Management of mcrpc: Hormonal therapy and treatment sequence for CRPC

Transcription

1 Management of mcrpc: Hormonal therapy and treatment sequence for CRPC Professor Bertrand Tombal, MD, PhD Cliniques universitaires Saint-Luc Université catholique de Louvain Brussels, Belgium

2 Credentials and conflict of interests Professor and Chairman, Division of Urology, Cliniques universitaires Saint Luc, Brussels, BE President of European Organization Of Research and Treatment of Cancer (EORTC) PI of Prevail, 9785-CL-0321, and EORTC GUCG 1333 Investigator and paid advisor for Amgen, Astellas, Bayer Pfizer, Ferring, Janssen, Sanofi Aventis This meeting is organized and funded by Astellas Pharma SRL SmPC is available at the promotional booth or Astellas employees. This presentation has been prepared by and reflects the personal view of Bertrand TOMBAL XTA/17/0096/SEEd; for healthcare professionals only; date of preparation: 10/2017.

3 The advanced PCa landscape in 2016 M1 HNPC ADT PSA progr. RX progr. SRE PAIN ± 2-4 years High-risk localized PCa PSA progr. PSA progr. PSA progr. RX progr. SRE PAIN Local T/ Salvage ADT ± ADT Local T/ ± MTT ± ADT ± 7-15 years T/ treatment; ADT: androgen deprivation therapy; HNPC: hormone-naïve prostate cancer; PCa: prostate cancer; PSA: prostate-specific antigen; RX progr.: radiological progression; SRE: skeletal-related events Mottet N et al. EAU guidelines on prostate cancer, update 2015; (accessed March 2016); Vale CL et al. Lancet Oncol 2016;17: mcrpc M0 CRPC

4 CRPC portfolio in 2017 Relative reduction in risk of death, % Abiraterone/P vs. placebo/p (post-doc) 1 26 Abiraterone/P vs. placebo/p (pre-doc) 2 19 Enzalutamide vs. placebo (post-doc) 3 37 Enzalutamide vs. placebo (pre-doc) 4 23 DOC (q3w)/p vs. mitoxantrone/p 5 24 Cabazitaxel/P vs. mitoxantrone/p (post-doc) 6 30 Sipuleucel-T vs. placebo (pre-doc) 7 22 Radium-223 vs. placebo (post-doc or DOC unfit) 8 30 CRPC: castration-resistant prostate cancer; DOC: docetaxel; P: prednisone; q3w: every 3 weeks HR (95% CI; P value) 0.74 ( ; P<0.001) 0.81 ( ; P=0.003) 0.63 ( ; P<0.001) 0.71 ( ; P=0.001) 0.76 ( ; P=0.009) 0.70 ( ; P<0.0001) 0.78 ( ; P=0.03) 0.70 ( ; P<0.0001) 1. Fizazi K et al. Lancet Oncol 2012;13:983-92; 2. Ryan C et al. Lancet Oncol 2015;16:152-60; 3. Scher HI et al. N Engl J Med 2012;367: ; 4. Beer C et al. N Engl J Med 2014;371:424-33; 5. Tannock IF et al. N Eng J Med 2004;2351: ; 6. de Bono JS et al. Lancet 2010;76: ; 7. Kantoff PW et al. N Engl J Med 2010;363:411-22; 8. Parker et al. N Engl J Med

5 PSA (ng/ml) Case 1: 71 y.o. EBRT + 2 years ADT for locally-advanced PCa (T3b, Gleason 8 (5+3), PSA 47 ng/ml, NO, MO), testosterone 43 ng/dl, PSA doubling time 7 months , Months post RT Months post initiation of ADT following RP Hot spot, negative X-Rays EBRT: external beam radiation therapy; ADT: androgen deprivation therapy, Images provided by B.Tombal & F.Lecouvet, Clinique Universitaires Saint-Luc, Belgium

6 When do you recommend initiating additional treatment for M0 CRPC patients (negative imaging, rising PSA, outside of clinical trials) apart from maintaining ADT? Gillessen S et al. Annals of Oncology 2015; 26:

7 If you recommend treatment for M0 CRPC, what is your preferred treatment option for M0 CRPC patients (negative imaging, rising PSA, outside of clinical trials) apart from maintaining ADT? Gillessen S et al. Annals of Oncology 2015; 26:

