TALAPRO-2 Trial

[Slide 1] SATURDAY 5/31 1:15PM rapid orals RCC + BLADDER -Padeliporfin vascular targeted photodynamic therapy in LG UTUC -5yr f/u for KN-564 adjuvant pembro in RCC -Zanza + nivo +/- relatlimab in 1L RCC (STELLAR) -Ipi/nivo on PDIGREE: results from step 1 analysis -Sasanlimab + BCG in NMIBC -Neaodjuvant saci + pembro in MIBC (SURE-02) -Novel nectin-4 ADC + toripalimab in 1L mUC -Pre-op abemaciclib for cisplatin-ineligible MIBC -Axi/nivo VS nivo in TFE/translocation RCC (AREN1721) 5/31 3PM educational session: advancing peri-op tx in MIBC 5/31 4:30PM biomarkers in RCC --- [Slide 2] SUNDAY 6/1 9:45AM orals RCC + BLADDER -Final results from CM-901 -Avelumab + SC VS avelumab maintenance in JAVELIN Bladder Medley -Exploratory analysis of responders in EV-302 -ctDNA in MIBC from NIAGARA -MMC + BCG for NMIBC (ANZUP-1301) -Final analysis of CM-214 -Casdatifan + cabo in previously treated RCC -5-year f/u of phase II LITESPARK-004 (belzutifan) -Phase 1 TRAVERSE study (ALLO-316) 6/1 4:30PM rapid orals PROSTATE -Non-inferiority adjuvant platinum/taxol VS platinum/5FU in high-risk penile CA -Doce + ADT + RT in high-risk PCa -Intensified hormonal blockade with SBRT in PSMA-PET oligomet PCa (Metacure) -Novel B7H3 ADC in mCRPC -Phase 1 Pasritamig (anti-KLK2/CD3 bispecific) in mCRPC -Ipi/nivo +/- SBRT in mCRPC -Exploratory analysis of HRRm by gene subgroup from TALAPRO-2 -Clonal hematopoeisis in mCRPC Lu-617 VS cabazitaxel (TheraP) --- [Slide 3] MONDAY 6/2 9AM posters PROSTATE + RCC + BLADDER 6/2 1:15PM educational session refining tx for patients with metastatic GCT 6/2 3PM new frontiers in PSMA radioligand therapy TUESDAY 6/3 8AM personalizing tx for pts with mCRPC in 2025 6/3 9:45AM oral abstract PROSTATE -CAN-2409 + EBRT in localized PCa -Better treatments + selection in localized PCa -Prognostic significance of PSA>0.2 at 6-12mo in mCSPC -Transcriptome classification of PTEN inactivation to predict cervical from docetaxel at start of ADT for MPC -HRQoL ARANOTE (daro in mCSPC) -ARCHES 5-yr f/u (enza + ADT in mCSPC) -Phase 3 AMPLITUDE: nira + abi in mCSPC with HRRm -Olaparib + radium-223 VS radium-223 in mCRPC with bone metastases -Phase II carbo/cabazi/cetrelimab followed by niraparib +/- cetrelimab in men with aggressive variant PCa

[Slide 1] Abstract #5019, ASCO Annual Meeting 2025 Exploratory analyses of homologous recombination repair alterations (HRRm) by gene subgroup and potential associations with efficacy in the HRR-deficient population from TALAPRO-2 Stefanie Zschaebitz, Karim Fizazi, Nobuaki Matsubara, Douglas Laird, Arun Azad, Neal D. Shore, Consuelo Buttigliero, Cezary Szczylik, Andr Poisl Fay, Joan Carles, Robert J. Jones, Eric Voog, Fong Wang, Ugo De Giorgi, Steven Yip, Diana Hubbard, Xun Lin, Matko Kalac, Neeraj Agarwal @neerajaiims --- [Slide 2] Abstract #5019, ASCO Annual Meeting 2025 Exploratory analyses of homologous recombination repair alterations (HRRm) by gene subgroup and potential associations with efficacy in the HRR-deficient population from TALAPRO-2 Presenting Author: Stefanie Zschaebitz TALAPRO-2: A Randomized, Double-blind, Placebo-Controlled Study Patient population Talazoparib 0.5 mg* + Primary endpoint First-line mCRPC enzalutamide 160 mg, Radiographic progression-free survival (rPFS) by once daily ECOG performance status (PS) 0 or 1 blinded independent central review (BICR) (N=402) Stratification factors ("0.35 mg daily if moderate renal impairment) Key secondary endpoint Prior abiraterone or docetaxel in Overall survival (alpha protected) castration-sensitive setting (yes vs no) 1:1 (N=805) HRR gene alteration status Other secondary endpoints (deficient vs nondeficient or unknown) Time to cytotoxic chemotherapy Placebo + PFS2 by investigator assessment All comers (Cohort 1). N=805 enzalutamide 160 mg, once Objective response rate (ORR) daily Patient-reported outcomes Nondeficient HRRm HRRm or unknown (N=403) Safety N=169 N=230 N=636 (Data cutoff: August 16, 2022) HRRm only (Cohort 2), N=399 Samples prospectively assessed for HRR gene alterations (BRCA1, BRCA2, PALB2, ATM, ATR, CHEK2, FANCA, RAD51C, NBN, MLH1, MRE11A, CDK12) using FoundationOneCD: and/or FoundationOneLiquid CDx We report results only from the all-comers cohort of men unselected for HRR gene alterations To maintain the overall type error at or below 1-sided 0.025, alpha for IPFS by BICR was split equally between the all-comers and forthcoming molecularly selected cohort (1-sided alpha of 0.0125 for each). If the PFS showed statistically significant improvement, overall survival was tested in a hierarchical stepwise procedure to preserve the overall type error. *Two patients in each treatment arm received prior orteronel *Time from randomization to the date of documented progression on the first subsequent antineoplastic therapy or death from any cause, whichever occurred first ClinicalTrials.gov (NCT03395197) Trial design: ASCO GU 2023 @neerajaiims --- [Slide 3] Abstract #5019, ASCO Annual Meeting 2025 Exploratory analyses of homologous recombination repair alterations (HRRm) by gene subgroup and potential associations with efficacy in the HRR-deficient population from TALAPRO-2 Presenting Author: Stefanie Zschaebitz Results: For all HRRm pts, TALA + ENZA was superior to ENZA + PBO across all efficacy endpoints: ORR, 69.4% vs 39.1% (odds ratio [OR], 0.28 [95% CI, 0.13-0.61]); rPFS, median 30.7 VS 12.3 months (mo) (hazard ratio [HR]=0.47 [0.36-0.62]); OS, median 45.1 vs 30.8 mo (HR=0.60 [0.46-0.78]). TALA + ENZA vs ENZA + PBO demonstrated benefit for BRCA2m across endpoints: ORR, 86.4% vs 31.0% (OR, 0.07 [95% CI, 0.01-0.35]); rPFS, median not reached (NR) VS 10.9 mo (HR=0.25 [0.15-0.42]); OS, median NR vs 28.5 mo (HR=0.47 [0.29- 0.76]). Similar rPFS and OS benefit was seen for BRCA1m and PALB2m (allowing for small n in the groups); for ORR, evaluable n of 8 across arms for each gene was too low to meaningfully assess ORR differences. Benefit for TALA + ENZA was also evident for CDK12m: ORR, 63.6% vs 22.2% (OR, 0.16 [95% CI, 0.01-1.61]); rPFS, 19.3 vs 13.8 mo (HR=0.36 [0.19-0.70]); OS, 36.4 VS 22.8 mo (HR=0.41 [0.23-0.74]). ATMm also showed benefit for TALA + ENZA: ORR, 75.0% VS 33.3% (OR, 0.17 [95% CI, 0.02-1.32]); rPFS, 30.4 vs 18.3 mo (HR=0.66 [0.37-1.18]); OS, 45.1 VS 39.5 mo (HR=0.70 [0.38-1.29]). CHEK2m showed modest overall benefit for TALA + ENZA: ORR, 53.3% VS 42.9% (OR, 0.66 [95% CI, 0.07-5.59]); rPFS, 24.8 vs 18.3 mo (HR=0.65 [0.34-1.22]); OS, 34.2 VS 39.5 mo (HR=0.96 [0.51-1.81]). The remaining six HRR12 genes could not be meaningfully assessed for efficacy benefit by gene with TALA + ENZA vs ENZA + PBO due to low mutational prevalence. Conclusions: An efficacy benefit was evident for TALA + ENZA VS PBO + ENZA across multiple mutational subgroups assessed by gene, and was most pronounced for the BRCA1-PALB2-BRCA2 axis and CDK12, with benefit also apparent for ATM. Analyses of additional efficacy endpoints are planned and will be presented. X @neerajaiims

