(UroToday.com) The 2025 ASCO annual meeting featured a prostate cancer session and a presentation by Dr. Matthew Siskin discussing real world outcomes for patients with metastatic castration resistant prostate cancer (mCRPC) and AR T878A alterations treated with enzalutamide. Androgen receptor (AR) antagonists such as enzalutamide are standard therapy for mCRPC. AR alterations such as amplification and ligand binding domain point mutations, can cause resistance to hormonal therapies such as enzalutamide, with the most prevalent AR point mutations being T878A and L702H. Preclinical evidence suggests that AR T878A retains sensitivity to enzalutamide compared to AR L702H, which confers resistance by increasing activation by glucocorticoids. Clinical data evaluating the efficacy of enzalutamide in patients with these AR point mutations is limited. At the ASCO 2025 annual meeting, Dr. Siskin and colleagues analyzed real world data from patients with AR T878A compared to AR L702H, AR amplification, or no detected AR mutations, as identified by circulating tumor DNA (ctDNA), to assess enzalutamide efficacy in patients with AR T878A versus AR L702H.
This study used GuardantINFORM, a real-world database that combines genomic data from deidentified patients tested via ctDNA with clinical data taken from commercial-payer health claims. Adult mCRPC patients treated with enzalutamide who had baseline ctDNA testing and at least 2 claims post ctDNA testing were included, and patients with ≥2 AR point mutations were excluded. Matched cohorts were used to assess real-world overall survival, time to treatment discontinuation, and time to next treatment. Propensity score matching was conducted using age and NCI comorbidity index, race, ethnicity, testing location, and enzalutamide line-of-therapy, and was evaluated using Wilcoxon tests.
There were 1,316 mCRPC patients that met inclusion criteria, including 59 that had AR T878A, 56 with AR L702H, 231 with AR amplification, and 970 that had no detected AR mutations. There were 34 patients included in the matched cohort comparing outcomes in those with T878A versus L702H. Patients with T878A demonstrated significantly improved time to treatment discontinuation (median 8.0 versus 3.5 months, p < 0.001) and time to next treatment (median 15.8 versus 4.3 months, p = 0.0016), but not significantly different real-world overall survival (19.1 versus 13.6 months, p = 0.1975) relative to L702H
Patients with T878A demonstrated significantly improved time to treatment discontinuation (7.7 versus 4.8 months, p = 0.022), but not statistically improved time to next treatment (10.4 versus 6.4 months, p = 0.059) or real-world overall survival (20.2 versus 14.9 months, p = 0.14) relative to AR amplification.
Patients with T878A demonstrated significantly shorter real-world overall survival (median 19.2 versus 43.6 months, p = 0.03), but no difference in time to treatment discontinuation (7.7 versus 7.8 months, p = 0.88) or time to next treatment (10.4 versus 14.4 months, p = 0.423) relative to no detected AR mutations. The average maximum variant allele fraction was significantly higher in those with AR amplification relative to those with AR T878A (15.6% versus 7.6%, p = 0.0069). The maximum variant allele fraction in those with AR T878 versus AR L702H and AR wild type was not significantly different. The most common non-AR genomic alteration in all 3 cohorts was TP53.
Dr. Siskin concluded his presentation discussing real world outcomes for patients with mCRPC and AR T878A alterations treated with enzalutamide with the following take home points:
- This is the largest study assessing outcomes of mCRPC patients with AR point mutations subsequently treated with enzalutamide
- Using real-world evidence, this study showed that AR T878A patients have a longer time on therapy with enzalutamide relative to patients with AR L702H
- These findings suggest that AR T878A is relatively more sensitive to enzalutamide compared to other resistance mutations
- Future work in larger prospective cohorts comparing hormonal treatments in AR-altered patients will help confirm the clinical significance of different AR alterations
Presented by: Matthew Siskin, MD, Perlmutter Cancer Center, NYU Langone Health, New York, NY
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the American Society of Clinical Oncology (ASCO) 2025 Annual Meeting, Chicago, IL, Fri, May 30 – Tues, Jun 3, 2025.
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