8 Randomized placebo- controlled trials in M0 CRPC Trial Drug N Inclusion Expected completion Prosper (1) Enzalutamide 1560 PSA DT < 10 months 08/2015 Spartan (2) ARN Aramis (3) ODM PSA DT < 10 months 2016 PSA DT < 10 months 2018 Primary endpoint: metastases free survival (MFS). (1) NCT ; (2) NCT ; (3) NCT

9 509-to-treat-men-with-non-metastatic-castration-resistant-prostate-cancer _patients_with_non_metastatic_castration_resistant_prostate_cancer

10 PSA (ng/ml) Case 1. y.o. EBRT + 2 years ADT for locally-advanced PCa (T3b, Gleason 8 (5+3), PSA 47 ng/ml, NO, MO), testosterone 43 ng/dl, PSA doubling time 7 months , Months post RT Months post initiation of ADT following RP EBRT: external beam radiation therapy; ADT: androgen deprivation therapy, Images provided by B.Tombal & F.Lecouvet, Clinique Universitaires Saint-Luc, Belgium

11 EAU Prostate Cancer Guidelines Summary of Evidence No definitive strategy regarding first treatment choice (which drug/drug family first) can be devised. No clear-cut recommendation can be made for the most effective drug for secondary treatment (i.e. hormone therapy, chemotherapy or radium-223) as no clear predictive factors exist. LE 4 3 Recommendations LE GR Ensure that testosterone levels are confirmed to be < 50 ng/ml Counsel, manage and treat patients with metastatic (m)crpc in a multidisciplinary team. Treat patients with mcrpc with life prolonging agents. Base the choice of first line treatment on the performance status, symptoms, comorbidities, location and extent of disease (alphabetical order: abiraterone, docetaxel, enzalutamide, radium-223, sipuleucel-t). 4 A 3 A 1b A Mottet N et al. European Association of Urology Prostate Cancer Guidelines. Docetaxel is not registered for that indication in Romania

12 Case 2: 71; 10/2009: acromio-clavicular pain; PSA >2500 ng/ml, ALP 450 UI/L, Gleason 7 The historical standard of care i androgen deprivation therapy Additional treatment to be discussed: Docetaxel Other to come? Images copyrighted to CUSL, Brussels (BE ) ALP: alkaline phosphatase; PSA: prostate-specific antigen

13 Case 2: 71; 10/2009: acromio-clavicular pain; PSA >2500 ng/ml, ALP 450 UI/L, Gleason 7 Androgen deprivation therapy (ADT) started, pain disappears after 7 days. 10/ /2010 Images copyrighted to CUSL, Brussels (BE )

14 O-09 J-10 A-10 J-10 O-10 J-11 A-11 J-11 O-11 J-12 A-12 J-12 O-12 J-13 A-13 J-13 O-13 J-14 Case 2: 71; 10/2009: acromio-clavicular pain; PSA >2500 ng/ml, ALP 450 UI/L, Gleason 7 ADT stopped after 2 years and then restarted PSA (ngl/ml) Al.P (UI/L)

15 The androgen receptor (AR) is the main driver of the adaptation mechanisms Tombal B et al. Eur J Cancer 2011;47:S179-88

16 Historical second line hormonal agents Drug Ref Patients (n) N Trials % PSA Response (range) Duration (months) Bicalutamide (150 mg qd ) Flutamide (250 mg tid) ,2 Nilutamide (200 or 300 mg qd) Ketoconazole ( mg tid) + cortisone ± AAW DES (1-3 mg) NA-2.8 % PSA response: % of patients achieving 50% decrease in PSA; AAW = antiandrogen withdrawal 1) JCO (8): ; 2) J Urol (1):149-53; 3) Urology (1):53-8; 4) Urology (5): ; 5) JCO (1):62-71; 6) J Urol (5):1742-4; 7) Urology (6): ; 8) J Urol (4):1204-7; 9) Cancer (9):1755-9; 10) JCO (6): ; 11) J Urol (2):542-5; 12) Urol Oncol (3): ; 13) Clin Cancer Res (22): ; 14) JCO (18): ; 15) Urology (2):257-60

17 Molecular biology of CRPC Enzalutamide (Apalutamide) (Darolutamide) Enzalutamide (Apalutamide) (Darolutamide) Abiraterone Imamura et al. International Journal of Urology (2016) 23,

