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prostate

1. Epidemiology of Prostate Cancer

2. Slide credit: clinicaloptions.com Prostate Cancer Diagnosis May Occur at Various Stages and Progress Through Different Pathways Biochemical recurrence* Definitive therapy mCRPC mHSPC nmCRPC Localized/locally advanced prostate cancer Rising PSA Start ADT Criterion 2: Rising PSA despite castrate levels of testosterone Criterion 1: Identification of metastases Rising PSA despite castrate levels of testosterone Identification of metastases Both criteria met Anantharaman. Expert Rev Anticancer Ther. 2017;17:625. NCCN. Clinical practice guidelines in oncology: prostate cancer. v.1.2023. nccn.org. *Slow PSA doubling time (eg, >12 mo) suggests indolent disease.

3. Clinical Risk Stratification: D’Amico NCCN = National Comprehensive Cancer Network. NCCN, 2022; D’Amico et al, 1998. Risk group Clinical/pathologic features Additional evaluation Very low Has all of the following: cT1c Grade group 1 PSA <10 ng/mL <3 prostate biopsy fragments/cores positive, ≤50% cancer in each fragment/core PSA density <0.15 ng/mL/g Confirmatory testing can be used to assess the the appropriateness of active surveillance Low Has all the following but does not qualify for very low- risk: cT1- cT2a Grade group 1 PSA <10 ng/mL Confirmatory testing can be used to assess the the appropriateness of active surveillance Intermediate Has all the following: No high-risk or very high- risk risk group features Has ≥1 intermediate risk factor factor (IRF): cT2b- cT2c Grade group 2 or 3 PSA 10- 20 ng/mL Favorable intermediate Has all the following: 1 IRF Grade group 1 or 2 <50% biopsy cores positive (eg, <6 of 12 cores) Confirmatory testing can be used to assess the the appropriateness of active surveillance Unfavorable intermediate Has one or more of the following: 2 or 3 IRFs Grade group 3 ≥50% biopsy cores (eg, ≥6 of 12 cores) Bone and soft tissue imaging If regional or distant metastases are found, found, additional stratification per NCCN High Has no very-high-risk features and has exactly 1 high-risk feature: cT3a OR Grade group 4 or 5 OR PSA >20 ng/mL Bone and soft tissue imaging If regional or distant metastases are found, found, additional stratification per NCCN Very high Has ≥1 of the following: cT3b- cT4 Primary Gleason pattern 5 2 or 3 high-risk features >4 cores with Grade group 4 or 5 Bone and soft tissue imaging If regional or distant metastases are found, found, additional stratification per NCCN

4. Biomarkers to Guide Treatment Selection Localized Prostate Cancer NCCN, 2022. a Molecular testing NOT recommended for VERY–low- risk patients age >65. b Currently ongoing clinical trials: ERADICATE (EA8183), PREDICT- RT (NRG GU-009), and GUIDANCE (NRG GU-010). RNA = ribonucleic acid ; BCR = biochemical recurrence; RT = radiation therapy; mets= metastases. Test name Methodology Clinical role(s) Publication(s) Prolaris ® Tumor RNA: 31 cell cycle genes BCR after surgery Cuzick et al Lancet Oncology, 2011 Oncotype DX ® Tumor RNA: 12 cancer- related genes Low- /intermediate- risk: active surveillance a . Risk of upstaging at at surgery, BCR Klein et al Eur Urol, 2014 Decipher ® Tumor RNA: 22 coding and non-coding High- risk: need for adjuvant RT, risk risk of mets, intensification/de- intensification b Intermediate- risk: intensification/de- intensification/de- intensification b of Den et al JCO, 2015 Ross et al PCAN, 2014

5. Decipher Score Changes Treatment Decisions ADT = androgen deprivation therapy. Gore et al, 2017. Post- Prostatectomy Management Decipher Low- risk Decipher High- risk Decipher Intermediate- risk

