1413P - Tumor transcriptomic profiling of patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) who do not achieve optimal PSA response to intensified androgen deprivation therapy (ADT-I)

Background

Pts with mCSPC undergoing ADT-I and achieving a PSA nadir ≤0.2 ng/mL (PSA-L) any time after start of therapy was associated with improved overall survival (OS) versus those with a PSA nadir >0.2 ng/mL (PSA-H) (HR: 0.17, P<0.0001) (Chi AUA 2021, abstract 1281). We hypothesized that tumor gene expression profiling in PSA-H would be distinct from PSA-L.

Methods

Eligibility: confirmed mCSPC on ADT-I with Androgen Receptor Axis Targeted Therapy (ARAT) and availability of RNAseq profiling performed by a CLIA-certified lab using primary prostate biopsies collected before treatment. DEseq2 package was used to identify differentially expressed genes in PSA-H versus PSA-L cohorts. Gene Set Enrichment Analysis (GSEA) was used to identify pathways enriched in each cohort. All analyses were done using R v4.2.

Results

Eligible pts= 33 (11 PSA-H, 22 PSA-L) had a median age 65 years, median baseline PSA of 23.3 ng/ml, Gleason ≥8 ∼79%, de novo 55% and high-volume disease per CHAARTED criteria ∼52%. Pts with PSA-H had downregulation of the androgen response, estrogen response, and TNF-α signaling pathway, and upregulation of the interferon-alpha and coagulation pathway (Table). Table: 1413P

GSE Scores contrast PSA-H versus PSA-L

Positive NES = upregulation in PSA-H pts, and negative NES = downregulation in PSA-H pts

Conclusions

mCSPC pts not achieving an optimal response to ADT-I have downregulated pre-treatment tumor AR signaling and TNF-α signaling and upregulation of inflammatory molecular pathways characterized by increased angiogenesis, adhesiveness, and invasiveness (PMIDs: 34696780, 12429291). After external validation, these data may provide upfront identification of patients who may not respond to intensified ADT, and aid with counselling, prognostication, and trial enrollment.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

E.J. Hernandez: Financial Interests, Personal, Advisory Role: Fabric Genomics. M. Yandell: Financial Interests, Personal, Leadership Role: Backdrop Health, IDbyDNA. 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 Role: Janssen Oncology, Exelixis, Bristol Myers Squibb, Bayer, AVEO, Clovis Oncology, Merck, Peloton Therapeutics, Pfizer, Bavarian Nordic, Astellas Medivation; Financial Interests, Personal, Advisory Board: Tempus; Financial Interests, Institutional, Research Grant: Clovis Oncology, Bristol Myers Squibb, Bavarian Nordic, Exelixis; Financial Interests, Personal, Other, Travel Expenses: Exelixis. N. Agarwal: Financial Interests, Personal, Advisory Role: Astellas, AstraZeneca, Aveo, Bayer, Bristol Myers Squibb, Calithera, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Foundation Medicine, Genentech, Gilead, Janssen, Merck, MEI Pharma, Nektar, Novartis, Pfizer, Pharmacyclics, and 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,. All other authors have declared no conflicts of interest.