Paradigm Shift in the Management of Metastatic Castration-Sensitive Prostate - PowerPoint Presentation

1. Paradigm Shift in the Management of Metastatic Castration-Sensitive Prostate Cancer (mCSPC)1Neal Shore, MD, FACSCarolina Urologic Research CenterMyrtle Beach, SCAlicia Morgans, MD, MPHNorthwestern UniversityChicago, IL

2. PROSTATE CANCER IS HORMONE DEPENDENT2Huggins CB. Nobel lecture. Available from http://nobelprize.org/nobel_prizes/medicine/laureates/1966/huggins-lecture.html. Dec 13, 1966. Accessed August 2020.“Despite regressions of great magnitude,it is obvious that there were many failures of endocrine therapyto control the disease”Charles B. Huggins Nobel lecture, December 13, 1966

3. Androgen deprivation therapy (ADT) monotherapy for metastatic prostate cancer has been foundational yet has limited to poor clinical outcomes Tumor burden, location, and biology affect overall survivalA new standard of care for metastatic castration-sensitive prostate cancer (mCSPC) is combined therapyADT plus the early addition of either docetaxel or an androgen receptor pathway inhibitor (ARPI)Background3Lowrance W, et al. Advanced prostate cancer: AUA/ASTRO/SUO guideline. Available from https://www.auanet.org/guidelines/advanced-prostate-cancer. Accessed Jul 27, 2020; Schaeffer E, et al. NCCN clinical practice guidelines in oncology. Prostate cancer, V2.2020. Available from www.nccn.org. May 21, 2020. Accessed Jul 27, 2020

4. Treatment Options for mCSPC 20204ADT, androgen deprivation therapy; EBRT, external beam radiation therapy; M0, nonmetastatic; M1, metastatic; mo, months; PSA, prostate specific antigenSchaeffer E, et al. NCCN clinical practice guidelines in oncology. Prostate cancer, V2.2020. Available from www.nccn.org. May 21, 2020. Accessed Jul 27, 2020How to choose?

5. Development of Novel Hormone Therapy and Chemotherapy5

6. The Development of Novel Hormone Therapy and Chemotherapy in mCSPC6ASCO, American Society of Clinical Oncology; ESMO, European Society for Medical Oncology; GU, genitourinary; mCSPC, metastatic castration-sensitive prostate cancer; RT, radiation therapy1. Maughan BL, et al. J Clin Oncol. 2015;33(suppl):e16079; 2. Fizazi K, et al. J Clin Oncol. 2017;35(suppl):LBA3. 3. Hoyle AP, et al. Ann Oncol. 2018;29(suppl 8):viii722 (abstract LBA4); 4. Chi KN, et al. J Clin Oncol. 2019;37(suppl):5006; 5. Armstrong AJ, et al. J Clin Oncol. 2019;37(suppl 7S):687; 6. Sweeney C, et al. J Clin Oncol. 2019;37(suppl):LBA2; 7. NCT01957436 at www.clinicaltrials.gov; 8. NCT02799602 at www.clinicaltrials.govCHAARTED (docetaxel)First patient in 2007ASCO 20151LATITUDE(abiraterone)First patient in 2013ASCO 20172STAMPEDE(abiraterone)First patient in 2006 ESMO 2018 (arm G)3 TITAN(apalutamide)First patient in 2015ASCO 20194ARCHES(enzalutamide)First patient in 2016ASCO GU 20195ENZAMET(enzalutamide)First patient in 2014ASCO 20196ARASENS8(darolutamide + docetaxel)First patient in 2016;primary completion: 2021PEACE17(abiraterone + docetaxel + RT)First patient in 2013,last patient in 2020

7. Chemohormonal Therapy7Sweeney CJ, et al. N Engl J Med. 2015;373:737-46; James ND, et al. Lancet. 2016;387:1163-77

8. Chemohormonal Therapy: overall survival8ADT, androgen deprivation therapy; CI, confidence interval; HR, hazard ratio; mo, months; OS, overall survival; SOC, standard of care 1. Sweeney CJ, et al. N Engl J Med. 2015;373:737-46; 2. James ND, et al. Lancet. 2016;387:1163-77CHAARTED1STAMPEDE2Median OS docetaxel: 81 moMedian OS SOC: 71 moHR 0.78, 95% CI 0.66–0.93; P = 0.006No. at risk (events)SOCSOC + docetaxelTime from randomization (months)

