Sorting Out the Androgen Deprivation Therapy Options for Locally Advanced CSPC Supported by an educational grant from Astellas and Pfizer Inc EPISODE 3 Cora N Sternberg MD FACP Clinical Director ID: 1033749
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1. Castration-Sensitive Prostate Cancer: Navigating the Current Diagnostic and Treatment LandscapeSorting Out the Androgen Deprivation Therapy Options for Locally Advanced CSPCSupported by an educational grant from Astellas and Pfizer, Inc.EPISODE 3
2. Cora N. Sternberg MD, FACPClinical Director, Englander Institute for Precision Medicine Professor of Medicine Sandra and Edward Meyer Cancer Center Weill Cornell MedicineNew York, NY
3. Neal D. Shore, MD, FACSDirector, CPICarolina Urologic Research CenterChief Surgical OfficerGenesis CareAtlantic Urology ClinicsMyrtle Beach, SC
4. Learning Objective Evaluate strategies for the management of locally advanced CSPC.1
5. Learning Objective Differentiate the potential for adverse effects amongst androgen-deprivation therapies.2
6. Prostate Cancer (PCa) Stage and Expected Survival at Initial DiagnosisMost newly diagnosed PCa is localizedOverall, 5-year survival is 97.5%Still, in 2021, > 34,000 men will die from prostate cancerADT = androgen deprivation therapySEER. Cancer Stat Facts: Prostate Cancer. https://seer.cancer.gov/statfacts/html/prost.html. Accessed May 11, 2021.Stage% of casesTreatmentLocalized~78%Radiation or surgeryRegional lymph nodes~14%ADT and eitherradiation or surgery Metastases~8%ADT100.0% 100.0%30.4%
7. ADT Evolution1941: Huggins reports the effects of castration advanced prostate gland carcinoma1LHRH = luteinizing hormone, follicle-stimulating hormone1. Huggins C, Hodges CV. J Urol. 2002;168(1):9-12.Leuprolide HistrelinGoserelin TriptorelinFlutamide Nilutamide DarolutamideEnzalutamideAbirateroneBicalutamide ApalutamideDegarelix Relugolix1985 1990 1995 2000 2005 2010 2015 2020LHRH agonistsLHRH antagonistsAntiandrogensCYP17A inhibitor
8. ADT AdministrationDaily (oral)Months (injection)3X2X1X1m3m4m6m12mLHRH agonistLeuprolideXXXXTriptorelinXXHisterlinXLHRH antagonistDegarelixXRelugolixX
9. Which Disease Stages Should Receive ADT?T1-T2: No evidence of 15-year survival benefit of ADT primary therapy vs observationLAPC: Evidence favors definitive therapy (RT or RP) over ADT primary therapyUnless life expectancy < 5 years or comorbiditiesIntermediate-, high-, or very-high-risk LAPC: level 1 evidence supports use of RT with 2-3 years ADTMetastatic disease: ADT is gold standard for initial treatment of patients with metastatic castration-naïve PCa at presentation….yet, is monotherapy ADT still adequate?ADT = androgen deprivation therapy; LAPC = locally advanced prostate cancer; RP = radical prostatectomy; RT = radiation therapy
10. Duration of ADT With RT Is DebatedNCCN:s 4-6 months ADT with external beam RT, for intermediate-risk LAPC1RTOG 9910 demonstrated that 4 months with RT for PCa intermediate-risk disease is enoughDuration ADT for high- or very-high-risk LAPC is less clear255% of experts favor 2-3 years ADT (41% favor 1-2 years, none favor life-long ADT)3LAPC = locally advanced prostate cancer; LTADT = long-term ADT; STADT = short-term ADT; RT = radiotherapy1. NCCN. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) 2021. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed May 11, 2021. 2. Kishan AU, et al. JAMA Oncol. 2019;5(1):91-96. 3. Gillessen S, et al. Eur Urol. 2020;77(4):508-547.SourceHR, 95% (CI)P ScoreLTADT0.43 (0.26-0.72)0.99STADT0.59 (0.38-0.93)0.62Lifelong ADT0.84 (0.54-1.30)0.32RT Alone1.000.08FavorsvariableFavorsRT alone0.1110HRGleason grade group 4FavorsvariableFavorsRT alone0.1110HRSourceHR, 95% (CI)P ScoreLifelong ADT0.48 (0.31-0.76)0.97LTADT0.80 (0.45-1.43)0.61RT Alone1.000.30STADT1.13 (0.69-1.85)0.12Gleason grade group 5