6. After prostatectomy According to AUA guidelines, a biochemical recurrence is defined as a serum PSA ≥0.2 ng/mL, which is confirmed by a second determination with a PSA ≥0.2 ng/ mL. After radiotherapy A PSA rise of 2 ng/mL or more above the nadir PSA is considered the standard definition for biochemical failure after external beam RT, regardless of whether or not a patient receives androgen deprivation therapy. High Risk relapse Various clinical, pathologic, and molecular factors can be used to predict an increased likelihood of metastatic disease and death from prostate cancer. The most important of these are: a short PSA doubling time after radical prostatectomy, A short interval to biochemical recurrence after radiotherapy, a higher Gleason score and a local recurrence following local therapy Hormone-sensitive Castration-resistant relapse Most of these individuals have testosterone levels that are >50 ng/mL, and their prostate cancer is described as castration-sensitive. However, some will have rising PSA despite suppressed testosterone levels, and such patients are said to have a castration-resistant biochemical recurrence Definitions of biochemical recurrence

7. Treatment Options in M0 CRPC Non-metastatic defined by conventional imaging LN = lymph node; bPSA = benign prostate- specific antigen; MI = myocardial infarction. Smith et al, 2018; Fizazi et al, 2019; Hussain et al, 2018. Agent Apalutamide 240 mg daily Darolutamide 600 mg BID Enzalutamide 160 mg daily Study name SPARTAN ARAMIS PROSPER Design 2:1 apa/placebo 2:1 daro/placebo 2:1 enza/placebo Number of patients 1,207 1,509 1,401 Inclusion: PSA DT <10 months Pelvic LN <2 cm OK PSA DT ≥10 months Pelvic LN <2 cm OK bPSA ≥2 PSA DT ≤10 months bPSA ≥2 Metastasis- free survival 40.5 vs 16.2 months placebo placebo (HR 0.29) 40.4 vs 18.4 months placebo (HR 0.41) 36.6 vs 14.7 months placebo (HR 0.29) Discontinuation 10.6% apa, 7.0% placebo 8.9% daro, 8.7% placebo 10% enza, 6% placebo Adverse events Higher rate of rash, hypothyroidism, and fracture fracture Incidence similar to placebo, except higher rate of fatigue Higher rate of grade ≥3; higher higher rate of hypertension, MI, MI, fatigue, falls, and fractures

8. Treatment Options in M0 C S PC ADT for M0 Castration-Sensitive Disease After Maximal Pelvic Therapy • Monitoring until diagnosis of metastatic disease is preferred for patients with non-metastatic castration-sensitive disease who are not candidates for pelvic therapy. • PSADT and Grade Group should be considered when deciding whether to begin ADT for patients with M0 disease. • ADT monotherapy is an option or these patients, and intermittent ADT can be considered. • Enaluztamide with or without leuprolide is an option for patients who have the following high-risk criteria ( EMBARK trial): M0 by conventional imaging; 2. PSADT ≤9 months; PSA≥2 ng/mL above nadir after RT or ≥1 ng/mL after RP with or without postoperative RT; 4. and not considered a candidate for pelvic-directed therapy.

9. Randomized phase III trial Stratified by PSA (≤10 ng/mL vs >10 ng/mL), PSADT (≤3 mo vs >3 to ≤9 mo), prior hormonal therapy (Y/N) Primary endpoint: MFS by BICR for enzalutamide + leuprolide vs leuprolide Secondary endpoint: MFS by BICR for enzalutamide vs leuprolide, time to PSA progression, time to first use of new therapy, OS, safety EMBARK: Enzalutamide or Placebo + Leuprolide or Enzalutamide Alone in Biochemically Recurrent PC Patients with PC post RP with screening PSA ≥1 ng/mL and ≥2 ng/mL above nadir for primary EBRT; PSADT ≤9 mo; no bone mets by bone scan or CT/MRI and central review; testosterone ≥150 ng/dL; prior hormonal therapy ≥9 mo before randomization (N = 1068) Enzalutamide 160 mg oral QD + Leuprolide Acetate 22.5 mg IM/q12w (n = 355) Placebo + Leuprolide Acetate 22.5 mg IM/q12w ( n = 358) Enzalutamide Monotherapy 160 mg oral QD ( n = 355) PSA <0.2 ng/mL at Wk 36 Suspend treatment at Wk 37; monitor PSA Continue therapy Yes No Slide credit: clinicaloptions.com Shore. AUA 2023. Abstr LBA02-09.