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[Slide 1] TALAPRO-2: Background ary Real-world median OS for mCRPC <3 years, nearly half of patients - AR downregulates HRR gene E receive only one stemic expression ACa AS treatment Ca Precincal evidence for PARPI plus PARP imbition suppresses AR ARPI combination to extend benefit transcriptional activity Denpts 558 repair to patients with mCRPC without leading CS8 HRR gene alterations PARP trapping Suppresses VIN nbb transcription AR activity and destablizes TALAPRO-2, talazoparib plus DNA replication bills improved PFS versus placebo plus enzalutamide unselected as well as HRR. Co-inbilition of AR and PARP may deficient mCRPC os data were not enhanced benefit in tunos N, immature at primary analysis with or without HRR gine sheratons IN G 20 ASCO® Genitourinary ASCO Contractory IN 25 Cancers Symposium - Carcers Symposum @neerajalims ASCO rticipate using the ASCO Meetings mobile app or at meetings.asco.org ASCO Gentourinary Cancers Symposium A SCO Genitourinary C Sym osium --- [Slide 2] TALAPRO-2: Trial Design Patient population Primary endpoint 1L mCRPC rPFS by BICR ECOG 0 or 1 Talazoparib + enzalutamide Ongoing androgen deprivation (N=402) Key secondary endpoint therapy OS (alpha protected) Stratification factors 1:1 Unselected Cohort 1 (N=805) Other secondary endpoints Prior abiraterone or docetaxel for CSPC (yes VS no) Time to cytotoxic chemotherapy HRR gene alteration status Placebo + enzalutamide PFS2 (deficient vs non-deficient or (N=403) ORR unknown) Patient-reported outcomes Safety Sequential enrollment In two cohorts: Unselected (Cohort 1), N=805 Samples prospectively assessed for HRR gene alterations (ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, NBN, MLH1, MRE11A, PALB2, RADS1C) Non-deficient HRRm HRRm using FoundationOne/FoundationOne-CDx and FoundationOne*Liquid CDx or unknown N=169 N=230 N=636 DCO1: Aug 16, 2022 DCO2: March 28, 2023 DCO3: Sept 3, 2024 rPFS (primary) OS (interim) OS (final) current HRRm only (Cohort 2). N=399 Analysis timeline: (unselected) Prior orteronel was received by two patients in each treatment arm in Cohort 1 and one patient in each treatment arm in Cohort 2. Unselected cohort only. independent central neverw, CSPC-castration sersive prostate cancer DCOrdata response rate PFS2=1ime to second progression or death, ASCO Genitourinary Cancers Symposium #GU25 PRESENTED IT: Professor Neeraj Agarwal X supporty be - and - @neerajaiims ASCO AMERICAN SOCIETY OF CURICAL OHCOLOGY | ASCO Permission - KNOWLEDGE CONQUERS CANCER --- [Slide 3] TALAPRO-2 Un Primary Endpoint: rPFS by BICR Statistically significant and clinically meaningful benefit maintained with ~2 years of additional follow-up Primary analysis (DCO: Aug 16, 2022)¹ Update (DCO: Sept 3, 2024) Median Median Events/ Median rPFS Events/ Median rPFS follow-up, follow-up, patients (95% CI), mo patients (95% CI), mo 1.0 mo 1.0 mo TALA + ENZA 151/402 NR (27.5-NR) 24.9 TALA + ENZA 202/402 33.1 (27.4-39.0) 47.0 0.8 PBO + ENZA 191/403 21.9 (16.6-25.1) 24.6 0.8 PBO + ENZA 231/403 19.5 (16.6-24.7) 46.9 ... 13.6 months improvement Probability of rPFS 0.6 Probability of rPFS 0.6 04 0.4 0.2 02 HR=0.627 (0.506-0.777); P<0.0001 HR=0.667 (0.551-0.807); P<0.0001° 0.0 0.0 0 4 8 12 16 20 24 28 32 30 40 44 48 52 56 60 64 65 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 Time (Months) No. at risk No. at risk Time (Months) TALA + ENZA 402 353 318 256 226 193 136 67 29 2 1 0 0 0 0 0 0 0 TALA + ENZA 402 353 318 257 228 196 180 155 138 122 108 101 63 50 13 7 1 0 PEO + ENZA 403 311 272 200 179 140 96 43 14 1 1 0 0 0 0 0 0 0 PBO + ENZA 403 312 273 201 180 138 128 100 92 81 72 66 44 35 5 2 1 0 Stratified hazard ratios (HRs) and 2-sided P values are reported throughout this presentation unless otherwise stated. "The updated IPFS data are descriptive. DCO=data cutoff, NRmot reached, PBOrpiacetic : Repreduced with permission from Agaiwal N, et al. Lancer 2023,402,291.303 ASCO Genitourinary Cancers Symposium #GU25 PRESENTED ev: Professor Neeraj Agarwal X @neerajaiims ASCO AMERICAN SOCIETY or CLINICAL ONCOLOGY Presentation to property of the other and ASCO Parmission required for now