11. Mechanism of Action of ADTsDHT = dihydrotestosteroneSharifi N, et al. JAMA. 2005;294(2):238-244.Drug ClassDrugsSite of ActionMOAComments/RisksLHRH agonistsLeuprolide GoserelinHistrelinTriptorelinAnterior pituitary glandDecreases release of LH through down-regulation of LHRH receptorsTestosterone surge;Requires co-administration of anti-androgenLHRH antagonistsDegarelixRelugolixAnterior pituitary glandDirectly inhibits LHRH receptorsNo testosterone flareAdrenal ablating drugsKetoconazoleAbirateroneAdrenal glandCYP17A inhibitor decreases androgen synthesisRequires prednisone supplementationAndrogen receptor antagonistsFlutamideBicalutamideNilutamideApalutamideDarolutamideProstate glandCompetitive AR inhibitorNon-steroidal AR inhibition;No need for prednisone supplementationEnzalutamideNon-competitive AR inhibitor5α-reductase inhibitorsFinasterideProstate glandDecreases conversion of testosterone to DHTNo defined role in PC therapy
12. Balancing Benefits and Harms of ADTSide effectsCost and accessibilityPatient convenience/complianceORR = overall response rate; CSPS = castration-sensitive prostate cancer; PSA = prostate-specific antigen; QoL = quality of lifeORR > 80% in CSPCSerum PSA normalization > 90%Improves QoLPlethora of side effectsand challenges
13. Testosterone Surge and Clinical FlareLHRH agonists can cause testosterone to surge and may worsen symptoms, when used as single agent1Volume of disease affects magnitude of flareTypical to add several weeks of antiandrogen therapy, beginning a week prior to LHRH agoniste.g., ketoconazole, abirateroneHowever, transient flare may not be clinically meaningful for disease progression or adverse events2Exception for men with extensive vertebral metastasesRelevance to LAPC is questionableLHRH antagonists do not cause testosterone surge or disease flare1. Pokuri et al. J Natl Compr Canc Netw. 2015;13(7):e49-55. 2. Krakowsky, et al. Eur Urol Focus. 2019;5(1):81-89.
14. Side Effects of ADTFatigueBody habitusLipid profile changesType 2 diabetesOsteoporosisCardiovascular morbidityPseudo-metabolic syndromeHot flashesSexual dysfunctionInsulin resistance
15. CVD and Prostate CancerCauses of death in men with prostate cancer:1-332% CVD (ischemic heart disease 26%, cerebrovascular 6%)20% Prostate cancer14% All other causesPatients with prostate cancer have a higher incidence of CVD than patients without prostate cancer465% of patients with prostate cancer had high Framingham risk scoresMultiple shared risk factors between CVD and prostate cancer1. Sturgeon KM, et al. Eur Heart J. 2019;40(48):3889-3897. 2. Leong DP, et al. J Urol. 2020;203(6):1109-1116. 3. Epstein MM, et al. J Natl Cancer Inst. 2012;104(17):1335-1342. 4. Challa AA, et al. Curr Treat Options Oncol. 2021;22(6):47-47.SmokingDyslipidemiaObesityOld ageMale gender
16. Cardiovascular side effectsLHRH agonists carry a warning for cardiovascular side effectsPatients with LAPC receiving LHRH agonists (compared to ADT-naïve patients) had an increased risk ofLower risk of cardiovascular events or mortality with LHRH antagonists compared with LHRH agonists (HR 0.60, 95%CI 0.41–0.87)3In patients with pre-existing cardiovascular disorders, the risk of cardiac events was lowered by 56% with LHRH antagonistsAll patients had ADT-naïve disease and had an indication for ADT, including patients with BCR after RP or RT1. Gandagliaet G, et al. BJU Int. 2014;114(6b):E82-e89. 2. Hu JC, et al. Eur Urol. 2012;61(6):1119-1128. 3. Albertsen PC, et al. Eur Urol. 2014;65(3):565-573.Cardiovascular eventHR (95%CI)Coronary artery disease 1.11 (1.07–1.15)1Acute myocardial infarction 1.09 (1.04–1.15)1Sudden cardiac death 1.18 (1.12–1.24)1Peripheral arterial disease 1.15 (1.11–1.19)2Venous thromboembolism 1.09 (1.04–1.15)2
