Enzalutamide/Abiraterone Acetate/Prednisolone Combo in mHSPC Not Recommended

Treatment with enzalutamide (Xtandi) plus abiraterone acetate (Zytiga) and prednisolone (AAP) could not be recommended in patients with metastatic hormone-sensitive prostate cancer (mHSPC) even though AAP alone resulted in a long-lasting clinically meaningful overall (OS) benefit, according to findings from a combined analysis of phase 3 trials from the STAMPEDE platform protocol (NCT00268476) presented at the 2022 ESMO Congress.¹

In 1 trial focused on AAP, investigators reported a total of 293 OS events for patients treated with ADT and AAP plus 371 events for patients treated with ADT alone (HR, 0.62; 95% CI, 0.53-0.73; P = 1.6x10^-9). In a trial focused on AAP plus enzalutamide, investigators observed a total of 228 events among patients who were treated with ADT, AAP, and enzalutamide, and 292 events for patients treated with ADT (HR, 0.65; 95% CI, 0.55-0.77; P = 1.4x10^-6; interaction HR, 1.05; 95% CI, 0.83-1.32; P = 0.71; between-trial heterogeneity, I² P = 0.7).

In terms of other survival outcomes, OS at 84 months among patients treated with ADT was 30% (95% CI, 26%-34%) compared with 48% (95% CI, 43%-52%) in those treated with ADT plus AAP. Moreover, the restricted mean survival time was 50.4 months and 60.6 months in each respective arm (P = 6.6x10^-9).

“This is clear and significant evidence of an improvement in survival in both trials was as you would expect for the abiraterone trial,” Gerhardt Attard, MD, PhD, FRCP, a clinician scientist, team leader, honorary medical oncology consultant, and John Black Charitable Foundation Endowed Chair in Urological Cancer Research at University College London. “But we see no evidence of difference in treatment effect between the 2 trials, and there is no evidence between trial heterogeneity.”

The population included in the STAMPEDE platform protocol featured patients with M1 mHSPC with 1 or more bone metastases and CT scan of the pelvis, abdomen, and chest, as well as patients with M0, high-risk, localized disease that is node-positive, node-negative with 2 or more high-risk features, or relapsed with high-risk features. To be eligible for the analysis, patients were required to have histologically confirmed prostate adenocarcinoma and adequate organ function but were excluded if they had confirmed clinically significant cardiovascular disease.

In the AAP trial, a total of 502 patients were treated with standard of care (SOC) ADT plus or minus docetaxel and 501 patients received SOC and AAP.² In the AAP plus enzalutamide trial, a total of 454 patients were treated with SOC compared with 462 patients who received SOC, AAP, and enzalutamide.³ The trials could not have overlapping controls and were required to have the same protocol and eligibility criteria. The primary outcome measure was OS. Investigators reported that the goal of the analysis was to assess the impact of AAP plus enzalutamide compared with AAP and other enzalutamide trials.

Follow-up for the study was based on available funding. The trials stopped further trial data collection on November 30, 2021, with a final data freeze on July 3, 2022.

All groups were randomized and well balanced. The median patient age was 68 years (range, 63-72) with a median prostate-specific antigen before ADT of 96 ng/mL. Moreover, 94% of patients had de novo disease and 6% had relapsed following radical treatment. The AAP study had a median follow-up of 95.8 months compared with 71.7 months in the AAP plus enzalutamide trial. At the end of the trials, 117 of 498 patients in the AAP and enzalutamide trial were still being treated with AAP, 98 were still being treated with AAPand enzalutamide, 3 were still on enzalutamide, and 10 were still on AAP.

In a prespecified subgroup analysis based on stratification factors, Attard described an interaction based on age and regular non-steroidal anti-inflammatory drug and/or aspirin use within the AAP trial. The correlation was not observed in the enzalutamide trial. The subgroup analysis also assessed docetaxel use in patients who received SOC and SOC plus AAP and enzalutamide.

“This was a late amendment to our protocol. Nine percent of patients or about 148 were randomized in the AAP and enzalutamide trial,” according to Attard. “Physicians were given the option to decide whether to offer docetaxel and as you would expect, those patients who were planned [to receive] docetaxel were younger, had a higher Gleason sum, and were more likely to have pain from prostate cancer. Overall, the number is very small.”

In terms of metastatic progression-free survival, the HR was 0.50 (95% CI, 0.43-0.58) in the AAP trial compared with 0.52 (95% CI, 0.44-0.62) in the AAP plus enzalutamide trial. There was no evidence of a difference in treatment effect or between-trial heterogeneity.

In terms of safety, toxicity was similar between arms, although adverse effects (AEs) occurred more frequently in the AAP plus enzalutamide arm. Compared with SOC, common AEs associated with the experimental treatments were fatigue, liver function derangement, and hypertension. The most significant grade 5 AEs were respiratory in the AAP trial and cardiac in the AAP plus enzalutamide trial.

_References:

_{1. Attard G, Murphy L, Clarke N, et al. Comparison of abiraterone acetate and prednisolone (AAP) or combination enzalutamide (ENZ) + AAP for metastatic hormone sensitive prostate cancer (mHSPC) starting androgen deprivation therapy (ADT): overall survival (OS) results of 2 randomised phase III trials from the STAMPEDE protocol. Ann Oncol. 2022;33(suppl 7):LBA62. doi:10.1016/annonc/annonc1089}

_{2. Sydes MR, Spears MR, Mason MD, et al. Adding abiraterone or docetaxel to long-term hormone therapy for prostate cancer: directly randomised data from the STAMPEDE multi-arm, multi-stage platform protocol. Ann Oncol. 2018;29(5):1235-1248. doi:10.1093/annonc/mdy072}

_{3. Attard G, Murphy L, Clarke NW, et al. Abiraterone acetate and prednisolone with or without enzalutamide for high-risk non-metastatic prostate cancer: a meta-analysis of primary results from two randomised controlled phase 3 trials of the STAMPEDE platform protocol. Lancet. 2022;399(10323):447-460. doi:10.1016/S0140-6736(21)02437-5}