treatment already completed.

For Patients

If you or a family member has high-risk, localized prostate cancer being considered for surgery, it's worth asking whether adding hormone therapy before and after the operation, a strategy now supported by strong trial data, might improve the odds of a successful outcome. And for men living with metastatic prostate cancer who are doing well on treatment, with an undetectable or near-undetectable PSA, it's a reasonable question to raise with your oncologist whether a supervised treatment break might be appropriate; new data suggest this can be done safely in the right circumstances, without needing to commit to treatment indefinitely.

Key Takeaways

  • PROTEUS showed perioperative apalutamide plus ADT around radical prostatectomy nearly doubles the rate of pathologic complete response/minimal residual disease and improves metastasis-free survival in high-risk localized prostate cancer, positioning it as a new standard of care.

  • CAPItello-281 (capivasertib plus abiraterone, PTEN-deficient) and AMPLITUDE (niraparib plus abiraterone, HRR-deficient) both support routine molecular testing at diagnosis of metastatic hormone-sensitive prostate cancer, since either result now changes the standard first-line regimen.

  • Darolutamide shows fewer cognitive side effects than enzalutamide in head-to-head testing, though this has not yet changed prescribing practice on its own.

  • A treatment-holiday trial found that well-selected, stable metastatic prostate cancer patients can safely pause therapy for a median of 24 months, with most deaths in this population unrelated to prostate cancer itself.

References

  1. Taplin M-E, Gleave M, Shore ND, et al. Perioperative apalutamide plus androgen-deprivation therapy vs placebo plus ADT with radical prostatectomy in high-risk localized or locally advanced prostate cancer: final analysis of the PROTEUS phase III study. Presented ASCO 2026, Abstract LBA1; N Engl J Med. 2026.

  2. Fizazi K, Clarke NW, De Santis M, et al. Capivasertib plus abiraterone in PTEN-deficient metastatic hormone-sensitive prostate cancer: CAPItello-281 phase III study. Ann Oncol. 2026.

  3. Chi KN, et al. Niraparib and abiraterone acetate plus prednisone for HRR-deficient metastatic castration-sensitive prostate cancer (AMPLITUDE). Presented ASCO 2026; Nat Med. 2026.