order permissions@gmail.org KNOWLEDGE CONGUERS CANCER 1 --- [Slide 4] TALAPRO-2 Un Overall Survival (Final Analysis) 20.4% reduction in risk of death, >8 months improvement in median OS 1.0 Median os Events/patients (95% CI), mo 0.8 TALA + ENZA 211/402 45.8 (39.4-50.8) PBO + ENZA 243/403 37.0 (34.1-40.4) Probability of OS 0.6 8.8 months improvement 0.4 Median follow-up for os was 52.5 months 0.2 HR=0.796 (0.661-0.958); P=0.0155 0.0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 No. at risk Time (Months) TALA + ENZA 402 390 371 347 319 296 285 250 226 212 193 183 158 89 42 11 1 0 PBO ENZA 403 391 362 331 305 267 257 231 207 163 163 145 127 77 33 4 1 0 For statistical significance at the final overall survival analysis, the stratified log-rank 2-sided P value needed to be 50.022 based on a group sequential design with O'Brien-Fleming spending function. Data cutoff: September 3, 2024. ASCO Genitourinary #GU25 PRESENTED BY Professor Neeraj Agarwal Cancers Symposium X @neerajaiims ASCO AMERICAN society or CUNCAL ONCOLOGY Presentation property after - ASCO Pensulat required X - - KNOWLEDGE CONQUERS CANCER

[Slide 1] BJU Int 2025 doi:10.1111/bju.16776 BJUI Comment BJU International Precision medicine in genitourinary oncology: are we pivoting towards imprecision? David J. Benjamin¹ ID and Arash Rezazadeh Kalebasty² ¹Hoag Family Cancer Institute, Newport Beach, and ²Division of Hematology and Medical Oncology, Department of Medicine, University of California Irvine, Orange, CA, USA In February 2025, the final overall survival (OS) results from In addition to targeted therapies, immune checkpoint the phase III trial TALAPRO-2 (ClinicalTrials.gov identifier: inhibitors have transformed the treatment of several NCT03395197) evaluating the poly-(ADP-ribose)-polymerase malignancies. While some individuals experience significant, (PARP) inhibitor talazoparib plus enzalutamide in treating long-lasting clinical benefit, only 20-40% of treated metastatic castrate-resistant prostate cancer (mCRPC) were individuals derive any benefit from immunotherapy. As presented at the American Society of Clinical Oncology such, there have been efforts to identify biomarkers, such (ASCO) Genitourinary Cancers Symposium. The trial had as tumour mutational burden, to pair immunotherapy with previously met its primary endpoint of radiographic the individual with the highest probability of clinical progression-free survival (PFS), leading to United States benefit. Similar efforts to identify biomarkers have been Food and Drug Administration approval for mCRPC with attempted with ADCs such as enfortumab. However, such homologous recombination repair (HRR) deficiency. efforts were recently refuted by the enfortumab clinical trial However, updated analysis demonstrated an OS benefit in investigators. As such, TALAPRO-2 and enfortumab both not only the HRR deficient population, but also HRR represent a potential pivot in the field of genitourinary proficient population. This distinction is noteworthy as prior oncology away from precision medicine. Hereafter, we mCRPC trials evaluating PARP inhibitors only included discuss several concerns with this movement towards individuals with BRCA, ATM or other eligible HRR gene imprecision oncology. alterations given the therapy's distinct mechanism of action Poly-(ADP-ribose)-polymerase inhibitors were initially [1]. Given the survival benefit seen with TALAPRO-2, it is developed for cancers harbouring deficiencies in HRR. anticipated the trial's sponsor will seek regulatory approval Specifically, PARP inhibitors primarily bind to PARP1 to for all men with mCRPC as opposed to only those with prevent PARP-mediated repair of single-stranded DNA HRR