Non metastatic castrate-resistant prostate cancer (M0 CRPC) Karim Fizazi, MD, PhD Institut Gustave Roussy Villejuif, France

Size: px

Start display at page:

Download "Non metastatic castrate-resistant prostate cancer (M0 CRPC) Karim Fizazi, MD, PhD Institut Gustave Roussy Villejuif, France"

Eileen Knight
5 years ago
Views:

1 Non metastatic castrate-resistant prostate cancer (M0 CRPC) Karim Fizazi, MD, PhD Institut Gustave Roussy Villejuif, France

2 Disclosure Participation to advisory boards/honorarium for: Amgen, Astellas, Astrazeneca, Bayer, Clovis, Curevac, Janssen, Orion, Sanofi

3 CRPC M0: Definition A man withprostate cancer: Whooftenpreviouslyreceiveda local treatment Whoexperienceda PSA relapse and then receivedandrogendeprivationtherapy (or together with local Tx) Whoisnowprogressingby PSA whileon ADT No detectable metastases on conventional imaging (bone scan, CT scan) Testosterone at castrated levels

4 Impact of PSA Doubling Time on Disease Progression Men (N=201) with non-metastatic prostate cancer and rising PSA despite ADT were followed for 48 months to assess development of metastatic disease and survival Time to bone metastases or death by PSA level Time to bone metastases or death by PSA doubling time (PSADT) Smith M et al. J Clin Oncol. 2005;23:

5 Imaging: How Should Patients be Monitored? Current imaging techniques 99m Tc bone scan Emerging imaging strategies Does not allow tumor measurement Underestimates prevalence of bone metastases PET MRI No clear recommendations for frequency of follow-up scans 2 Data are lacking to support recommendations 2 New imaging techniques may detect metastases at a much lower burden and may create a group of early oligo-metastatic (M+) CRPC 3 Tombal B & Lecouvert F. Advances Urol. 2012; 2. Horwich A et al. Annals Oncol. 2013;24: Tombal B. Ann Oncol Sep;23 Suppl 10:x

6 a PSMA-Pet: detection of 17 lymph nodes with diameter below the morphological detection limit; Median 0.46mm; Max 0.66; Min 0.32 b 18 F-PSMA PET 18 F-PSMA PET/CT CT CT/LN Segmentation SUVmax=12.5 SAD=6 mm SUVmax=14.5 SAD=5 mm SUVmax=17.9 SAD=4 mm PSMA-1007 PET Little radioactivity in the bladder Cleavage of the tracer in the kidneys Renal storage of the chelator SUVmax=10.7 Giesel et al., Clinical Genitourinary Cancer 2017 SAD=5 mm

7 PreviousPhase III trials in M0 CRPC Atrasentan(n=941) Zibotentan: Enthuse15 trial (n=1421) Denosumab(n=1432) Miller K, Prostate Cancer Prostatic Dis 2013; 16: Nelson JB, Cancer 2008; 113: Smith MR, Lancet 2012; 379: 39-46

8 Next-generationAR targetedagents in M0 CRPC Study name N patients Treatments Primary end-point SPARTAN (NCT ) 1200 Apalutamide240mg oncedailyor Pbo Metastasis-free survival PROSPER (NCT ) ARAMIS (NCT ) 1560 Enzalutamide160mg once dailyor Pbo 1500 Darolutamide600mg twicedailyor Pbo Metastasis-free survival Metastasis-free survival

9 PROSPER Study design Key Eligibility Criteria M0 CRPC (central review) Rising PSA despite castrate testosterone level ( 50 ng/dl) Baseline PSA 2 ng/ml PSA doubling time 10 months N=1401 R 2:1 Enzalutami de 160 mg/day + ADT Nov 2013 Jun 2017 Stratification Factors PSA doubling time (< 6 months vs 6-10 months) Baseline use of bone-targeted agent (yes vs no) Placebo + ADT First patien t enroll ed MFS primary completion date OS (secondary endpoint) Primary endpoint MFS (defined as time from randomization to radiographic progression or time to death without radiographic progression from randomization to 112 days of discontinuation of trial regimen) Statistical Design: Target difference in Kaplan-Meier estimated median MFS of 9 months (24 months vs 33 months) Target of 440events provides 90% power to detect a target HR of 0.72 Secondary endpoints Safety Time to PSA progression Time to use of new antineoplastictherapy OS PSA response Quality of life Abbreviations: ADT, androgen deprivation therapy; HR, hazard ratio; R, randomization. Hussain M, Fizazi K, Saad F et al. Enzalutamide in men with Nonmetastatic, Castration-Resistant Prostate Cancer N Engl J Med 2018; 378:

10 Slide 5 Presented By Eric Small at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

11 PROSPER: Metastases-Free Survival Median (CI 95 ), moi HR (IC 95 ) p ENZA + ADT (n = 933) 36.6 (33.1-NR) 0.29 ( ) < PBO + ADT (n = 468) 14.7 ( ) MFS (%) PBO + ADT ENZA + ADT

