Abstract 1399P
Background
AR gene alterations, detected by ctDNA sequencing, in the first line mCRPC setting were associated with worse outcomes on ARATs (abiraterone and enzalutamide) in a phase 2 trial (PMID: 29367197). Our objective was to correlate AR alterations with outcomes in real-world patients with treatment naïve mCRPC treated with ARATs, and to assess outcomes based on the presence of AR amplification (AR amp) versus AR mutation (AR mut).
Methods
This was an IRB-approved retrospective study. Eligibility: confirmed diagnosis of mCRPC, first-line treatment with an ARAT (abiraterone or enzalutamide), no prior exposure to an ARAT in the castration-sensitive setting, and available comprehensive genomic profiling (CGP) of ctDNA from a CLIA certified laboratory. Receipt of docetaxel in the castration-sensitive setting was allowed. Pts were categorized based on AR status: wild-type (AR wt) or alteration positive (AR+). Subgroup analyses were based on the type of AR alteration: AR amp, AR mut or both (AR amp+mut). The endpoint was to evaluate overall survival (OS) and progression-free survival (PFS) by AR status. Kaplan Meier and Log Rank Test were used as implemented in R-Studio (v.4.2).
Results
138 mCRPC pts were eligible: 69 with AR wt, 69 with AR+ (40 with AR amp, 17 with ARmut and 12 with AR amp+mut). The Median follow-up was 44.3mos (IQR; 38.8-70.4). See Table for results. Median PFS and OS for AR wt was significantly higher than AR+ pts. In the subgroup analyses median PFS and OS were similar regardless of AR amp or AR mut. Table: 1399P
| Median PFS Months (HR, 95% CI; P-value) | Median OS Months (HR, 95% CI; P-value) | |
| ARwt vs AR+ | 12 vs 7 mos (0.66, 0.46-0.94; 0.02) | 53 vs 27 mos (0.42, 0.27-0.66; >0.01) |
| ARwt vs ARamp | 12 vs 8 mos (0.64, 0.42-0.97; 0.04) | 53 vs 27 mos (0.35, 0.21-0.59; >>0.01) |
| ARwt vs ARmut | 12 vs 6 mos (0.83, 0.47-1.47; 0.53) | 53 vs 35 mos (0.49, 0.26-0.93; 0.03) |
| ARamp vs ARmut | 8 vs 6 mos (0.76, 0.41-1.40; 0.37) | 27 vs 35 mos (0.76, 0.40-1.44; 0.40) |
Conclusions
In this hypothesis-generating study, pts with mCRPC harboring AR alterations in ctDNA had worse outcomes on first-line ARAT compared to AR wt. These data may aid in patient counseling, prognostication, and treatment decision.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
U. Swami: Financial Interests, Personal, Invited Speaker: Astellas; Financial Interests, Personal, Advisory Board: Seagen, Exelixis; Financial Interests, Institutional, Research Grant: Janssen, Exelixis; Financial Interests, Institutional, Invited Speaker: Astellas/Seattle Genetics. B.L. Maughan: Financial Interests, Personal, Advisory Board: Abbive, Pfizer, AVEO Oncology, Janssen, Astellas, Bristol Myers Squibb, Clovis, Tempus, Merck, Exelixis, Bayer Oncology and Peloton Therapeutics; Financial Interests, Institutional, Research Grant: Exelixis, Bavarian-Nordic, Clovis, Genentech, Bristol Myers Squibb. N. Agarwal: Financial Interests, Personal, Advisory Board: Astellas, AstraZeneca, Aveo Oncology, Bayer, Bristol Myers Squibb, Calithera, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Foundation Medicine, Genentech, Gilead, Janssen, Merck, MEI Pharma, Nektar, Novartis, Pfizer, Pharmacyclics, Seattle Genetics; Financial Interests, Institutional, Research Grant: Astellas, AstraZeneca, Bavarian Nordic, Bayer, Bristol Myers Squibb, Calithera, Celldex, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, Gilead, Glaxo Smith Kline, Immunomedics, Janssen, Medivation, Merck, Nektar, New Link Genetics, Novartis, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle genetics, Takeda, Tracon. All other authors have declared no conflicts of interest.