deficiency. breaks [3]. By doing so, HRR deficient cells accumulate DNA --- [Slide 2] Comment Therefore, TALAPRO-2 and its movement towards PARP inhibitor exposure to more men might represent a step Disclosure of Interests forward in managing this challenging-to-treat disease, while David J. Benjamin has the following disclosures: Consulting/ also representing two steps backward for biomarker-driven Advisory Role: AIMED BIO, Astellas, AVEO Oncology, cancer treatment. Bayer, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Janssen, Janux, Seagen. Speakers' Bureau: Merck. Travel and Since its recent regulatory approvals, the combination of enfortumab vedotin plus pembrolizumab (EVP) has been Accommodations: DAVA Oncology, Merck, Seagen. Arash adopted as the preferred first-line regimen in advanced UC. Rezazadeh Kalebasty has the following disclosures: Stock and Several studies have attempted to identify biomarkers that Other Ownership Interests: ECOM Medical. Consulting or predict responsiveness with enfortumab. In fact, pre-clinical Advisory Role: Exelixis, AstraZeneca, Bayer, Pfizer, Novartis, Genentech, Bristol Myers Squibb, EMD Serono, data from several groups has supported nectin-4 expression as being required for enfortumab-induced cell death and Immunomedics, Gilead Sciences. Speakers' Bureau: Janssen, Astellas Medivation, Pfizer, Novartis, Sanofi, Genentech/ that decrease in nectin-4 expression during metastatic spread is a resistance mechanism to this nectin-4 targeting Roche, Eisai, AstraZeneca, Bristol Myers Squibb, Amgen, Exelixis, EMD Serono, Merck, Seattle Genetics/Astellas, ADC [5]. Additionally, research has suggested that NECTIN4 amplification may serve as a biomarker for Myovant Sciences, Gilead Sciences, AVEO. Research Funding: responsiveness to enfortumab and OS [5]. In response to Genentech, Exelixis, Janssen, AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Macrogenics, Astellas Pharma, these studies, EV-302 investigators presented exploratory biomarker analysis at the European Society for Medical BeyondSpring Pharmaceuticals, BioClin Therapeutics, Clovis Oncology (ESMO) Congress in late 2024. While the Oncology, Bavarian Nordic, Seattle Genetics, Immunomedics, investigators concluded that there was a consistent benefit Epizyme. Travel, Accommodations, Expenses: Genentech, Prometheus, Astellas Medivation, Janssen, Eisai, Bayer, Pfizer, for EVP among all subgroups regardless of nectin-4 Novartis, Exelixis, AstraZeneca. expression, closer analysis of their data disputes this claim. In fact, in individuals with a nectin-4 histochemical score References (H-score) from 150 to 225, the PFS benefit was 6.3 months compared to 6.2 months in those who received 1 Bourlon MT, Valdez P, Castro E. Development of PARP inhibitors in advanced prostate cancer. Ther Adv Med Oncol 2024; 16: chemotherapy (hazard ratio 0.680, 95% CI 0.408-1.133) as 17588359231221337 opposed to those with a H-score >225 (PFS benefit of 2 Fu Z, Li S, Han S, Shi C, Zhang Y. Antibody drug conjugate: the 14.6 months with EVP versus 6.4 months compared to "biological missile" for targeted cancer therapy. Signal Transduct Target chemotherapy) [6]. These findings, taken together with Ther 2022; 7: 1-25 previous biomarker studies on nectin-4, suggest further 3 Li S, de Camargo Correia GS, Wang J, Manochakian R, Zhao Y, Lou Y. research is warranted to identify which patients may Emerging targeted therapies in advanced non-small-cell lung cancer. Cancer 2023; 15: 2899 benefit from EVP and those who may benefit from another 4 Markowski MC, Antonarakis ES. PARP inhibitors in prostate cancer: time therapeutic approach. to narrow patient selection? Expert Rev Anticancer Ther 2020; 20: 523-6