Abiraterone With or Without Enzalutamide Added to Androgen Deprivation Therapy (ADT) Versus ADT Alone in Men with High-Risk, Non-Metastatic (M0) Prostate Cancer— STAMPEDE

By Akhil Abraham Saji, MD - December 14, 2021

Abiraterone acetate and prednisone (AAP) added to androgen deprivation therapy (ADT) should be considered a new standard of care in men with high-risk localized or locally advanced prostate cancer (M0), according to new data from the STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) trial, presented during a presidential symposium of the 2021 European Society for Medical Oncology (ESMO) congress.1 Gerhardt Attard, MD, PhD, Chair in Urological Cancer Research at University College London, UK, reported that 2 years of AAP-based therapy significantly improved metastasis-free survival (MFS) and overall survival (OS) in high-risk non-metastatic prostate cancer. However, addition of enzalutamide to AAP increased toxicity without having any discernible effect on efficacy.

STAMPEDE (NCT00268476) is an ongoing platform, multi-arm, multistage trial being run at over 100 hospitals in the UK and Switzerland in which men with locally advanced (M0) or metastatic (M1) prostate cancer starting long-term ADT are randomized to one of a number of different treatment approaches, including docetaxel, zoledronic acid, AAP, or enzalutamide. The primary results for addition of AAP, published in 2017,2 showed a clear benefit for ADT plus AAP in M1 disease (HR 0.61, 95% CI 0.49-0.75), but only 21% of events occurred in the patients with M0 disease, leading to uncertainty about the potential benefit of AAP in these patients.2

In order to determine whether there is a benefit associated with ADT plus AAP compared with ADT alone in high-risk M0 prostate cancer, and to have a sufficient number of events for analysis, the STAMPEDE study reporting plan was amended to include a prespecified statistical analysis of outcomes with AAP in all M0 patients separately from M1.3 The data utilized came from two cohorts of M0 patients: the cohort from the AAP comparison that reported on in 2017, who continued follow-up with no further efficacy inspections, and a second cohort from the (later) AAP plus enzalutamide comparison. This was possible, Dr. Attard explained, because all patients received standard of care (ADT for ≥3 years and local radiotherapy), there were no overlapping controls, all patients received 2 years of AAP (alone or with enzalutamide), and protocol and eligibility criteria were the same for both cohorts. The two cohorts together made up a total of 1974 patients, median age 68 years with a median PSA of 34 ng/mL, 39% of whom had node-positive disease. Local radiotherapy was mandated for all newly diagnosed N0 patients and highly recommended for most (71%) newly diagnosed N1 patients. Median follow-up for the study was 72 months (85 months in the AAP and 60 months in the AAP, plus enzalutamide comparison cohorts).

At data freeze on August 3, 2021, Dr. Attard reported, the “headline” result was that the primary endpoint of the analysis, MFS (a valid surrogate for OS) was substantially improved by 47% with ADT plus AAP with or without enzalutamide compared with ADT alone (HR 0.53, 95% CI 0.44-0.64, P=2.9×10-11). In terms of absolute benefit, 6-year MFS improved from 69% to 82%. There was no evidence of nonproportional hazard. This was “clearly excellent news for patients and for us physicians,” Dr. Attard declared.

A prespecified subgroup analysis by randomization period showed no difference in MFS between the two experimental arms (HR 0.54 for ADT plus AAP) vs HR 0.53 for ADT plus AAP plus enzalutamide, suggesting that addition of enzalutamide to AAP in this setting provided no additional benefit. “This is in keeping with reports from metastatic castration-resistant prostate cancer, which showed no benefit in overall survival for this combination,” Dr. Attard said. Subgroup analysis by baseline nodal status, age, performance status, NSAID use, or radiation therapy showed no clinically relevant evidence of treatment effect heterogeneity, he added.

A much greater magnitude of benefit in OS was seen with AAP with or without enzalutamide than previously estimated compared with ADT (HR 0.60, 95% CI 0.48- 0.73, P=9.3×10-7). Six-year survival improved from 77% to 86%. Similar to the MFS data, no difference was seen in OS by randomization period for either comparison.

“We observed clear benefit of treatment effect across all secondary outcome measures,” Dr. Attard reported. These, including prostate cancer-specific survival (HR 0.49, 95% CI 0.37-0.65, P=1.3×10-6), which translated into an improvement in 6-year prostate cancer-specific survival from 85% to 93%, and progression-free survival, including local progression, distant metastasis, or death from prostate cancer (HR 0.44, 95% CI 0.36-0.54, P=5.2×10-15).

As well as apparently producing no additional clinical benefit, the addition of secondary androgen blockade with enzalutamide to AAP was also associated with increased toxicity during the first 2 years of treatment, Dr. Attard noted. There was a higher incidence of Grade 3-4 toxicities (53% vs 33%), particularly Grade 3 erectile dysfunction, hypertension, and fatigue, and Grade 3/4 transaminitis.

Seven Grade 5 events were reported, 3 in the AAP comparison and 4 in the AAP plus enzalutamide comparison.

Among the limitations of this analysis was a lack of data on long-term complications beyond 2 years and on treatment durations other than 2 years, so the question remains as to whether longer treatment duration may be more effective, Dr. Attard noted. Another limitation was the under-representation of relapsed patients, but since this size of treatment benefit has consistently been seen in patients with metastatic disease, and with the findings in nonmetastatic disease, “I would expect [these] patients…to derive the same benefit,” Dr. Attard remarked.

This analysis did not provide any evidence for single-agent androgen receptor antagonist efficacy, but these trials are ongoing, such as ENZARAD (NCT02446444), which is assessing enzalutamide as an adjunct to ADT for patients with high-risk localized prostate cancer being treated with radiation therapy. “We look forward to those results in the next few years,” Dr. Attard remarked. Meantime, abiraterone has become the “star of the show” with respect to ESMO presidential symposia, he declared.

Akhil Abraham Saji, MD is a urology resident at New York Medical College/Westchester Medical Center. His interests include urology education and machine learning applications in urologic care. He is a founding and current member of the EMPIRE Urology New York AUA section team.


  1. Attard G, Brown LC, Clarke N, et al. Abiraterone acetate plus prednisolone (AAP) with or without enzalutamide (ENZ) added to androgen deprivation therapy (ADT) compared to ADT alone for men with high-risk non-metastatic (M0) prostate cancer (PCa): Combined analysis from two comparisons in the STAMPEDE platform protocol. Ann Oncol. 2021;32(Suppl):S1298. Abstract LBA4. DOI: https://doi.org/10.1016/j.annonc.2021.08.2098
  2. James MD, de Bono JS, Spears MR, et al; STAMPEDE Investigators. Abiraterone for prostate cancer not previously treated with hormone therapy, N Engl J Med. 2017;377(4):338-351. DOI: 10.1056/NEJMoa1702900
  3. Attard G, Brown LC, Clarke NW, Parmar MKB, James ND. Should patients with high-risk localised or locally advanced prostate cancer receive abiraterone acetate in addition to androgen deprivation therapy? Update on a planned analysis of the STAMPEDE trial. Eur Urol. 2021;80(4):522-523. DOI: 10.1016/j.eururo.2021.06.023