10. EMBARK Enzalutamide/Leuprolide vs Leuprolide/Placebo: MFS Enzalutamide Combination (n = 355) Leuprolide Acetate (n = 358) 60.6 92 (26) 60.7 45 (13) NR (NR) NR (85.1- NR) Median follow- up, mo Events, n (%) Per BICR, median MFS, mo (95% CI) HR: 0.42 (95% CI: 0.31- 0.61; P <.0001) 3- Yr Rate 92.9% 83.5% 5- Yr Rate 87.3% 71.4% Patients at Risk, n Enzalutamide combination 366 331 324 318 304 292 281 265 251 234 180 116 60 24 6 Leuprolide acetate 368 336 321 303 280 259 238 221 203 183 138 88 32 15 6 1 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 Mo MFS (%) 100 80 60 40 20 Enzalutamide combination Leuprolide acetate Slide credit: clinicaloptions.com Shore. AUA 2023. Abstr LBA02-09.

11. Slide credit: clinicaloptions.com EMBARK: Selected AEs Shore. AUA 2023. Abstr LBA02-09. AEs, % Enzalutamide Combination Enzalutamide Monotherapy Leuprolide (n = 353) (n = 354) (n = 354) Any Grade ≥3 Any Grade ≥3 Any Grade ≥3 Any TRAE 86.4 17.6 88.1 16.1 79.9 8.8 Serious TRAE 7.4 6.2 4.8 4.8 2.3 2.0 Hot flash 68.8 0.6 21.8 0.3 57.3 0.8 Fatigue 42.8 3.4 46.6 4.0 32.8 1.4 Falls 21.0 0.8 15.8 1.4 14.4 0.6 Cognitive and memory impairment 15.0 0.6 14.1 6.5 0.6 Ischemic heart disease 5.4 4.0 9.0 5.9 5.6 3.1 Gynecomastia 8.2 44.9 0.3 9.0

12. Slide credit: clinicaloptions.com Randomized, open- label phase III trial PRESTO: Apalutamide ± Abiraterone + ADT vs ADT in Biochemically Recurrent Prostate Cancer Aggarwal. ESMO 2022. Abstr LBA63. Aggarwal. AUA 2023. Abstr LBA02-11. Patients with PC post RP and PSA ≥0.5 ng/mL; PSADT ≤9 mo; no mets by conventional imaging; last ADT dose >9 mo before entering study; prior adjuvant/salvage RT unless not a candidate for RT (N = 504) LHRH Analogue* LHRH Analogue + Apalutamide LHRH Analogue + Apalutamide + Abiraterone Acetate + Prednisone F/u for PSA progression Stratified by PSADT (<3 mo vs 3-9 mo) 52 wk Investigator’s choice of therapy and long-term f/u *Degarelix or leuprolide with bicalutamide. Primary endpoint: PSA PFS in ITT population Secondary endpoint: PSA PFS in testosterone- evaluable patients, PSA PFS comparison between ITT and testosterone evaluable, time to castration resistance, serum testosterone, MFS, OS, safety, QoL