18 Mode of action of new AR pathways inhitor lead to increase in overall survival in post-docetaxel setting, thus demonstrating the depency of mcrpc on the AR Overall Survival abiraterone + prednisone vs. prednisone (COU-AA_301) Abiraterone /P OS 95%CI Placebo/P HR P < De Bono et al. N Engl J Med 2011;364:

19 Mode of action of new AR pathways inhitor lead to increase in overall survival in post-docetaxel setting, thus demonstrating the depency of mcrpc on the AR Overall Survival enzalutamide vs. placebo post-docetaxel (AFFIRM) Enzalutamid e OS 95%CI NYR Placebo H.I. Scher, NEJM 2012 Sep 27;367(13):

20 O-09 J-10 A-10 J-10 O-10 J-11 A-11 J-11 O-11 J-12 A-12 J-12 O-12 J-13 A-13 J-13 O-13 J-14 Case 2: 71; 10/2009: acromio-clavicular pain; PSA >2500 ng/ml, ALP 450 UI/L, Gleason 7 Degarelix stopped after 2 years and then restarted PSA (ngl/ml) Al.P (UI/L)

21 The management of mcrpc before abiraterone and enzalutamide Chemo-based treatment 3 Radiographic progression Symptoms M0 CRPC survival

22 Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for Advanced Prostate Cancer. Tannock IF et al. N Engl J Med 2004;351: Graph and table are updated results from J Clin Oncol 26:

23 When Should Chemotherapy be Started? Disease Burden Median Survival Chemotherapy Indicated Rising PSA only ~4 years? No Asymptomatic metastases (limited) Asymptomatic metastases (extensive) ~18 to 24 months Individualize ~18 months Yes Symptomatic metastases ~9 to 16 months Yes Calabrò F, Sternberg CN., Eur Urol Jan;51(1):17-26, modified

24 Efficacy vs. sequencing Efficacy trial: evaluating the benefit of Enzalutamide when the rest has failed N Engl J Med Sep 27;367(13):

25 Efficacy vs. sequencing Efficacy trial: evaluating the benefit of Enzalutamide when the rest has failed N Engl J Med Sep 27;367(13): Sequencing trial: opposing a new approach, immediate enzalutamide, to the older one, wait and give chemotherapy

26 Randomisation COU-AA-302 and PREVAIL are sequencing Trial Historical reference arm Docetaxel SOC mcrpc ARpI AAO Advanced PCa SOC mcrpc ARpI Docetaxel AAO Investigational arm SOC: standard of care (ADT ± local T) ARpI: AR pathways inhibitors abiraterone or enzalutamide Docetaxel AAO: all available options Tumour load Pain, QoL deterioration, SRE, fatigue.

27 Impact of PREVAIL and COU-AA-302 on the modern CRPC landscape Enzalutamide 2 Abiraterone 1 Chemo-based treatment Radiographic progression Symptoms M0 CRPC survival CRPC: castration-resistant prostate cancer Ryan CJ, et al. N Engl J Med 2013;368: Basch E, et al. Lancet Oncol Nov;14(12):

28 Abiraterone (COU-AA-302) Important secondary endpoints Abi/Pred Pred. Δ p Time to chemotherapy < Time to PSA progression (months) < Time to SRE < Time to time to opiate use NR 23.3 Median time to progression of mean pain intensity (1) Time to HRQoL degradation (months) (2) PSA response > 50% (%) Objective response (% < Median time to progression of pain interference 2. Median time to functional status deterioration (FACT-P total score) Ryan CJ, et al. N Engl J Med 2013;368: Basch E, et al. Lancet Oncol Nov;14(12):

29 Enzalutamide (PREVAIL): Important secondary endpoints Enzalutamide Placebo P Time to chemotherapy (mo) <0.001 Time to PSA progression (mo) <0.001 Median time to 1 st SRE (mo) <0.001 SRE at first analysis (%) 32% 37% 0.74 <0.001 Time to pain (mo) 1 NR yet Time to HRQoL degradation (FACT-P) (mo) ² < PSA response >50% (%) <0.001 Objective response (%) < Median time to progression of pain interference; ²Time to deterioration in HRQoL based on FACT-P total score. FACT- P: Functional Assessment of Cancer Therapy Prostate; HRQoL: health-related quality of life; SRE: skeletal-related event Beer TM et al. N Engl J Med 2014;371:424-33; Loriot Y et al. Lancet Oncol 2015;16:509-21

