Androgen receptor alterations and survival in veterans who develop metastatic castrate resistant prostate cancer.

Abstract

269 Background: Despite the increasing use of comprehensive genetic tumor profiling, molecular data has limited influence in determining treatment. However, with new therapies that target the androgen receptor in metastatic castration-resistant prostate cancer (mCRPC), molecular alterations in the androgen receptor signaling pathway have increasing importance. We sought to examine the association between androgen receptor (AR) alterations and overall survival in patients with metastatic hormone sensitive prostate cancer (mHSPC). Methods: In this retrospective study, we identified patients diagnosed with de novo mHSPC and treated with androgen deprivation therapy (ADT) between 2017 to 2021 within the Veterans Health Affairs. AR gene alterations were identified using National Precision Oncology testing from samples collected within 90 days before or after the mCRPC diagnosis date. Overall survival (OS) and time to mCRPC were compared between patients with and without AR alterations in patients whose samples were collected during mCRPC. Normally distributed variables were analyzed via t-test, nonnormal continuous variables via Kruskal-Wallis, and categorical variables via chi-square. Results: We identified 2431 patients with de novo metastatic prostate cancer who had somatic tumor testing (551 mCRPC samples and 1922 mHSPC samples). In samples collected in mCRPC, 40.8% (225) had AR alterations compared to 3.3% (65) in mHSPC patients (p<0.001). Of the mCRPC samples, 68.1% (375) were obtained via liquid biopsy, 74.2% (167) had a single AR alteration, and 25.8% (58) had two or more AR alterations (p<0.001). The most frequent AR alterations identified were amplification (n=135), T878A (n=48), L702H (n=40), H875Y (n=27), exon 4-8 rearrangement or deletions (n=23), W742L (n=11), and W742C (n=11). In patients with mCRPC samples, time to mCRPC was 31.3 months in patients with AR alterations compared to 34.7 months without AR alterations, HR 1.08 (95% CI: 0.91-1.28) (p=0.4). In mCRPC samples with AR alterations, the median overall survival was 56.8 months compared to 76.7 months in patients without AR alterations, HR 1.40 (95% CI: 1.15-1.70) (p<0.001). Conclusions: There are significantly more AR alterations in tissue samples collected from de novo metastatic prostate cancer patients who have progressed to mCRPC compared to samples collected at mHSPC. In patients tested during mCRPC, presence of AR alteration was associated with shorter overall survival compared to those without AR alterations. Genomic analysis of tumors at the time of disease progression may be an informative prognostic indicator and facilitate selection of therapy. No AR alteration (n=326) AR alteration present (n=225) HR (95% CI) p-value Time to mCRPC (months) 34.7 31.3 1.08 (0.91-1.28) 0.4 Overall survival (months) 76.6 56.8 1.40 (1.15-1.70) <0.001