Cas clinique cancer de la prostate

Transcription

1 Cas clinique cancer de la prostate Cours chimio 2017 Pr Karim Fizazi

2 Q1 Un patient âgé de 69 ans présente une douleur lombaire. La scintigraphie osseuse identifie 6 lésions hyperfixantes. Le PSA est à 43 ng/ml. Des biopsies de la prostate montrent un adénocarcinome Gleason 8. Vous proposez: A) Radios/TDM des zones fixantes +/- IRM rachis B) Agoniste LHRH + inhibiteur du RA en continu C) Agoniste LHRH + inhibiteur du RA pendant 3 semaines puis arrêt D) Une castration + acide zoledronique E) Une castration + docetaxel

3 Zoledronic acid in hormone-sensitive CaP: Survival (Stampede) SOC SOC+ZA 405 deaths 197 deaths HR (95%CI) 0.93 (0.79, 1.11) P-value 0.44 Non-PH p-value 0.83 Median OS (95% CI) SOC 67m (60, 91m) SOC+ZA 80m (70, NR) Restricted mean OS time SOC 58.5m SOC+Doc 59.5m Diff (95%CI) 1.0m (-1.4, 3.4m) James N, ASCO 2015

4 No benefit of zoledronic acid in pts with castrate-sensitive metastatic CaP n= 645 pts with HSPC and bone mets R Immediate Zoledronic Acid Zoledronic Acid when CRPC Median time to SRE: 32 mo vs 30 mo (HR=0.97) Smith MR, J Clin Oncol 2014; 32:

5 Docetaxel in mhspc: Overall Survival GETUG 15 (1/2 poor-risk pts) ADT + D: 61 months ADT: 47 months HR: 0.9 [ ]; P =.44 CHAARTED (2/3 poor-risk pts) ADT + D: 58 months ADT alone: 44 months HR = 0.61 ( ) P =.0003 Gravis G. Lancet Oncol. 2013;14: ; Gravis G. ASCO GU Abstract LBA2; Sweeney C. ASCO Abstract 140.

6 STAMPEDE: Docetaxel Survival, M1 Patients SOC SOC + Doc 343 deaths 134 deaths HR (95% CI) 0.73 (0.59, 0.89) P value Median OS (95% CI) SOC 43 mo (24, 88 mo) SOC + Doc 65 mo (27, NR) Non-PH P value 0.23 Restricted mean OS time SOC 49.3 mo SOC + Doc 56.1 mo Diff (95% CI) 6.8 mo (2.8, 11.0 mo) James N. ASCO Abstract 5001.

7 Patient s price: What is the price to pay for this clinical benefit? Slightly higher docetaxel toxicity Toxicity-related deaths (1%) G-CSF recommended Society: Docetaxel=generic Large magnitude of clinical/survival benefit Likely very cost-effective

8 Chaarted: OS by extent of metastatic disease at start of ADT Update ESMO 2016 Hazard Ratio 0.63 (95% CI ) P=< Hazard Ratio 1.04 (95% CI ) P=<0.86 Sweeney C, ESMO 2016

9 Metastatic hormone-sensitive prostate cancer: Abiraterone? Local treatment?

10 LATITUDE: Phase III Trial of Abiraterone in Patients with Newly Diagnosed Metastatic Prostate Cancer Metastatic prostate cancer At least 2 poor-risk factors: Visceral mets >2 bone mets Gleason score >7 Max: 3 months previous ADT 1200 pts planned R A N D O M I Z E D Androgen deprivation therapy (ADT) + Placebo ADT + Abiraterone 1000 mg Prednisone 5 mg Primary endpoints: OS (HR: 0.80) rpfs Recruitment completed ClinicalTrials.gov. Identifier: NCT

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12 PEACE-1: European Phase III Trial in de novo Metastatic Prostate Cancer (revised design) Androgen deprivation therapy (ADT) +/- docetaxel Patients with newly diagnosed (hormone-naive) metastatic CaP 916 patients planned R A N D O M I Z E D ADT + Abiraterone 1000 mg Prednisone 5 mg BID +/- docetaxel ADT + Local radiotherapy +/- docetaxel Co-primary endpoints: OS and PFS (HR: 0.75) ADT + Local radiotherapy + Abiraterone-Pred +/- docetaxel Study sponsor: Unicancer ClinicalTrials.gov. Identifier: NCT

13 Q2: Si ce patient est traité par castration seule pour son cancer métastatique, que décidezvous lors de la résistance à la castration (asymptomatique)? 1- Abiraterone 2- Enzalutamide 3- Bicalutamide 4- Chimiothérapie (docetaxel) 5- Poursuite castration seule

14 Should We Keep Using Old Hormonal Manipulations Before Using Next-generation AR-Targeting Drugs?

15 TERRAIN Study Design Patient population 375 men with progressive mcrpc Asymptomatic/mildly symptomatic Chemotherapy naive No requirement for steroids R A N D O M I Z E D 1:1 ENZA 160 mg/day n = 184 BIC 50 mg/day n = 191 Primary endpoint Progression-free survival (PFS) Radiographic progression (central review) Skeletal-related event Change in new antineoplastic therapy Death TERRAIN trial: NCT Statistical design The final analysis was planned at 220 progression events with 85% power to detect a target hazard ratio of 0.67 (assuming a median PFS of 9 months vs 6 months 1 ) The data cutoff date was 19 October 2014, with 240 events for the primary efficacy endpoint Secondary endpoints PSA response Time to PSA progression 1. Kucuk O, et al. Urology. 2001;58: Heidenreich A. EAU Abstract 234.