9. Definitions of “High Volume” and “high risk”9mets, metastasesIacovelli R, et al. Crit Rev Oncol Hematol. 2019;139:83-61. Sweeney CJ, et al. N Engl J Med. 2015;373:737-46; 2. Fizazi K, et al. N Engl J Med. 2017;377:352-60“Low volume” is not high riskDEFINITION OF HIGH-VOLUME DISEASE (CHAARTED STUDY)1At least one of the following criteria:DEFINITION OF HIGH-RISK DISEASE (LATITUDE STUDY)2At least two of the following criteria:

10. Median follow-up 53.7 months in patients with mCSPC randomly selected to receive ADT + docetaxel vs ADT alone (n = 790)CHAARTED: High volume vs Low Volume10ADT, androgen deprivation therapy; CI, confidence interval; HR, hazard ratio; NR, not reached; OS, overall survivalKyriakopoulos CE, et al. J Clin Oncol. 2018;36:1080-7HIGH VOLUMELOW VOLUME

11. STAMPEDE: Survival Outcomes by Volume11CI, confidence interval; HR, hazard ratio; M1, metastaticClarke NW, et al. Ann Oncol. 2019;30:1992-2003OVERALL SURVIVAL: LOW-BURDEN M1Time since randomization (years)0128765439HR 0.76, 95% CI 0.54–1.07, P = 0.10700.20.40.6Survival0.81.0Number at risk(events)Controldocetaxel238124(4)(5)227117(24)(11)201105(29)(7)17296(22)(6)14986(20)(3)10470(8)(11)(7)(3)6938(1)(1)111610(0)(4)3324OVERALL SURVIVAL: HIGH-BURDEN M1Time since randomization (years)0128765439HR 0.81, 95% CI 0.64–1.02, P = 0.06400.20.40.6Survival0.81.0Number at risk(events)Controldocetaxel320148(40)(13)277132(75)(29)200102(43)(23)15477(49)(17)10259(29)(13)5740(13)(5)(0)(2)3221(1)(1)1072(4)(3)169ControldocetaxelControldocetaxel

12. Absolute improvement in survival at 4 years: 9%Meta-Analysis of RCTs of Docetaxel in mCSPC12CI, confidence interval; Doc, docetaxel; mCSPC, metastatic castration-sensitive prostate cancer; NA, not available; RCT, randomized clinical trial; SOC, standard of care; ZA, zoledronic acidVale CL, et al. Lancet Oncol. 2016;17:243-56 OVERALL SURVIVAL

13. Abiraterone Acetate13Fizazi K, et al. N Engl J Med. 2017;377:352-60; James ND, et al. N Engl J Med. 2017;377:338-51LATITUDEDe novo metastatic disease and high risk = 2 of the following 3 factors:Gleason score ≥ 8 Presence of ≥ 3 lesions on bone scanPresence of a measurable visceral lesion

14. HR 0.63, 95% CI 0.52–0.76, P < 0.001LATITUDE: M1 HIGH-RISK mCSPC1STAMPEDE: M1 and M0 mCSPC2 Abiraterone Acetate14ADT, androgen deprivation therapy; CI, confidence interval; HR, hazard ratio; M0, nonmetastatic; M1, metastatic; mCSPC, metastatic castration-sensitive prostate cancer1. Fizazi K, et al. N Engl J Med. 2017;377:352-60; 2. James ND, et al. N Engl J Med. 2017;377:338-51Months0100597602abirateronePlacebo5655645295044794323883322331729357926121824303642HR 0.62, 95% CI 0.51–0.76, P < 0.001Overall survival (%)2030401009080706050PlaceboabirateroneMonths since randomization00960957Combination therapyADT aloneOverall survival probability0.20.41.00.80.661218544842363024(26)(37)917909(63)(88)840806(67)(92)541491(25)(36)161123No. of patients (no. of deaths)No. at riskADT aloneCombination therapy

