Another STAMPEDE.

Top Line: Should abiraterone and enzalutamide be added to ADT and radiation for men with high risk or node positive prostate cancer?

The Study: Since ESMO 2021, we’ve all been discussing whether to start adding abiraterone and/or enzalutamide to ADT and radiation for “high risk” prostate cancer. So, let’s take a look at the full manuscript of a pair of STAMPEDE trials. For these trials, high risk included node positive disease or node negative disease with at least two of the following: ≥T3, Gleason ≥8, or PSA ≥40. The vast majority of men (97%) fell into this category, and 39% were N+ and 79% had Gleason ≥8 disease. However, men with high risk biochemical recurrence also qualified. This included those with nodal relapse, those with biochemical-only relapse and PSA ≥20, and those with a biochemical-only relapse and PSA ≥4 who also had ≤12 months total ADT, a ≥12 month treatment-free interval, and a PSA doubling time <6 months. In both trials, 1974 men were randomized to standard ADT alone with or without abiraterone and prednisolone. In the second trial, those randomized to abiraterone also received enzalutamide. ADT duration was 3 years and any combination therapy was given for 2 years. Overall, 85% of patients received radiation, which was mandated for N0 disease and encouraged for N+ disease (71%). Per protocol, radiation consisted of 74 Gy in 37 fractions to the prostate and SV’s with pelvic nodal radiation recommended for N+ disease at physician discretion. Equivalent hypofractionated regimens (eg, 60 Gy in 20 fractions) were allowed. If radiation wasn’t delivered, then ADT and combination therapy were given until progression. Combination therapy significantly improved metastasis-free survival at 6 years (82% v 69%) as well as overall survival (86% v 77%) and prostate cancer specific survival (93% v 85%). Survival curves showed a clear separation over time. In addition, all subgroups of patients appeared to benefit from combination therapy. Grade 3+ toxicity was around 30% in the control arms compared to 37% in the abiraterone arms and 57% in the abiraterone + enzalutamide arm. The most common grade 3+ toxicities with combination therapy were hypertension (41% v 5%) and liver enzyme abnormalities (14% v 5%). Importantly, adding enzalutamide to abiraterone did not further improve treatment outcomes compared to abiraterone alone. So, the trial doesn’t tell us if enzalutamide could be used in place of abiraterone.

TBL: The addition of abiraterone to ADT and radiation for men with high risk and node-positive prostate cancer improves overall and metastasis-free survival. | Attard, Lancet 2021