30 Patients showing improvement in FACT-P (%) Enzalutamide efficacy: QoL (PREVAIL) Improvement is defined by a score increase of: 10 (Total score); 4 (Social/family WB); 3 (Physical, emotional and functional WB and PCa subscale) P< P= P< P< P< P< Total Physical WBSocial/family WBEmotional WB Functional WB PCa subscale WB: wellbeing Loriot Y et al. Lancet Oncol 2015;16: Enzalutamide Placebo

31 Adjusted mean (95% CI) change in FACT-P PCa subscale Loriot Y et al. Lancet Oncol 2015;16:509-21

32 Randomisation COU-AA-302 and PREVAIL are sequencing Trial Historical reference arm Docetaxel SOC mcrpc ARpI AAO Advanced PCa SOC mcrpc ARpI Docetaxel AAO Investigational arm SOC: standard of care (ADT ± local T) ARpI: AR pathways inhibitors abiraterone or enzalutamide Docetaxel AAO: all available options Tumour load Pain, QoL deterioration, SRE, fatigue.

33 The impact of PREVAIL and COU-AA-302 in the modern mcrpc landscape Subsequent therapy for mcrpc Abiraterone N (%) Prednisone N (%) 365 (67) 435 (80) Abiraterone 69 (13) 238 (44) Cabazitaxel 100 (18) 105 (19) Docetaxel 311 (57) 331 (61) Enzalutamide 87 (16) 54 (10) Ketoconazole 42 (8) 68 (13) Radium (4) 7 (1) Sipuleucel-T 45 (8) 32 (6) Subsequent therapy for mcrpc Enzalutamide N (%) 457 (52.4) Docetaxel 358 (41.1) Abiraterone 256 (29.4) Cabazitaxel 79 (9.1) Enzalutamide 21 (2.4) 1. Ryan et al. Lancet Oncol 2015;16:152-60; 2. Beer TM et al. N Engl J Med 2014;371: Placebo N (%) 685 (81.1) 504 (59.6) 417 (49.3) 149 (17.6) 249 (29.5) Sipuleucel-T 17 (1.9) 11 (1.3) Radium (1.8) 22 (2.6)

34 Randomisation COU-AA-302 and PREVAIL are sequencing Trial Historical reference arm Docetaxel SOC mcrpc ARpI AAO Advanced PCa SOC mcrpc ARpI Docetaxel AAO Investigational arm SOC: standard of care (ADT ± local T) ARpI: AR pathways inhibitors abiraterone or enzalutamide Docetaxel AAO: all available options Tumour load Pain, QoL deterioration, SRE, fatigue.

35 The impact of PREVAIL and COU-AA-302 in the modern mcrpc landscape Abiraterone/P vs. placebo/p (COU-AA-302) 1 Enzalutamide vs. placebo (PREVAIL) 2 Improvement in OS (median) 4.4 mo 4 mo HR (95% CI; P-value) 0.81 ( ; P <0.001) 0.77 ( ; P =0.0002) The benefit is for the sequence not for simply the drug. 1. Ryan et al. Lancet Oncol 2015;16:152-60; 2. Beer TM et al. N Engl J Med 2014;371:424-33

36 The Standard treatments sequence in 2017 Enzalutamide 2 Abiraterone 1 docetaxel Enzalutamide Abiraterone Cabazitaxel Radiographic progression Symptoms M0 Bone targeted therapies, including RA223 CRPC survival CRPC: castration-resistant prostate cancer Ryan CJ, et al. N Engl J Med 2013;368: Basch E, et al. Lancet Oncol Nov;14(12):

37 First line treatment of early mcrpc: The view from the experts of APCC What is your preferred first-line mcrpc treatment option: Asymptomatic men who did not receive docetaxel in the HNPC setting Asymptomatic men who did receive docetaxel in the HNPC setting Abiraterone or enzalutamide Cabazitaxel Docetaxel Radium 223 Sipuleucel-T Gillessen S, Eur Urol Jun 24. pii: S (17)

38 The Standard treatments sequence in 2017 ADT + docetaxel has supplanted ADT as upfront systemic treatment. Enzalutamide or Abiraterone are the reference treatments of early mcrpc. How early is early? Docetaxel is not registered for that indication in Romania