15. 1,003 (52%) of randomised population had metastatic diseaseSTAMPEDE: SOC + AAP VS SOC15a Per LATITUDE risk criteriaAAP, abiraterone acetate + prednisolone; CI, confidence interval; HR, hazard ratio; IQR, interquartile range; M1, metastatic disease; OS, overall survival; PSA, prostate specific antigen; SOC, standard of care James ND, et al. N Engl J Med. 2017;377:338-51; James N, et al. ESMO 2020. Abstract #611O. Oral presentationOS: SOC + AAP VS SOC1.0050200At riskCensoredDiedProportion surviving0.750.500.250.00012345678464434380811429791962411125039141322182302901009131121713295010047442342167435710134314121755620424128419198176952306251244M1 patient characteristicsSOC(N=502)SOC + AAP(N=501)Median age (range), years67(39-84)67(42-85)Metastatic burden,a % Low risk4443 High risk4648Unclassified109Eligibility criteria, % Newly diagnosed9593 Relapsing57Median PSA (IQR), ng/mL 97.2(26-358)96.3(29-371)SOC, nAt riskCensoredDiedSOC + AAP, nHR 0.60, 95% CI 0.50-0.71;p=0.00000000032017 (M1 only)HR 0.61, 95% CI 0.49-0.75 SOC(N=502)ISOC + AAP(N=501)Median survival, years3.86.6Events, n329244

16. Toxicity at 4 years post-randomisation was similar between treatment arms, with 16% of patients in each group reporting grade ≥3 toxicity STAMPEDE: SOC + AAP VS SOC16AAP, abiraterone acetate + prednisolone; CI, confidence interval; HR, hazard ratio; SOC, standard of careHoyle AP, et al. Eur Urol 2019;76:719-728; James N, et al. ESMO 2020. Abstract #611O. Oral presentationOS BY RISK GROUP (LATITUDE)1.0022200At riskCensoredDiedProportion surviving0.750.500.250.00021400At riskCensoredDied21327121103191328219222016545331725371465714161548109149951496596250110695447529771167311067711011208513277HR 0.55, 95% CI 0.41-0.76;p=0.000011.0023200Proportion surviving0.750.500.250.00024100206224122121815257521912481065121315438473615341245112561316351119121283317166639136651175719791430541788195145HR 0.54, 95% CI 0.43-0.69;p<0.00001SOC, nSOC + AAP, nAt riskCensoredDiedAt riskCensoredDiedSOC, nSOC + AAP, n2018 analysisHR 0.66 (0.44-0.98)P=0.0412018 analysisHR 0.54 (0.41-0.70)P<0.001Low RiskHigh Risk

17. HR 1.16 (95% CI 0.82–1.65), P = 0.40SOC + AAPSOC + DocPSTAMPEDE Comparison: Overall Survival17AAP, abiraterone acetate + prednisone; CI, confidence interval; DocP, docetaxel + prednisone; HR, hazard ratio; KM, Kaplan-Meier; OS, overall survival; SOC, standard of careSydes MR, et al. Ann Oncol. 2018;29:1235-48Prostate cancer-specific survival HR 1.02 (0.70–1.49)Time from randomization (months)0Overall survivalNumber of patients (events)SOC + DocPSOC + AAP189377(7)(9)0.20.40.60.81.0012243648KM OS: ABIRATERONE VS DOCETAXEL183371175358(5)(16)(1)(3)(7)(17)168339(7)(12)158320146307(4)(24)139278(10)(9)(2)(12)11224074161

18. AR-Targeted Agent: Trial Design and Patient Population OverviewADT, androgen deprivation therapy; AR, androgen receptor; NSAA, nonsteroidal antiandrogen1. Armstrong AJ, et al. J Clin Oncol. 2019;37:2974-86; 2. Davis ID, et al. N Engl J Med. 2019;381:121-31; 3. Chi KN, et al. N Engl J Med. 2019;381:13-24ARCHES1(double blind)ENZAMET2,a(open label)TITAN3(double blind)Treatmentenzalutamide + ADT (n = 574) vs placebo + ADT (n = 576)enzalutamide + ADT (n = 563) vs NSAA + ADT (n = 562)apalutamide + ADT (n = 525) vs placebo + ADT (n = 527)Key inclusion criteriaMetastasisBone or soft tissueBone or soft tissue≥ 1 bone lesion, patients excluded if visceral metastasis onlyPrior ADTAllowedAllowedAllowedPriordocetaxelAllowed (18%)Not allowedAllowed (11%)Early concomitant docetaxelNot allowedAllowed (45%)Not allowedAverage duration of therapy14 months34 months23 monthsa The early administration of docetaxel with testosterone suppression was permitted in protocol version 2 as a stratification factor before randomization, according to evidence showing improved survival with this approach. 18

