Real world outcomes for patients with metastatic castration resistant prostate cancer (mCRPC) and AR T878A alterations treated with enzalutamide

• Published in: Journal of clinical oncology Vol. 43; no. 16_suppl; p. 5053
• Main Authors: Siskin, Matthew, Saha, Jayati, Antonarakis, Emmanuel S., Leal, Alessandro, Parry, Samuel, Tsai, Jill, Wise, David R.
• Format: Journal Article
• Language: English
• Published: 01.06.2025
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2025.43.16_suppl.5053

5053 Background: Androgen receptor (AR) antagonists such as enzalutamide (enza) are standard therapy for mCRPC. AR alterations such as amplification (amp) and ligand binding domain (LBD) point mutations (PMs) can cause resistance to hormonal therapies such as enza. The most prevalent AR PMs are T878A and L702H. Preclinical evidence suggests that AR T878A retains sensitivity to enza compared to AR L702H which confers resistance by increasing activation by glucocorticoids. Clinical data evaluating the efficacy of enza in patients with these AR PMs is limited. Here, we analyzed real world data from patients with AR T878A compared to AR L702H, AR amp, or no detected AR mutations ( AR no alt), as identified by circulating tumor DNA (ctDNA), to assess enza efficacy in patients with AR T878A versus AR L702H. Methods: We 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 enza who had baseline ctDNA testing and at least 2 claims post ctDNA testing were included. Patients with ≥2 AR PMs were excluded. Matched cohorts were used to assess real-world overall survival (rwOS), time to treatment discontinuation (rwTTD), and time to next treatment (rwTTNT). 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. Results: 1,316 mCRPC patients met inclusion criteria. 59 had AR T878A, 56 had AR L702H, 231 had AR amp, and 970 had AR no alt. T878A was compared to L702H, amp, and no alt. Patients with T878A demonstrated significantly improved rwTTD (median 8.0 vs 3.5 mo, P =0.001) and rwTTNT (median 15.8 vs 4.3 mo, P =0.003), but not significantly different rwOS (19.1 vs 13.6 mo, P =0.066) relative to L702H. Patients with T878A demonstrated significantly improved rwTTD (7.7 vs 4.8 mo, P =0.022), but not statistically improved rwTTNT (10.4 vs 6.4 mo, P =0.059) or rwOS (20.2 vs 14.9 mo, P =0.14) relative to AR amp. Patients with T878A demonstrated significantly shorter rwOS (median 19.2 vs 43.6 mo, P =0.03), but no difference in rwTTD (7.7 vs 7.8 mo, P =0.88) or rwTTNT (10.4 vs 14.4 mo, P =0.423) relative to AR no alt. Conclusions: To our knowledge, this is the largest study assessing outcomes of mCRPC patients with AR PMs subsequently treated with enza. Using real-world evidence, we show that AR T878A patients have longer time on therapy with enza relative to patients with AR L702H. rwOS following enza was numerically longer for T878A versus L702H. These findings suggests that AR T878A is relatively more sensitive to enza 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.