Module 6: Prostate Cancer - PowerPoint Presentation

1. Module 6: Prostate CancerVictoria Sinibaldi, RN, MS, CS, CANP, BCDaniel P Petrylak, MD

2. Disclosures for Ms SinibaldiNo financial interests or affiliations to disclose

3. Disclosures for Dr PetrylakConsulting AgreementsAdvanced Accelerator Applications, Amgen Inc, Astellas, AstraZeneca Pharmaceuticals LP, Bayer HealthCare Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals Inc, Bristol-Myers Squibb Company, Clovis Oncology, Exelixis Inc, Incyte Corporation, Janssen Biotech Inc, Lilly, Pfizer Inc, Pharmacyclics LLC, an AbbVie Company, Roche Laboratories Inc, Seattle Genetics, UroGen PharmaContracted ResearchAdvanced Accelerator Applications, Astellas, AstraZeneca Pharmaceuticals LP, Bayer HealthCare Pharmaceuticals, Bristol-Myers Squibb Company, Clovis Oncology, Endocyte Inc, Genentech, Innocrin Pharmaceuticals Inc, Lilly, Merck, Novartis, Pfizer Inc, Progenics Pharmaceuticals Inc, Roche Laboratories Inc, Sanofi Genzyme, Seattle GeneticsOwnership InterestBellicum Pharmaceuticals Inc, Tyme Inc

4. Approximately how many patients with the following types of cancer have you interacted with over the past year?Type of cancerMedianBreast cancer40Lung cancer35Colorectal cancer30Myelodysplastic syndromes20Multiple myeloma20Chronic lymphocytic leukemia15Pancreatic cancer10Diffuse large B-cell lymphoma10Prostate cancer10Follicular lymphoma7Melanoma6Type of cancerMedianOvarian cancer6Renal cell carcinoma6Hepatocellular carcinoma5Gastric cancer5Acute myeloid leukemia4Hodgkin lymphoma4Urothelial bladder cancer4Endometrial cancer3Cervical cancer2Mantle cell lymphoma2

5. Day in the Life: Prostate Cancer 71, cabazitaxel, My first time using this drug in 30+ years in oncology. It is working. Couldn't be happier for this lovely gentleman.67, bone mets, cabazitaxel, attitude71, pembrolizumab, has MSI-high prostate cancer; has had multiple therapies; prior to starting pembrolizumab had a PSA of 180, now it's nondetectable; has been on therapy for less than 6 months83, abiraterone, leuprolide, denosumab, alcoholism75, watchful waiting, knows exactly when his next scan is due and continually reminds you of it71, Bone mets, passed away, my favorite patient that always came in with a smile on his face and would never listen

6. Day in the Life: Prostate Cancer 78, apalutamide, discussed interaction with CYP enzyme system with his other medications for comorbidities including but not limited to tramadol, lisinopril and atorvastatin, celecoxib.62, clinical trial, resilient82, cabazitaxel, great head of white hair77, Leuprolide, Humorous

7. Case #1A 67 YO retired physician, presented with PSA = 8.1; Gleason’s 5+4 = 9, s/p RP 3/15 with pT2N0M0PSA ↓ <0.1 ng/ml, but ↑ to 0.2 by 12/15. Bone and CT scans NED. Received IMRT plus neoadjuvant + concurrent HT x 4 months (completed 6/16)11/16 PSA = 1.7; initiated on IHT, but required CHT in 6/2017.9/18 PSA ↑ to 7.8 while on LHRH. Testosterone <20. Bone and CT scans NED. He now has M0 disease, progressed on LHRH, recommended enzalutamide

8. Case #1 (cont)Feeling good; quite active- consulting/volunteering. He has intermittent hot flashes, decreased stamina, decreased libido and ED, using Trimix with some success.PMH: GERD, hyperlipidemiaMeds: Atorvastatin, Vit D3, esomeprazole, eszopiclone, leuprolideSH: Married, 3 grown children, 3 grandchildren, dog.Habits: Never smoked. Alcohol social. Exercises routinely. Healthy diet.FH: Sister alive-h/o endometrial cancer, mother died- h/o lung cancer, father died- COPD, PGM died- h/o leukemiaPE: Unremarkable. Empty prostatic fossa

9. Case #1 (cont): You tell him…Recommended enzalutamide.Enzalutamide- indicated for castration resistant non-metastatic disease, who are asymptomatic/mildly symptomatic in whom chemotherapy is not yet indicated.Enzalutamide - androgen receptor inhibitor - interferes with the connection between androgens and androgen receptors - can help to slow tumor growth, decrease proliferation and induce cell deathPO: 160 mg (four 40-mg capsules) QD. Take whole; do not crush.Take same time each day. Take missed doses as soon as remembered within the same day. If a whole day is missed, omit dose and take next day's scheduled dose; do not double doses.