19. TITAN: Apalutamide for mCSPC19HR, hazard ratio; mCSPC, metastatic castration-sensitive prostate cancerChi KN, et al. N Engl J Med. 2019;381:13-24RADIOGRAPHIC PROGRESSION-FREE SURVIVALOVERALL SURVIVAL100Placeboapalutamide7550250061218243036MonthsHR 0.67, P = 0.005 HR 0.48, P < 0.001apalutamidePlaceboPlacebo0061218243036Months100755025Patients free of radiographic progression (%)Patients surviving (%)

20. Overall survival: HR 0.81 (95% CI 0.53–1.25), P = 0.3361, but survival data were immature, with only 14.4 months median follow-up and 84 deathsARCHES: Enzalutamide for mCSPC20ADT, androgen deprivation therapy; CI, confidence interval; HR, hazard ratio; mCSPC, metastatic castration-sensitive prostate cancer; NR, not reached; rPFS, radiographic progression-free survivalArmstrong AJ, et al. J Clin Oncol. 2019;37:2974-86 enzalutamide + ADT33Months10Placebo + ADTrPFS rate (%)2030405060708090100302724211815129630Median (95% CI), months enzalutamide + ADTNR (NR–NR)Placebo + ADT19.0 (16.6–22.2)HR0.39 (0.30–0.50)P < 0.001

21. ENZAMET: Enzalutamide for mCSPC21CI, confidence interval; mCSPC, metastatic castration-sensitive prostate cancer; NSAA, nonsteroidal antiandrogenDavis ID, et al. N Engl J Med. 2019;381:121-31; Sweeney C, et al. Journal of Clinical Oncology 2019; 37, no. 18_Suppl.LBA2 (Oral Presentation) CLINICAL PROGRESSION-FREE SURVIVALOVERALL SURVIVAL (Primary endpoint)Months100enzalutamide48423630241812607550250Hazard ratio 0.40 (95% CI 0.33–0.49)P < 0.001 by log-rank testNSAAHazard ratio 0.67 (95% CI 0.52–0.86)P = 0.002 by log-rank testMonths48423630241812601007550250NSAAenzalutamidePatients free of clinical progression (%)Patients surviving (%)Varied inclusion criteria: high and low volume, de novo vs metachronous metastasis, concurrent docetaxel, many permutationsProportion alive at 36 months (95% CI)NSAAenzalutamide 0.72 (0.68 to 0.76)0.80 (0.75 to 0.83)

22. ENZAMET: Concurrent Docetaxel 22CI, confidence interval; NSAA, nonsteroidal antiandrogenDavis ID, et al. N Engl J Med. 2019;381:121-31; Sweeney C, et al. Journal of Clinical Oncology 2019; 37, no. 18_Suppl.LBA2 (Oral Presentation) Testosterone suppression+docetaxeln = 503(71% high volume)Testosterone suppression+no docetaxeln = 622(37% high volume)CLINICAL PROGRESSION-FREE SURVIVALOVERALL SURVIVAL

23. Adverse event duringfirst 6 monthsTS + NSAA,docetaxeln = 246TS + ENZA,docetaxeln = 254TS + NSAA,no docetaxeln = 312TS + ENZA,no docetaxeln = 309Neutropenic fever32 (13%)35 (14%)01 (< 1%)Sensory neuropathy, grade 27 (3%)24 (9%)2 (< 1%)0Sensory neuropathy, grade 31 (< 1%)3 (1%)00Motor neuropathy, grade 21 (< 1%)4 (2%)00Motor neuropathy, grade 30001 (< 1%)Nail discoloration13 (5%)25 (10%)00Watery eyes, grade 1 or 215 (6%)52 (20%)00Fatigue, grade 235 (14%)52 (20%)9 (3%)32 (10%)ENZAMET: Selected docetaxel-relevant Adverse Events23ENZA, enzalutamide; NSAA, nonsteroidal antiandrogen; TS, testosterone suppressionSweeney C, et al. Journal of Clinical Oncology 2019; 37, no. 18_Suppl.LBA2 (Oral Presentation)