13. Median f/u: 26.7 mo Median PSA PFS: 27.6 mo vs 21.0 mo (HR: 0.53; 95% CI: 0.38- 0.74; P = .00006) for triple vs ADT alone Slide credit: clinicaloptions.com Median f/u: 26.5 mo Median PSA PFS: 24.5 mo vs 21.0 mo (HR: 0.59; 95% CI: 0.42- 0.81; P = .0006) for ADT/APA vs ADT PRESTO: PSA Progression- Free Survival Aggarwal. AUA 2023. Abstr LBA02-11. ADT + Apalutamide vs ADT ADT + Apalutamide + Abiraterone/Prednisone vs ADT ARM LHRH LHRH + APA Events/Total 75/166 71/168 + censor % Without Event 100 80 60 40 20 LHRH + APA + AAP ARM Events/Total LHRH 75/165 67/169 + censor % Without Event Mo Patients at Risk, n 6 12 18 24 30 Mo 36 42 48 Patients at Risk, n 6 12 18 24 30 36 42 48 LHRH 166 121 31 8 LHRH 166 121 31 8 LHRH + APA 168 137 52 17 3 LHRH + APA + AAP 169 133 60 20 2 100 80 60 40 20

14. CONCLUSIONS In patients with high-risk biochemical recurrence, compared with leuprolide acetate, enzalutamide combination with leuprolide acetate demonstrated a statistically significant and clinically meaningful improvement in MFS (HR: 0.42, 95% CI: 0.30 – 0.61, p<0.0001) according to EMBARK tria l results A consistent treatment effect was observed across pre-specified subgroups Significant delays in time to PSA progression and time to first new antineoplastic therapy were observed A trend towards improved survival in the interim analysis was noted; the study is ongoing for final analysis Enzalutamide monotherapy also demonstrated statistically significant and clinically meaningful improvements in MFS, time to PSA progression, and time to first antineoplastic therapy A trend toward improved survival in interim analysis No new safety signals were observed As such, enzalutamide in combination with ADT, if approved in this setting, has the potential to become a new standard of care for patients with high-risk BCR with a PSADT <9 months and no evidence of metastasis on conventional imaging Results of PRESTO trial are still considered immature

15. CASE-1

16. Axial T2-weighted images of the prostate at the midgland at different levels show a PIRADS 5 lesion in the left peripheral zone. However, the zone of hypointensity can be seen extending beyond the capsule toward the periprostatic fat with an interruption of the capsule ( white arrows ) (ESUR Score 4, high risk of ECE).

17. Surgical specimen confirmed a pT3a Gleason 4 + 5 PCa with infiltration of the periprostatic fat of up to 4 mm ( black arrows )

18. CASE-1 BRIEF HISTORY OF RELAPSE

19. PSA MONTHS PSA KINETICS AFTER RELAPSE 6/23-1.1 10/23-1.8 1/24-2.2 4/24-1.3 7/24-0.4 TREATMENT INITIATION

20. We continue monitoring PSA and testosterone levels every three months, bone scan and CT imaging every six months and checking for adverse events , especially cardiometabolic and bone health. Six months later he has a PSA response and the only adverse event is Grade 1 fatigue. A patient with biochemical recurrent prostate cancer began treatment in January 2024, according to Embark trial , with enzalutamide and leuprolide acetate Summary-Case 1

21. CASE-1 CASE-2

22. Invasion of seminal vesicles (T3b disease) (a) Axial, (b) coronal T2-weighted images show tumoral invasion of the right seminal vesicle extending from a PCa located in the right prostatic base (partially seenas a hypointense lesion in B). The right seminal vesicle presents an ill defined abnormal hypointensity in its most caudal segment Tumor is recognized within the smooth muscle wall of seminal vesicle tissue

23. BRIEF HISTORY OF RELAPSE

24. PSA KINETICS AFTER RELAPSE 8/23-4 11/23-5.7 2/24-8 5/24-4 8/24-2

25. We continue monitoring PSA and testosterone levels every three months, bone scan and CT imaging every six months and checking for adverse events , especially cardiometabolic and bone health. Six months later he has a PSA response without any adverse event. His coronary heart disease is improved A patient with biochemical recurrent prostate cancer began treatment in February 2024, according to Embark trial , with enzalutamide monotherapy Summary-Case 2