10. Case #1 (cont) Nursing implications: toxicityFatiguePosterior reversible encephalopathy syndrome (PRES), seizures, headache, weakness, anxiety, dizziness, insomnia, mental impairmentPeripheral edemaHypertensionDiarrheaHot flashesArthralgia, Myalgias, ParesthesiasMetabolized in the liver, metabolites are primarily excreted through the kidney

11. Case #1 (cont) Nursing implications: drug-drug interactionsStrong CYP2C8 inhibitors, including gemfibrozil, may ↑ levels and risk of toxicity; avoid concurrent use (if concurrent administration necessary, ↓ enzalutamide dose).Strong CYP3A4 inducers, including carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and rifapentine may ↓ levels and response; avoid concurrent use (if concurrent administration necessary, ↑ enzalutamide dose).May ↓ levels of CYP3A4, CYP2C9, and CYP2C19 substrates that have narrow therapeutic indexes including cyclosporine, fentanyl, phenytoin, sirolimus, tacrolimus, and warfarin; avoid concurrent use.St. John’s Wort may ↓ levels and response

12. Case #1 (cont): Back to 67 yo patientAfter 3 months on enzalutamide, patient reported significant fatigue and questioned his overall QOL with regard to the possible survival benefit. He was told that it is reasonable to decrease the dose; however, after great thought he decided to continue on the recommended dose. His PSA is <0.1 and scans remain NED.He has adjusted his life style (healthy diet, listens to his body when tired, exercise) and PSA remains undetectable. He points out at every visit that it is important to him to stay on the drug.

13. Prostate CancerDaniel P. Petrylak, MDProfessor of Medicine and UrologyDirector, GU Translational Working GroupCo Director, Signal Transduction ProgramSmilow Cancer Center, Yale University

14. PROSTATE CANCER DISEASE STATESLocalized Prostate CancerCancer that has not spread outside of the prostate.PSA FailureIf PSA levels rise after initial treatment.Hormone Sensitive Prostate CancerCancer that responds to hormone therapy (medical or surgical) to stop testosterone production.nmCRPCNon-Metastatic Castration Resistant Prostate Cancer is no longer responding to a surgical or medical treatment (like androgen deprivation therapy) to stop testosterone production. There are no signs of cancer outside ofthe prostate on images or scans. The testosterone levelsare low and the PSA blood test levels are rising. mCRPCMetastatic Castration Resistant Prostate Canceris resistant to medical or surgical treatments. Cancer is found outside of the prostate on images or scans, and testosterone and/or PSA are rising. mCSPCMetastatic Castration-Sensitive Prostate Cancer has spread to other parts of the body, still responds to hormone therapy (medical or surgical) to stop testosterone production. Monitoring prostate cancer closely will help ensure you are able to receive treatments that are available in each of these stages

15. Treatment of Metastatic Prostate Cancer2015Tumor Volumeand ActivityTimeAndrogen BlockadeAbirateroneEnzalutamideSipuleucel-TAbirateroneEnzalutamideCabazitaxel Radium 223Docetaxel

16. Tumor Volumeand ActivityTimeAndrogen Blockade + Abiraterone+ Docetaxel+ Apalutamide+ EnzalutamideAbirateroneEnzalutamideSipuleucel-TAbirateroneEnzalutamideCabazitaxel Radium 223DocetaxelTreatment of Metastatic Prostate Cancer 2019 and Beyond

17. Time to First Bone Metastasis and Death in Men With Progressive nmCRPCIn multivariate analyses, baseline PSA ≥13.1 ng/mL was associated with shorter overall survival (RR, 2.34; P<0.0001), time to first bone metastasis (RR, 1.98; P<0.0001), and bone metastasis-free survival (RR, 1.98; P< 0.0001)At 2 years, 46% of subjects (N=331) had developed bone metastases, and 20% had diedSmith MR et al. Cancer. 2011;117(10):2077-2085.RR= relative risk.