24. Should we treat the primary tumor?24

25. Radiation therapy to the Primary Tumor:STAMPEDE (Arm H)25Parker CC, et al. Lancet. 2018;392:2353-66

26. Stratification variablesAge (< 70 vs ≥ 70 years), nodal involvement (N0 vs N+ vs Nx), randomizing siteWHO performance status (0 vs 1 or 2), type of ADT, aspirin or NSAID use, docetaxel useSTAMPEDE (Arm H) STUDY DESIGN26ADT, androgen deprivation therapy; N0, no nodal involvement; N+, nodal involvement; NSAID, nonsteroidal anti-inflammatory drug; Nx, indeterminate nodal involvement; SOC, standard of care; WHO, World Health OrganizationParker CC, et al. Lancet. 2018;392:2353-6636 Gy (in 6 weekly fractions of 6 Gy) or 55 Gy (in 20 daily fractions of 2.75 Gy over 4 weeks)Schedule nominated before randomizationADT ± docetaxel (SOC)ADT ± docetaxel (SOC)+ prostate irradiation1:1Men with newly diagnosedmetastatic prostate cancer

27. Potential Role of Primary Tumor Therapy in mCSPC: STAMPEDE (Arm H) CI, confidence interval; HR, hazard ratio; mCSPC, metastatic castration-sensitive prostate cancerParker CC, et al. Lancet. 2018;392:2353-6627No. at risk (events)ControlRadiotherapy(5)(1)400405012618243036424854Time since randomization (months)Overall survival (%)100080604020ControlRadiotherapyHR 0.68 (95% CI 0.52–0.90)P = 0.007409410(9)(4)387399(17)(12)361366(17)(12)265301(12)(19)217242(22)(10)155200(16)(15)110137(8)(11)6777(5)(5)2525A) Overall survival in low metastatic burden(11)(10)547537012618243036424854Time since randomization (months)ControlRadiotherapyHR 1.07 (95% CI 0.90–1.28)P = 0.420567553(42)(38)500487(58)(48)428424(41)(59)312282(27)(30)245216(43)(31)161146(20)(19)10090(7)(14)4844(3)(5)1320B) Overall survival in high metastatic burdenNo. at risk (events)ControlRadiotherapy(78)(29)324377012618243036424854Time since randomization (months)Failure-free survival (%)100080604020409410(50)(57)269318(49)(45)211255(39)(32)121178(16)(16)83142(15)(8)53113(8)(7)3275(4)(8)1635(1)(2)612C) Failure-free survival in low metastatic burden(207)(168)350279012618243036424854Time since randomization (months)567553(126)(135)223237(68)(64)147166(32)(34)8396(8)(17)5960(10)(11)4135(5)(2)2122(3)(6)1110(0)(1)35HR 0.59 (95% CI 0.49–0.72)P < 0.0001HR 0.88 (95% CI 0.71–1.01)P = 0.059D) Failure-free survival in high metastatic burden012618243036424854Time since randomization (months)Proportion on life-prolonging treatment (%)100080604020ControlRadiotherapyNo. at risk(events)ControlRadiotherapy10291032(73)(37)930963(120)(128)772792(111)(114)607620(83)(79)388411(37)(41)280306(25)(23)193228(14)(19)125148(6)(10)7275(1)(0)2429

28. Primary Directed Therapy in Low Volume mCSPC?28mCSPC, metastatic castration-sensitive prostate cancer; SWOG, Southwest Oncology Group1. Parker CC, et al. Lancet. 2018;392:2353-66; 2. NCT03678025 at www.clinicaltrials.govTrialInterventionSTAMPEDE-H1Radiation to primary, low volumeSWOG 18022 (results pending)Radical prostatectomy or radiation

