PCBETS PROSTATE CANCER BIOMARKER ENRICHMENT TREATMENT SELECTION Daniel

PC-BETS: PROSTATE CANCER – BIOMARKER ENRICHMENT TREATMENT SELECTION Daniel Khalaf, MD FRCPC Medical Oncologist BC Cancer Clinical Assistant Professor UBC July 2 nd 2020

BIOMARKER ENRICHMENT

CTDNA IN PROSTATE CANCER Leaders at the Vancouver Prostate Centre

Circulating cell-free DNA (ct. DNA) • Tumor-derived component or circulating cell-free DNA (cf. DNA) is termed circulating-tumor DNA (ct. DNA) • Fragmented DNA released into the bloodstream (~180 bp) • less than 30 minutes in circulation 1 Adapted from Roschewski M, et al. Lancet Oncology. April 2, 2015.

Advantages of using ct. DNA in metastatic setting • Simple and non-invasive • Allows tumour DNA sampling where biopsy is difficult or of low yield (e. g. sclerotic bone metastasis) • Serial sampling • Captures intratumoral and intrapatient heterogeneity

CTDNA Mutations Chromosome changes

Treatment selection ct. DNA analysis

Palbociclib – cell cycle inhibitor

Palbociclib mechanism

Palbociclib in breast cancer

Androgen deprivation therapy

Sequencing NHAs in m. CRPC Lancet Oncol, Nov 11 2019 EPUB ahead of print

Abiraterone – enzalutamide, Excellent 1 st line treatments Best PSA Decline from Baseline (%) Best PSA decline for first-line therapy: 12 weeks Abiraterone + Prednisone 100. 00 50. 00 Enzalutamide 100. 00 PSA decline > 50%: 55% 50. 00 -50. 00 -100. 00 PSA decline > 50%: 77% P = 0. 0012 Chi et al, ASCO 2017 abstract 5002

Abiraterone and enzalutamide – not as efficacious in second-line

Androgen receptor mutations Enzalutamide / abiraterone

Darolutamide – a new androgen receptor blocker Darolutamide

DNA damage repair – essential for cell survival Accelerated cancer cell mutations / evolution Mutation (BRCA 2 and similar) DNA – repair deficiency Vulnerability to further DNA damage

DNA damage – deficiency, the Achilles heel : inducing further DNA damage Parp inhibitor Further inhibition of DNA repair Adavosertib Induction of further DNA damage Carboplatin

Immunotherapy – Identifying the right patients CKD 12 loss Major DNA errors : Novel proteins Mismatch repair gene mutation

Immunotherapy, unlocking the immune system Tremelimumab - Durvalumab

CTDNA CORRELATIVE STUDIES

Outcomes correlations with genomics TP 53 AR Time to Progression BRCA 2/ATM TTP 1. 8 vs 8. 0 mo 5. 34 (2. 84 -10. 03) TTP 1. 8 vs 8. 0 mo 2. 21 (1. 38 -3. 55)

Outcomes correlations with ct. DNA fraction Time to Second Progression Overall survival • 30 – 100% vs Not detected: HR 7. 72 (95% CI 4. 29 -13. 9), p < 0. 001 • 2 -30% vs Not detected, HR 1. 56 (95% CI 1. 04 -2. 32), p=0. 030 • 2 -30% vs Not detected, HR 2. 77 (95% CI 1. 53 -4. 99), p=0. 001 % Alive % without progression • 30 – 100% vs Not detected: HR 3. 77 (95% CI 2. 41 -5. 89), p < 0. 001 months

Biobank – Expanding Prospective GU Cancers Plasma biobank Accrual Patient Consent obtained • Vancouver • Germline and somatic tumour DNA sequencing • Victoria • Fraser Valley • Centre for the Interior • Anonymized Clinical data collection ct. DNA sequencing Plasma collection Timepoints: 1. Before line of treatment Clinical database 2. On – treatment (816 weeks) 3. At progression Frozen samples

HSD 3 B 1 gain of function polymorphism Hettel el al, Nat Reviews 2017 Hearn et al, Lancet Oncol 2016

HSD 3 B 1 genotype in ABI-ENZA trial P=0. 598 Combined prospective cohort Determine the effect of HSD 3 B 1 genotype on ADT and ARPI outcomes Determine effect of abiraterone vs enzalutamide Khalaf D, Canadian Cancer Research Conference 2017

Biobank Goals (Specifically) • Large prospectively accrued cohort • Through correlative analysis explore the prognostic/predictive value of plasma genomic biomarkers • Comprehensive clinical data • Comprehensive outcomes data • Explore biomarkers for many disease states • m. CSPC • m. CRPC • Explore resistance mechanisms to treatments • Identify novel drive alterations • Large data set for future biomarkers / outcomes studies

BIOMARKER DISCOVERY Beyond – omics

ABI vs ENZA: Patient-reported outcomes QOL Depression Cognitive function

Quality of Life scores and age P=0. 96 “Biomarker negative” P < 0. 001 “Biomarker positive”

Outcomes in the patients ≥ 80 years in BC Dose reduction, n (%) Reason for dose reduction, n ABI+P N=106 ENZA N=104 P-value 8 (7. 5) 31 (29. 8) < 0. 001 Toxicity (n=8) Fatigue (n=4) Increase ALT/AST (n=2) Diarrhea (n=1) Hypertension (n=1) Toxicity (n=31) Fatigue (n=22) Weakness (n=2) Cognitive decline (n=2) Falls (n=1) Other toxicity (n=3)

Outcomes in patients ≥ 80 years in BC Proportion progression-free Time to progression – patients with dose reduction versus patients with no dose reduction (ENZALUTAMIDE cohort only) Dose reduction Median: 11. 8 m No dose reduction P=0. 094 Months Median: 6. 2 m

Thank you ! Questions ?