18. Next Generation AntiandrogensMoilanen A et al. Sci Rep 2015; 5: 12007.CompoundAR-WT affinityKi (nM)AntagonismAR-WT IC50 (nM)AntagonismAR T878A IC50 (nM)AntagonismAR F877L IC50 (nM)ProliferationVCaP IC50 (nM)Enzalutamide78155296agonist400ARN-509531681130agonist300Darolutamide96570066500No CYP inhibition or induction with therapeutic dosesGeneral chemical structurefor darolutamide (ODM-201)Darolutamide (ODM-201) 3%Enzalutamide 29%ARN-509 19%

19. Apalutamide vs Placebo in Nonmetastatic CRPC (SPARTAN): Phase III Study DesignPrimary endpoint: metastasis-free survivalSecondary endpoints including: time to metastasis, PFS, time to symptomatic progression, OS, time to chemotherapyExploratory endpoints: time to PSA progression, PSA response rate, PFS2, PROSmall EJ, et al. ASCO GU 2018. Abstract 161. Smith MR, et al. N Engl J Med. 2018;378(15):1408-18.Pts with nonmetastatic CRPC and PSA doubling time ≤ 10 mos(N = 1207)Apalutamide 240 mg QD + Androgen Deprivation Therapy (n = 806)Placebo + Androgen Deprivation Therapy (n = 401)Stratified by PSA doubling time ≤ 6 vs > 6 mos, BL bone-targeting agent use (yes or no), N0 vs N1Upon distant metastasis, treatment for metastatic CRPC at discretion of treating physician

20. Enzalutamide vs Placebo in Nonmetastatic CRPC (PROSPER): Phase III Study DesignPrimary endpoint: metastasis-free survivalSecondary endpoints including: safety, time to PSA progression, time to next therapy, OS, PSA response, QoLHussain M, et al. ASCO GU 2018. Abstract 3.Pts with M0 nonmetastatic CRPC and PSA doubling time ≤ 10 mos(N = 1401)Enzalutamide 160 mg QD + Androgen Deprivation Therapy (n = 933)Placebo + Androgen Deprivation Therapy (n = 468)2:1Stratified by PSA doubling time < 6 mos vs 6-10 mos, BL bone-targeting agent use

21. Presented By Karim Fizazi at 2019 Genitourinary Cancers Symposium

22. Next Generation Antiandrogens in NMCRPCPROSPEREnzalutamideARAMISDarolutamideSPARTANApalutamideMetastasis-Free Survival (Months)36.6 vs 14.7HR= 0.2940.4 vs 18.4HR=0.4140.5 vs 16.2HR=0.28Time to PSA Progression (Months)37.2 vs 3.933.2 vs 7.3Not reached vs 3.7Duration of Treatment(Months)18.4 vs 11.114.8 vs 11Not Reported SurvivalHR 0.8; P=0.15HR=0.71; P=0.71HR 0.7 P=0.07

23. Current Options for Treating NMCRPC*Enzalutamide + ADTApalutamide + ADTDarolutamide + ADTAbiraterone + ADTADT alone*PSADT ≤ 10 monthsNCCN Guidelines Prostate Cancer v4.2019

24. Chemohormonal therapy for CSPCCHAARTED StudyHigh volume disease: ≥4 bony metastases, at least one outside of axial skeleton and/or visceral metastases17 mo overall survival benefit only in high volume disease (pre-specified analysis)No overall survival benefit in low volume diseaseSTAMPEDE StudyDid not stratify by low vs high volume diseaseConclusionsStandard of care for high volume disease: ADT + docetaxelStandard of care for low volume disease: ADT alone (CHAARTED) or ADT + docetaxel (STAMPEDE)

25. Comparing Overall Survival Across StudiesPresented By Eric Small at 2017 ASCO Annual MeetingDocetaxel vs. Abiraterone