17. Neurocognitive Side Effects of ADTData is inconsistent on association of ADT with depression, cognitive impairment, and mood disorders11. Freedland JS, Abrahamsson PA. Asian J Androl. 2021;23(1):3-10. 2. Nead KT, et al. J Clin Oncol. 2016;34(6):566-571.Meta-analysis (N = 16,888)214% patients received ADTADT users were older, more often had diabetes, had been or currently were smokers, were on antiplatelet, anticoagulant, and antihypertensive medications, or had a history of cardiovascular (CV) diseaseRisk was greater for ≥ 12 months use versus < 12 monthsCumulative probability of remaining Alzheimer’s disease–free from the initiation of ADTProbabilityYears1.000.950.9003691215Non-ADT usersADT usersp = .001 (log rank)
18. Cardiovascular Side Effects: Relugolix Associated with Lower Risk of MACEPatientsNo MACE in past 6 months, eligible for ≥ 1 year continuous ADT92.5% with CV risk factors (13.9% with history of MACE)Primary endpoint: sustained castration rate:96.7% relugolix88.8% leuprolideMACE was a secondary endpointMACE = major adverse cardiovascular events Shore ND, et al. NEJM. 2020;382(23):2187-2196.HERO evaluated relugolix versus leuprolide308622305621303616298610298605293596292595288588281582279575278563269559259538No. at RiskLeuprolideRelugolixWeeks04812162024283236404448Cumulative Incidence (%)012345678910Cumulative Incidence of MACEAt End of Wk 48 (95% CI)LeuprolideRelugolix5.6% (3.5%-8.9%)2.8% (1.8%-4.5%)HR 0.46 (95% CI, 0.24-0.88)LeuprolideRelugolix
19. Impact of Concomitant Therapy on Efficacy and Safety of Relugolix vs Leuprolide ADT with or without concomitant enzalutamide or docetaxelGeorge DJ, et al. JCO. 2021;39(6_suppl):106. WithoutWithCastration rate(<50 ng/mL through week 48)ADT with or without concomitantradiotherapyCastration rate(<50 ng/mL through week 48) WithoutWith
20. Patient Compliance, Cost, and AccessibilityDelayed LHRH agonist injections may lead to ineffective testosterone suppression, "T escape," and CRPC1,2Adherence to ADT is relatively high393% LHRH agonists97% LHRH antagonists95% antiandrogen99% CYP17 inhibitorAdherence to ADT affected bySide effectsDrug interactionsCost4Access to therapy infusion sites1. Crawford ED, et al. J Urol. 2020;203(4):743-750. 2. Shore ND, et al. Clin Genitourin Cancer. 2021;19(3):199-207. 3. Cindolo L, et al. Minerva Urol Nefrol. 2020;72(5):615-621. 4. Sung YG, et al. Front Oncol. 2021;11:627083-627083.
21. SMART GoalsPatients with advance or metastatic CSPC will require ADTConsider multitude of factors affecting ADT selection in order to optimize PCa patient benefitConsider MOA, administration, drug interactions, safety, and adherence for the choice of ADTSpecific, Measurable, Attainable, Relevant, Timely
22. To receive CME/CE credits for this activity, participants must complete the post-test and evaluation online. Go to the Evaluations tab and click on the link to complete the process and print your certificate.To Receive Credit
23. Disease States of CSPCEPISODE 1www.CMEOutfitters.com/Treatment Options and Clinical Dilemmas in Biochemical RecurrenceEPISODE 2Management of Patients with Metastatic CSPCEPISODE 4