29. Phase 3 Trials in mCSPC29abi, abiraterone; ADT, androgen deprivation therapy; doc, docetaxel; enza, enzalutamide; mCSPC, metastatic castration-sensitive prostate cancer; pbo, placebo1. NCT00309985; 2. NCT00268476; 3. NCT01715285; 4. NCT02677896; 5. NCT02446405; 6. NCT02489318; 7. NCT02799602; 8. NCT01957436; 9. NCT04191096; 10. NCT04493853 at www.clinicaltrials.gov; 11. Chi KN, et al. N Engl J Med. 2019;381:13-24TrialTreatment armsCHAARTED,1 STAMPEDE-C2 ADT vs ADT + docetaxelSTAMPEDE-G,2 LATITUDE3ADT vs ADT + abirateroneARCHES,4 ENZAMET5ADT + doc vs ADT + (doc 17.9%, 65%) + enzalutamideTITAN6ADT (+ doc 11%) vs ADT (+ doc 11%) + apalutamide11ARASENS7 (results pending)ADT + doc + pbo vs ADT + doc + darolutamidePEACE18 (results pending)ADT + doc + pbo vs ADT + doc + abiraterone KEYNOTE-9919 (results pending)ADT + enza + pbo vs ADT + enza + pembrolizumabCAPItello-28110 (results pending)ADT + abi + pbo vs ADT + abi + capivasertib

30. Should we treat the metastases?Metastasis-Directed Therapy30

31. Oligometastases: either 1–3 or 1–5 metastases1Different presentations: de novo or synchronous vs oligorecurrent or metachronous vs oligoprogressiveMetastasis-directed therapy of regional and distant recurrences after curative treatment of prostate cancer: a systematic review of the literature2 15 single-arm case series: a total of 450 patients Conclusion: Metastasis-directed therapy is a promising approach for oligometastatic prostate cancer recurrence, but the low level of evidence generated by a small case series does not allow extrapolation to a standard of careIssues to considerHow many lesions and where?Has the primary been treated?Sensitivity and accuracy of imaging?Therapeutic objectives: impact on overall survival vs delay of ADT (STOMP3, ORIOLE4,5)Prospective, randomized, phase 3 data still neededOngoing Questions: OligometastasesADT, androgen deprivation therapy1. Reyes D, et al. Oncotarget 2015; 6: 8491-8524; 2. Ost P, et al. Eur Urol. 2015;67:852-63; 3. Ost P, et al. J Clin Oncol. 2018;36:446-53; 4. Radwan N, et al. BMC Cancer. 2017;17:453; 5. Phillips R, et al. JAMA Oncol. 2020;6:650-931

32. Other Considerations32

33. Treatment Options for mCSPC 202033ADT, androgen deprivation therapy; EBRT, external beam radiation therapy; M0, nonmetastatic; M1, metastatic; mo, months; mCSPC, metastatic castration-sensitive prostate cancer; PSA, prostate specific antigenSchaeffer E, et al. NCCN clinical practice guidelines in oncology. Prostate cancer, V2.2020. Available from www.nccn.org. May 21, 2020. Accessed Jul 27, 2020How to choose?Quality of life and patient preferencesmust be considered!

34. What contributes to QoL?34AE, adverse event; PROM, patient-reported outcome measure; QoL, quality of life

35. Considering All Factors in mCSPC Treatment Decisions35AE, adverse event; ALP, alkaline phosphatase; LDH, lactate dehydrogenase; mCSPC, metastatic castration-sensitive prostate cancer; OS, overall survival; QoL, quality of LifeBased on personal experience, N. Shore Cattrini C, et al. Cancers 2019; 11: 1355, doi:10.3390/cancers11091355Clinical benefitOS and cancer-specific survival QoLDisease specificDisease characteristics such as volume and riskSpecific alterations such as genomic alterationsPatient specificPatient characteristics such as age, comorbiditiesLaboratory values such as ALP and LDHDrug specificAEs, drug-drug interactions, cost and accessibility, route of administration, duration of treatment

36. De novo versus recurrent disease at presentationVolume of diseaseComorbiditiesAdverse effect profiles Patient preferencesCost: direct and indirect costsConvenienceCOVID-19 concernsAvailability of drugsSubsequent therapiesTreatment Considerations in mCSPC36COVID-19, coronavirus disease 2019; mCSPC, metastatic castration-sensitive prostate cancerBased on personal experience, N. Shore