26. Slide 20Presented By Eric Small at 2017 ASCO Annual MeetingDocetaxel vs. Abiraterone

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29. ARCHES study designOS final analysisKey eligibility criteria mHSPC (confirmed by bone scan, CT, or MRI), histologically confirmed adenocarcinomaECOG Performance Status 0 to 1Current ADT duration ≤3 months unless prior docetaxel, then ≤6 monthsStratification factors Volume of disease (low vs. high*)Prior docetaxel therapy for mHSPC (none, 1–5, or 6 cycles)Enzalutamide 160 mg/day + ADTPlacebo + ADTR1 : 1N = 1150Key discontinuation criteriaRadiographic progression, unacceptable toxicity, or initiation of an investigational agent or new therapy for prostate cancerOctober 14, 2018 rPFS final analysisOverall survival (OS) interim analysisFirst patient enrolledMarch 21, 2016Presented by: Andrew J. Armstrong, MD*Defined as metastases involving the viscera or, in the absence of visceral lesions, ≥4 bone lesions, ≥1 of which must be in a bony structure beyond the vertebral column and pelvic bonePrimary endpoint rPFS: time from randomization to first objective evidence of radiographic progression assessed centrally, or death from any cause within 24 weeks of treatment discontinuation, whichever occurs firstRadiographic disease progression was defined by RECIST 1.1 criteria for soft tissue disease or by appearance of ≥2 new lesions on bone scan compared to baseline (at week 13) or vs. best response on treatment (week 25 or later). New bone scan lesions observed at week 13 required confirmation of >2 additional new bone lesions on subsequent scans

30. Primary endpoint: rPFSAt data cut-off, there were 262 events of radiographic progression (enzalutamide + ADT, 77; placebo + ADT, 185) and 25 deaths without radiographic progression (enzalutamide + ADT, 12; placebo + ADT, 13) Median follow-up time is 14.4 months; median duration of therapy was 12.8 (range 0.2–26.6) months for enzalutamide + ADT and 11.6 (range 0.2–24.6) months for placebo + ADTAs of October 14, 2018 (cut-off date), 769 patients were still on treatment, 437 (76%) for enzalutamide + ADT and 332 (58%) for placebo + ADTPresented by: Andrew J. Armstrong, MD100807060504030201009003691215212733Time (months)rPFS (%)ENZA + ADTPBO + ADT574493257635ENZA + ADTNo. at risk576445192390PBO + ADT18243000ENZA + ADT (n = 574)PBO + ADT (n = 576)Median, month(95% CI)NR(NR, NR)19.45 (16.59, NR)HR (95% CI)0.39 (0.30, 0.50)p value<0.000112-month event-free rate estimate0.840.64

31. Phase 3 TITAN ADT + apalutamide vs ADT and placebo for mHSPCKey Eligibility CriteriaCastration sensitiveDistant metastatic disease by ≥ 1 lesion on bone scanECOG PS 0 or 1On-Study RequirementContinuous ADTPermittedPrior docetaxelADT ≤ 6 mo for mCSPC or ≤ 3 yr for local diseaseLocal treatment completed ≥ 1 yr priorStratificationsGleason score at diagnosis (≤ 7 vs ≥ 8)Region (NA and EU vs all other countries)Prior docetaxel (yes vs no)Apalutamide 240 mg daily + ADT (n = 525)Placebo + ADT(n = 527)1:1 RANDOMIZATIONN = 1052“All-comer” patient populationDual primary end points OSrPFSSecondary end pointsTime to cytotoxic chemotherapyTime to pain progressionTime to chronic opioid useTime to skeletal-related eventExploratory end pointsTime to PSA progressionSecond progression-free survival (PFS2)Time to symptomatic progressionECOG PS, Eastern Cooperative Oncology Group performance status; NA, North America; PSA, prostate-specific antigen; rPFS, radiographic progression-free survival.Dec 2015 – Jul 2017Chi KN et al. ASCO 2019;Abstract 5006.

32. ResultsrPFS20% difference in rPFS at 2 years Reduced risk of radiographic progression by 52%OS8% difference in OS at 2 yearsReduced risk of death by 33%More rash, fatigue, hypothyroidism, fracture with apalutamideCelestia S. Higano, MD, FACPChi KN et al. ASCO 2019;Abstract 5006.