39 The PREVAIL Study: Primary Outcomes by Site and Extent of Baseline Disease for Enzalutamide-treated Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer. Kaplan Meier estimates of OS by number of bone metastases at screening (<4 vs I4). CI = confidence interval; HR = hazard ratio; mets = metastases; NYR = not yet reached. Evans CP et al. Eur Urol Mar 19. pii: S (16)

40 The PREVAIL Study: Primary Outcomes by Site and Extent of Baseline Disease for Enzalutamide-treated Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer. Kaplan Meier estimates of OS in the non-visceral and visceral subgroups. CI = confidence interval; HR = hazard ratio; mets = metastases; NYR = not yet reached. Evans CP et al. Eur Urol Mar 19. pii: S (16)

41 The PREVAIL Study: Primary Outcomes by Site and Extent of Baseline Disease for Enzalutamide-treated Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer. CI = confidence interval; HR = hazard ratio; mets = metastases; NYR = not yet reached. Evans CP et al. Eur Urol Mar 19. pii: S (16)

42 The Standard treatments sequence in 2017 ADT + docetaxel has supplanted ADT as upfront systemic treatment. Enzalutamide or Abiraterone are the reference treatments of early mcrpc. How early is early? Is there still a role for hormonal therapies without proven benefit? Docetaxel is not registered for that indication in Romania

43 Use of first generation second line hormone therapies in Prevail and COU-AA-302 Enzalutamide 1 Abiraterone 2 M0 Radiographic progression Second line hormonal manipulations? Study % patient having received antiandrogen prior to entering the trial COU-AA- 100% (compulsory per protocol) 302 (1) PREVAIL (2) 65% CRPC survival (1) Ryan CJ, et al. N Engl J Med 2013;368: (appendix); (2) Beer TM, NEJM 2014;371: (appendix)

44

45 The Standard treatments sequence in 2017 ADT + docetaxel has supplanted ADT as upfront systemic treatment. Enzalutamide or Abiraterone are the reference treatments of early mcrpc. How early is early? Is there still a role for hormonal therapies without proven benefit? Is it abiraterone or enzalutamide, or both one after the other? Docetaxel is not registered for that indication in Romania

46 Administration and Side Effect profile and relative contra-indications of Zytiga Abiraterone: mg tablets without food (No food should be eaten for at least 2 hours before and for 1 hour after). Swallow whole. With prednisone 5 mg BID Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly. Measure ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment, and monthly thereafter. Side-effect of interest: hypertension, hypokalemia, fluid retention, liver enzyme Relatives contra-indications: patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in blood pressure, hypokalemia, or fluid retention. YP2D6 substrates with a narrow therapeutic index. Zytiga Summary of Product Characteristics (SmP) accessed on Nov 1, _Product_Information/human/002321/WC pdf

47 Administration and Side Effect profile and relative contra-indications of Xtandi Enzalutamide Four 40 mg capsules (160 mg) orally with or without food. No additional tests, except if is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring. Side-effect of interest: fatigue, HTA, arthralgia, Relatives contra-indications: patients who had a seizure, with predisposing factors for seizure, or using concomitant medications that may lower the seizure threshold. Avoid CYP3A4, CYP2C9 and CYP2C19 substrates with a narrow therapeutic index. Xtandi Summary of Product Characteristics (SmP) accessed on Nov 1, _Product_Information/human/002639/WC pdf

48 What is your preferred choice between Abiraterone and Enzalutamide at any time in the treatment sequence in men with mcrpc if all options are available in case of the following medical situations? Enzalutamide Abiraterone Either Stable brain metastases 6% 73% 10% History of falls 2% 94% 4% Baseline significant fatigue 6% 88% 6% Baseline significant neurocognitive impairment 4% 84% 10% Long QTc-syndrome or men on not replaceable drugs with 27% 31% 24% potential QT prolongation Diabetes mellitus requiring prescription drug therapy 84% 6% 10% Cardiac ejection fraction below 45-50% 63% 6% 27% Active liver dysfunction 68% 8% 14% Gillessen S et al. Eur Urol Jun 24. pii: S (17)

49 Conclusion CRPC prostate cancer is an heterogonous disease Early enzalutamide or abiraterone is the new reference treatment of early asymptomatic mcrpc There is no valid reason to delay treatment Optimal sequencing is based on the administration of a maximum of agents taking in consideration the very high rate of cross-resistance between agents.