Lower-dose abiraterone offers viable alternative to standard-dose for mCRPC

Lower-dose abiraterone acetate (Zytiga) demonstrated comparable efficacy to standard-dose abiraterone, offering a viable alternative for patients with metastatic castration-resistant prostate cancer (mCRPC), according to phase 3 data presented at the 2025 American Society of Clinical Oncology Annual Meeting in Chicago, Illinois.¹

"This challenges the traditional MTD-based dose determination of anti-cancer drugs," according to the authors.

The authors, led by Minit J. Shah, MBBS, MD, DM, noted that although standard-dose abiraterone (1000 mg fasting) has demonstrated improved survival in mCRPC, the therapy “poses challenges due to high cost, toxicity, compliance, and fasting requirements.” Lower-dose abiraterone, on the other hand, is dosed at 250 mg with food and has showed signs of improved absorption and early efficacy.

To clarify the clinical efficacy of the lower-dose approach, the investigators conducted a randomized, phase 3 non-inferiority trial in patients with mCRPC. For the study, patients were randomly assigned 1:1 to receive lower-dose abiraterone (250 mg with a low-fat meal) or to standard-dose abiraterone (1000 mg fasting).

In total, 239 patients were enrolled, and 164 underwent randomization. Eighty-two patients were allocated to each study arm. The median age of participants was 65 years (IQR, 60.0 to 71.6), with 31.7% of patients being aged 70 or older. Patients in the study had a median of 1 prior line of therapy, with 64% of patients having received prior docetaxel.

In total, 61 patients in the lower-dose arm and 52 patients in the standard-dose arm achieved a radiological response to treatment. The radiographic objective response rate was 13.1% in the lower-dose arm compared with 15.4% in the standard-dose arm.

Additionally, 49.4% of patients in the lower dose arm achieved at least a 30% reduction in prostate-specific antigen (PSA) level vs 55.4% of patients in the standard dose arm (P = .456). A PSA decline of at least 50% was achieved in 37.7% of patients in the lower-dose arm vs 45.9% of patients in the standard dose arm (P = .302).

At a median follow-up of 18.1 months, the median PSA progression-free survival was 5.6 months (95% CI, 4.6 to 9.2) in the lower-dose arm vs 3.8 months (95% CI, 3.3 to 7.8) in the standard-dose arm (HR, 0.971; 95% CI, 0.676 to 1.395; P = .87). The median overall survival (OS) was 20.4 months (95% CI, 16.2 to NA) in the lower-dose arm vs 32.9 months (15.1 to NA) in the standard-dose arm (P = .63).

Pharmacokinetic analysis showed that patients in the standard dose arm had an 8-fold higher concentration of abiraterone in the blood vs those in the lower-dose arm. Specifically, the median C_max was 80.5 ng/mL (range, 7.94 to 648) with an area under the curve (AUC) of 226 ng/mL*h (range, 27.2 to 1580) in the standard-dose arm vs a median C_max of 10 ng/mL (range, 0.44 to 134) with an AUC of 28.7 ng/mL*h (range, 0.22 to 158) in the lower-dose arm.

Regarding safety, 98.7% of patients in the lower-dose arm and 97.5% of patients in the standard dose arm experienced an adverse event. Grade 3 or higher toxicities were reported in 39% of patients in the lower-dose arm vs 30% of patients in the standard dose arm (P= .237).

Based on these data, the authors concluded, “Lower-dose [abiraterone acetate] shows comparable efficacy to the standard-dose despite significantly lower blood levels, making it a viable alternative. This challenges the traditional MTD-based dose determination of anti-cancer drugs.”

REFERENCE

1. Shah M, Noronha V, Menon N, et al. Lower-dose versus standard-dose abiraterone in patients with metastatic castration resistant prostate cancer: A multicentric randomized phase III non-inferiority trial. J Clin Oncol. 2025;43 (suppl 17, abstr LBA5078). doi:10.1200/JCO.2025.43.17_suppl.LBA5078