33. Current options for treating mHSPCTrialDrugComparisonCHAARTEDdocetaxelADTSTAMPEDEabirateroneADTLATITUDEabirateroneADTTITANapalutamideADT (+/- doce 11%)ENZAMET (LBA)enzalutamide?ADT (+/- doce 45%)Celestia S. Higano, MD, FACP

34. References: 1. Henriksen G, et al. Cancer Res. 2002;62:3120–3125. 2. Brechbiel MW. Dalton Trans. 2007;43:4918-4928.BoneShort range of α-particles could reduce bone marrow exposure1MarrowTumorRange of an α-emitting Radiopharmaceutical Compared to a β-emitterBone Mineral (Hydroxyapatite)Range of β-particle(long range – 10 to 1000 cell diameters2)RadionuclideRange of α-particle(short range – ~2 to 10 cell diameters2)

35. 6 injections at 4-week intervalsRadium-223 dichloride(50 kBq/kg) + best standard of care†Placebo (saline) +best standard of care†Total ALP: < 220 U/L vs. ≥ 220 U/LBisphosphonate use: Yes vs. NoPrior docetaxel: Yes vs. NoConfirmed Symptomatic CRPC≥2 bone metastasesNo known visceral metastasesPost-docetaxel or unfit for docetaxel*ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) Phase III Study Design1Reference: 1. Parker et al. J Clin Oncol. 2012;30(suppl): abstract LBA4512. Presented at ASCO 2012. *Unfit for docetaxel includes patients who were ineligible for docetaxel, refused docetaxel, or lived where docetaxel was unavailable †Best standard of care defined as a routine standard of care at each center, eg. local external beam radiotherapy, corticosteroids, anti-androgens, estrogens (e.g., stilbestrol), estramustine, or ketaconazole PATIENTSSTRATIFICATIONRANDOMIZE2:1N=921TREATMENT PHASE>100 centers in 19 countriesPlanned follow-up is 3 years

36. Radium-223 dichloride(n = 614)Placebo (n = 307)Median OS (months)14.911.3HR0.69595% CI0.581–0.832P value0.00007ALSYMPCA Updated Analysis:Overall SurvivalMonth036912151821242730333639Radium-2236145785043692741781056041187100Placebo30728822815710367392414742100102030405060708090100Patients (%)TreatmentRadium-223 dichloridePlacebo3.6 month OS benefitReference: Parker et al. J Clin Oncol. 2012;30(suppl): abstract LBA4512. Presented at ASCO 2012.

37. Analyses of DDR Gene Mutations in Prostate Cancer Report Frequencies of 8%-19% in Germline* and 23%-27% in Somatic Tissue†(n=451 patients)BRCA1, breast cancer susceptibility gene 1; BRCA2, breast cancer susceptibility gene 2; BRIP1, BRCA1-interacting protein C-terminal helicase 1; DDR, DNA damage response; FH, fumarate hydratase; MITF, melanogenesis-associated transcription factor; NBN, nibrin; PMS2, PMS1 homolog 2, mismatch repair system component; RECQL4, RecQ-like helicase 4.*124 of the overall germline patients were included in Pritchard CC, et al. N Engl J Med. 2016;375(5):443-453.†Metastatic (77%), biochemical recurrence after definitive therapy (12%), locoregional (11%).Abida W, et al. JCO Precis Oncol. 2017;2017.

38. Synthetic Lethality: PARP inhibition in HRD cancer

39. Synthetic Lethality: PARP inhibition in HRD cancerSynthetic Lethality

40. Olaparib in Prostate CancerTOPARP study: n=49 patients with mCRPC, who are docetaxel- pre-treated. (Mateo et al. 2015)32.7 % (16/49) response rate in “unselected” mCRPC patients.Genomic Analysis of their prospectively obtained tumor samples: 16 (33%) had mutations in DNA repair pathway (ATM, BRCA2 and others) (biomarker positive) 14 of these patients responded 33 (67%) had no such mutations (biomarker negative)2 of these patients responded

41. Phase 3 PROFound: Olaparib vs Enzalutamide or Abiraterone in Men With HRRm mCRPC Who Failed Prior Second-Generation Antiandrogen Treatment *Cohort B HRR genes include BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PP2R2A, RAD51B, RAD51C, RAD51D, RAD54L.†Subjects randomized to investigator choice arm will be given the opportunity to begin treatment with open-label olaparib (300 mg BID) only after objective radiographic progression by BICR. No intervening systemic anticancer therapy following discontinuation of randomized treatment will be permitted. Subjects may continue on olaparib as long as they show clinical benefit as judged by the investigator. ‡Subsequent anticancer therapy at investigator discretion.BICR, blinded independent review committee; BID, twice daily.In House Data, AstraZeneca Pharmaceuticals LP. Drug Substance Olaparib. D081DC00007; 2017.Primary objectiverPFS (cohort A)Key Secondary ObjectivesConfirmed ORR (cohort A)rPFS (cohort A + B)Time to plan progression (cohort A)OS (cohort A)RANDOMIZATIONKey Eligibility CriteriamCRPCPost-second-generation antiandrogen (abiraterone and/or enzalutamide)Qualifying HRR mutation in tumor tissueFMI’s olaparib HRR assay2:1Cohort BOther HRR gene mutations*(N≈100)StratificationPrevious taxane (yes/no)Measurable disease (yes/no)Olaparib300 mg BIDInvestigator ChoiceEnzalutamide, or Abiraterone + prednisoneOptional: Olaparibswitch post-BICR progression†Optional: Olaparibswitch post-BICR progression†Olaparib300 mg BIDInvestigator ChoiceEnzalutamide, or Abiraterone + prednisoneRadiographic Progression (BICR)2nd Progression + Survival Follow-up‡Cohort ABRCA1, BRCA2, or ATM mutation(N=240)