12 SPARTAN: Metastases-Free Survival Metastasis-Free Survival (%) PBO, 16.2 mo (median) HR=0.28 (95% CI, ) P < Months APA, 40.5 mo (median) No. at risk APA PBO

13 SPARTAN: Time to Symptomatic Progression Patients w/o symptomatic progression(%) HR=0.45 (95% CI, ) P < APA, not reached PBO, not reached Months No. at risk APA PBO

14 Secondaryendpoint: time topsa progression Time to PSA progression was 37.2 months with enzalutamide vs. 3.9 months with placebo (p<0.001). Enzalutamide treatment resulted in a 93% lower risk of PSA progression (HR: 0.07; 95% CI: 0.05, 0.08; p<0.001) Hussain M, Fizazi K, Saad F et al. Enzalutamide in men with Nonmetastatic, Castration-Resistant Prostate Cancer N Engl J Med 2018; 378:

15 SPARTAN: Time to PSA Progression

16 PSA RESPONSE* *Only patients with 1 postbaselinepsa assessment were included in the analysis. Reference: Sternberg CN, FizaziK, SaadF et al. Prostate-Specific Antigen (PSA) Response in Men With NonmetastaticCastration-Resistant Prostate Cancer (M0 CRPC) Treated With Enzalutamide: Results From PROSPER. EAU Annual Meeting. Copenhagen, Denmark. Poster#

17 SPARTAN: PSA response

18 PROSPER: overall survival At the first interim OS analysis, 103 of 933 patients (11%) receiving enzalutamide and 62 of 468 patients (13%) receiving placebo had died; median OS was NR in either group The first pre-planned interim analyses indicated a statistically non-significant 20% lower risk of death with enzalutamide vs. placebo (HR: 0.80; 95% CI: 0.58,1.09) Hussain M, Fizazi K, Saad F et al. Enzalutamide in men with Nonmetastatic, Castration-Resistant Prostate Cancer N Engl J Med 2018; 378:

19 SPARTAN: OS

20 PROSPER:Adverse events of special interest* A higher percentage of patients receiving enzalutamide reported falls and nonpathologicfractures than did those receiving placebo (17% vs. 8%) *Adverse events were collected up to 30 days after the last dose of study drug. Includes increased blood pressure. Enzalutamide Group (n = 930) All Grades No. (%) Includes acute myocardial infarcqon, hemorrhagic cerebrovascular condiqons, ischemic cerebrovascular condiqons, and heart failure. Includes memory impairment, disturbance in attention, cognitive disorders, amnesia, dementia Alzheimer s type, senile Adverse events were collected up to 30 days after the last dose of study drug. Hussain dementia, M, Fizazi K, mental Saad F et impairment, al. Enzalutamide and in men vasculardementia. with Nonmetastatic, Castration-Resistant Prostate Cancer N Engl J Med 2018; 378: Placebo Group (n = 465) Grade 3 All Grades Grade 3 Hypertension 114 (12) 43 (5) 25 (5) 11 (2) Major adversecardiovascular event 48 (5) 34 (4) 13 (3) 8 (2) Mental impairment disorders 48 (5) 1 (<1) 9 (2) 0 Hepatic impairment 11 (1) 5 (1) 9 (2) 2 (<1) Neutropenia 9 (1) 5 (1) 1 (< 1) 1 (<1) Convulsion 3 (< 1) 2 (<1) 0 0 Posterior reversible encephalopathy syndrome

21 SPARTAN: Adverse events Presented By Eric Small at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

Proportionofpatientswithimproved, stable, or deteriorating hrqol(fact-p total) Most patients reported no change or an improvement in HRQoL (FACT-P total) ENZA=enzalutamide; FACT-P=Functional

22 Proportionofpatientswithimproved, stable, or deteriorating hrqol(fact-p total) Most patients reported no change or an improvement in HRQoL (FACT-P total) ENZA=enzalutamide; FACT-P=Functional Assessment of Cancer Therapy Prostate; HRQoL=health-related quality of life; PBO=placebo Reference: Attard G, Saad F, Tombal B et al. Health-related quality-of-life deterioration and pain progression in men with non metastatic castrationresistant prostate cancer: Results from the PROSPER study. ASCO Annual Meeting. Chicago, IL, USA. Poster #

23 Slide 19 Presented By Eric Small at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

24 Conclusion: M0 CRPC Quite rare situation, unmet need Evenrarerif nextgenerationimagingisused Two agents (Enzalutamide, Apalutamide) Clear and meaningful improvement of MFS Acceptable toxicity, someissues though(cv, fractures, etc) No (yet?) demonstration of hard endpoint improvement(os, etc) Cost Darolutamide data to come soon

Francesco Massari Oncologia Medica Azienda Ospedaliero Universitaria di Bologna Policlinico S. Orsola-Malpighi

Prostata: Oral Communications Emerging strategies and controversial topics in advanced prostate cancer Francesco Massari Oncologia Medica Azienda Ospedaliero Universitaria di Bologna Policlinico S. Orsola-Malpighi