37. Most men with mCSPC are treated with LHRH therapy aloneA US physician-based syndicated patient-record tracking study captured use of anticancer and supportive care agents in prostate cancerData collected online between June 2018 and June 2019156 physicians reported on 1,360 patientsPatients with mCSPC were identified by using the following queryProstate, stage IV, not hormone refractory, metastatic line 1 by regimenReal-World Treatment Patterns in mCSPC37PATIENTS RECEIVING VARIOUS CATEGORIES OF TREATMENT (%)LHRH,  luteinizing hormone-releasing hormone; mCSPC, metastatic castration-sensitive prostate cancerIpsos. Healthcare US Oncology Monitor. Available from www.ipsos.com. Presented by Shore, N. ASCO 2020 Educational SessionLHRH therapyaloneFirst-generationantiandrogen ± LHRH therapyRegimencontaining anandrogenbiosynthesisinhibitorRegimencontaining anandrogenreceptorinhibitorRegimencontaining chemotherapyaOtherPatients (%)a Excluding regimens containing an androgen biosynthesis inhibitor or an androgen receptor inhibitor

38. New Molecular Taxonomy for Prostate Cancer38AR, androgen receptor; CRPC, castration-resistant prostate cancer; DLL3, delta-like ligand 3; DNA-BD, DNA binding domain; GR, glucocorticoid receptor; HRD, homologous recombination deficiency; mCRPC, metastatic castration-resistant prostate cancer; MMRD, DNA mismatch repair deficient; MSI, microsatellite instability; NEPC, neuroendocrine prostate cancer; PARPi, poly(ADP-ribose) polymerase inhibitor; PD-1, programmed cell death protein 1; PR, progesterone receptor Courtesy of E. Antonarakis, MD, Johns Hopkins UniversityAR-driven mCRPCHRD+ CRPC (BRCA1/2,ATM, PALB2, etc.)MSIhigh or MMRD mCRPCCDK12 biallelic lossmCRPCAR-independent CRPC(NEPC, “double negative”mCRPCMetastaticprostatecancerAR-variant (i.e. AR-V7) driven CRPC:AR degraders, cofactor inhibitors, taxanesInhibition of enhanced androgen synthesisAR N-terminal or DNA-BD inhibitorsGR or PR inhibitionPARPi based therapy, immuno-oncologic combinationsPD-1 based immunotherapyPD-1 based immunotherapyDLL3 inhibition, combinationsImmunotherapyPlatinum-based chemotherapy

39. Ongoing Trials:Triple Therapy39

40. Coprimary endpoints: OS and CRPC PFS Patients with newly diagnosed (castration-naïve) metastatic prostate cancer1,173 patients enrolledPrimary completion date: Dec 2018PEACE1: European Phase 3 Trial in Newly Diagnosed M1 Prostate Cancer (Revised Design)a40ABI/P, abiraterone + prednisone; ADT, androgen deprivation therapy; CRPC, castration-resistant prostate cancer; DOC, docetaxel; OS, overall survival; PFS, progression-free survival; RT, radiation therapyNCT01957436 at www.clinicaltrials.govADT + DOC + ABI/PADT + DOC + RTADT + DOCADT + DOC + ABI/P + RTRANDOMIZEDa Protocol was amended, in November 2015 after the accrual of 276 patients, to include docetaxel with ADT

41. Randomized, double-blind, phase 3 trial of darolutamide in hormone-sensitive mPCStudy initiated: November 2016Primary endpoint: overall survivalArasens41ADT, androgen deprivation therapy; b.i.d., twice a day; mPC, metastatic prostate cancer; OS, overall survival; R, randomizationNCT02799602 at www.clinicaltrials.govMen with newlydiagnosed, castration-sensitive mPCn = 1,303darolutamide 600 mg (2 × 300 mg) b.i.d. orally + standard ADT + docetaxel × 6 cyclesPlacebo b.i.d. orally + standard ADT + docetaxel × 6 cyclesR

42. Standard of care for mCSPC requires consideration of early addition of either docetaxel or an AR-targeted agent (abiraterone acetate, apalutamide, enzalutamide) to ADTTriple therapy adds toxicity but does not appear to add an early survival benefit (data continueto mature)ARPIs and docetaxel appear to have similar overall survival benefits in patients with high-risk or high-volume diseaseAR-targeted agents have similar relative benefits for patients with high-risk disease and patients with low-risk or low-volume diseaseOngoing RCTs are evaluating the efficacy and safety of combination treatments for mCSPCConclusionsADT, androgen deprivation therapy; AR, androgen receptor; ARPI, androgen receptor pathway inhibitor; mCSPC, metastatic castration-sensitive prostate cancer; RCT, randomized clinical trial42