42. Primary endpointrPFS by BICR in patients with alterations in BRCA1, BRCA2, or ATM (Cohort A) 02345678910111213141516171819202110.00.10.70.60.50.40.30.21.00.90.8Time from randomization (months)Probability of rPFS162126116102101827756534237262418111132000149OlaparibNo. at risk834744222013127633322111100079Physician's choiceOlaparib (N=162)Physician's choice(N=83)Events (%)106 (65.4)68 (81.9)Median rPFS (months)7.393.55Hazard ratio (95% CI)0.34 (0.25, 0.47)P<0.000112-mo rate28.11%9.40%6-mo rate59.76%22.63%

43. TRITON2: Phase II Study of Rucaparib in mCRPC With HRR Gene AlterationsInternational, multicenter, open-label phase II studyAbida. ESMO 2018. Abstr 793PD.Patients with mCRPC and deleterious somatic or germline alteration in HRR gene*; progression on AR-directed tx† for PC and 1 prior line of taxane-based CT for CRPC; no prior PARPi, mitoxantrone, cyclophosphamide, or platinum-based CT; ECOG PS 0/1(N = 85‡) Until radiographic progression or discontinuation for other reasonRucaparib 600 mg BID in 28-d cycles§ǁRECIST modified to include up to 10 target lesions (maximum 5 per site), excluding prostatic bed or bone lesions; MRI permitted.Primary endpointsAmong patients with measurable disease at BL: centrally assessed, confirmed ORR per modified RECISTǁ/PCWG3Among patients without measurable disease at BL: locally assessed, confirmed PSA response (≥ 50% decrease) rate*Local or central testing of blood or tumor samples for alterations in HRR genes: BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK2, FANCA, NBN, PALB2, RAD51, RAD51B, RAD51C, RAD51D, RAD54L. †Abiraterone, enzalutamide, or apalutamide. ‡Enrollment cutoff: April 16, 2018. §Assessments: tumor Q8W for 24 wks, then Q12W; PSA Q4W.

44. Best Change From BL in Sum of Target Lesions (n = 26†)TRITON2: Radiographic Responses in Evaluable Patients With BRCA1/2 AlterationsAbida. ESMO 2018. Abstr 793PD.Each bar represents a single patient; patients with no change from BL are shown as 0.5% for clarity. *Confirmed RECIST/PCWG3 response. †Patients with measurable disease at BL and ≥ 1 post-BL scan. 100806040200-100-80-60-40-20Change From BL (%)HRR gene BRCA1/2Alteration statusGermlineSomatic***********

45. TROPIC: Phase III Registration Study 146 Sites in 26 CountriesPrimary endpoint: OSSecondary endpoints: Progression-freesurvival (PFS), response rate, and safetyInclusion: Patients with measurable disease must have progressed by RECIST; otherwise must have had new lesions or PSA progression cabazitaxel 25 mg/m² q 3 wk + prednisone* for 10 cycles(n=378)mitoxantrone 12 mg/m² q 3 wk+ prednisone* for 10 cycles(n=377)*Oral prednisone/prednisolone: 10 mg daily.Stratification factorsECOG PS (0, 1 vs. 2) • Measurable vs. non-measurable diseasemCRPC patients who progressed during and after treatment with a docetaxel-based regimen (N=755)www.clinicaltrials.gov. NCT00417079

46. Primary Endpoint: Overall Survival (ITT Analysis) MP37730018867111 CBZP37832123190284Numberat riskProportionof OS (%)8060402001000 months6 months12 months18 months24 months30 months15.112.7Median OS (months)0.59–0.8395% CI<.0001P-value0.70Hazard RatioCBZPMPde Bono JS et al. Lancet 2010;376(9747):1147-54.

47.

48. CARD Trialde Wit R et al. ESMO 2019

49. CARD Trialde Wit R et al. ESMO 2019

50. ConclusionsNext generation antiandrogen therapy improves metastasis-free survival in non-metastatic CRPCEarlier use of next generation antiandrogen therapy and chemotherapy in HSPCA has a greater effect on survival than in CRPCAll patients will need to be tested for DNA repair mutations in the CPRC stateCabazitaxel has a superior rPFS and overall survival as a third line agent over next generation antiandrogen therapy

51. Case #368YO man, owner of a vending machine company, presented with PSA 4.7 ng/ml, Gleason’s 5+4=9, s/p RP 5/13 with pT3b, +margins and SVsPost-op PSA’s were detectable (ranging 1.8-1.9 ng/ml).1/14- PSA = 8.5. Bone scan positive lesions left iliac crest and T10, c/w metastatic disease – started ADT with decline in PSA11/17- Stable bone scan. PSA showed slow rise. Continued leuprolide, testosterone <20.9/18- PD on bone scan now with involvement in the ribs, T10/T11vertebral bodies, left iliac crest c/w metastatic castration resistant disease. CT showed no ST or visceral disease. PSA =2.5.

52. Case #3 (cont)10/18: Mildly symptomatic with intermittent back pain controlled with ibuprofen.PMH: Hypertension, kidney stones, seasonal allergiesMeds: Amlodipine, aspirin, ibuprofen, tadalafil, LisinoprilSH: Married with 2 daughters and 1 son. Never smoked. Enjoys golf and yard work. Living outside Florida. Given his high grade and stage pT3b, and his persistent post op PSAs, and his desire to not start chemo…Recommended: Radium-223

53. Case #3 (cont): Nursing implications: patient educationRad-223 is safe and effective and targets tumor cells in the bone.Rad-223 -form of liquid radiation, administered IV, given every 4 weeks x6Explain characteristics of RAD-223- has a short range that does limit damage to healthy cells. Data using this modality have shown improvement in QOL with improvement in pain, improved OS (by 3.6 months), delay in SSEs, Patients often focus on PSA. Point out that a decline in PSA is not an expected result of Rad-223; Patient benefits have been observed in the absence of a decreasing PSA.

54. Case #3 (cont): Nursing implications: toxicity-RAD-223FatigueGI: Nausea, Vomiting, DiarrheaPeripheral edemaPancytopenia: Anemia, Lymphopenia, leukopenia, thrombocytopenia, neutropeniaBlack tarry stoolsCP, Chills, CoughErythema at the injection site

55. Case #3 (cont): Nursing implications: important facts for the patient/familyObtain CBC, chem panel prior to each Radium-223 injectionBecause alpha particles have limited penetration, they are literally stopped by a piece of paper. There is no risk of RT exposure to anyone around you. May return to work or school the day of treatment.Cleared primarily through the feces; but is in body fluids.Caregivers- use gloves/ gowns when handling bodily fluids Bathroom habits: shut the lid and double flush the toilet after each urination/stool for 7 days after each and every treatment.If urine/feces/blood soils clothing, wash the clothing separately and promptly.  For undergarments (Depends, pad, etc.), double bag; discard in the regular trash.  

56. Case #3 (cont): Back to 68 yo patientStarted treatment in 11/18Received the first 3 doses of RAD-223 with increasing back pain, controlled with ibuprofen. Reporting intermittent back pain flares after each RAD-223. Reported that just prior to his RAD#4, the frequency and intensity of the pain had decreased. He also reported mild intermittent nausea and some diarrheaJust prior to RAD#5, he reported improvement in his pain and no longer required ibuprofen. His PSA had decreased from 1.9ng/ml to -1.1ng/ml3/21/19 RAD#6, reporting fatigue and diarrhea. Minimal back pain.8/26/19 ≤0.1- no pain, energy level improved

57. RAD-2239/4/2018 (pre-treatment)5/13/2019 (after 6 doses of RAD-223)

58. Special Issues in Oncology CareManagement of effects of endocrine therapy; prevention of adverse consequences