16 Patients without PFS event (%) Progression-Free Survival in TERRAIN ENZA Patients at risk BIC Patients at risk Bicalutamide Median (95% CI): 5.8 months (4.8, 8.1) Enzalutamide Median (95% CI): 15.7 months (11.5, 19.4) Time (months) ENZA BIC Hazard ratio (95% CI): 0.44 (0.34, 0.57); P < Shore N, Lancet Oncol 2016; 17:

17 Percentage Change in PSA from Baseline PSA Response by Week 13 with ENZA or BIC ENZA BIC Bicalutamide PSA response: 21% Observations Enzalutamide PSA response: 82% Shore ND, Lancet Oncol 2016: 17:

18 STRIVE trial: PFS (M0 and M1 CRPC) PFS included PSA progression, radiographic progression, and death events Penson D, et al. AUA, May 15-19, Oral Presentation. LBA-10.

19 Q3 Le patient ne souhaite pas de chimiothérapie et reçoit un «blocage androgénique complet». Après une amélioration initiale (nadir à 3 ng/ml), le PSA remonte à 22 ng/ml et les douleurs réapparaissent (bassin, rachis lombaire, côte) après 18 mois de traitement. Que proposez vous dans un premier temps? A) Arrêt de l agoniste de la LHRH B) Arrêt de l inhibiteur du Récepteur des Androgènes C) Un bisphosphonate (zoledronate) ou denosumab D) Dosage de la testostéronémie

20 Withdrawal syndrome Définition: baisse du PSA après arrêt de l inhibiteur du récepteur des androgènes Survient dans 20% des cas Toujours poursuivre l agoniste LHRH

21 Sous agoniste de la LHRH + denosumab, le PSA baisse et les douleurs disparaissent pendant 3 mois (withdrawal syndrome). Puis, progression tumorale marquée par une rétention urinaire aigüe nécessitant un sondage, des douleurs osseuses, PSA. Q4 Que proposez vous sur le plan urinaire? A- Irradiation de la prostate B- Prostatectomie radicale C- Sonde urinaire au long cours avec remplacement régulier D- Résection trans-uréthrale de prostate

22 PEACE-1: European Phase III Trial in de novo Metastatic Prostate Cancer (revised design) Androgen deprivation therapy (ADT) +/- docetaxel Patients with newly diagnosed (hormone-naive) metastatic CaP 916 patients planned R A N D O M I Z E D ADT + Abiraterone 1000 mg Prednisone 5 mg BID +/- docetaxel ADT + Local radiotherapy +/- docetaxel Co-primary endpoints: OS and PFS (HR: 0.75) ADT + Local radiotherapy + Abiraterone-Pred +/- docetaxel Study sponsor: Unicancer ClinicalTrials.gov. Identifier: NCT

23 Que proposez vous sur le plan général? Q5 A) Poursuite de l agoniste de la LHRH B) Poursuite du denosumab C) Association à un autre inhibiteur de l axe du Récepteur des Androgènes D) Abiraterone E) Une chimiothérapie par taxane F) Une irradiation métabolique osseuse

24 Overall Survival (%) COU 302: Final OS Analysis: Abiraterone in chemotherapy-naïve CRPC HR (95% CI): 0.81 ( ) p Value: Abiraterone, 34.7 mos Prednisone, 30.3 mos Abiraterone Prednisone Time to Death (Months) Median follow-up of 49.2 mos 44% of patients in the prednisone arm received abiraterone as subsequent therapy September 2014, Madrid, Spain esmo.org Ryan C, et al, ESMO 2014

25 Survival (%) Prevail: Enzalutamide reduced risk of death by 29% Hazard Ratio: (95% CI:0.60,0.84) P < Enzalutamide Placebo Duration of Overall Survival (Months) Enzalutamide 872 Placebo Beer T, N Engl J Med 2014

26 Several obvious situations History of seizure Enzalutamide Visceral metastases Radium-223 Patient too old/sick Taxanes Contra-indication to steroids (severe diabetes, etc) Abiraterone

27 Drug-drug interactions with enzalutamide CYP2C8 induces Enzalutamide metabolism into its active metabolite and its elimination: Avoid CYP2C8 inhibitors (gemfibrozil) and inducers (rifampicine) Enzalutamide = powerful CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer: Avoid Cabazitaxel, Be careful with many drugs (zolpidem, fentanyl, TK inh, anti-vit K, etc) Avoid any drug that increases the risk of seizure (anti-depressors, neuroleptics, tramadol)

28 First-line Docetaxel: Improvement in Overall Survival TAX 327 SWOG 9916 Tannock IF, et al: NEJM 351: , 2004 Petrylak DP, et al: NEJM 351: , 2004

29 Sous docetaxel, le PSA augmente de 30 à 40 ng/ml en 3 semaines. Les symptômes sont identiques. Q6: Que proposez vous? 1- Changer de chimiothérapie 2- Poursuivre la même chimiothérapie 3- Arrêter la chimiothérapie pour introduire une nouvelle hormonothérapie

30 Métastases de cancer de la prostate: le «Post-chemotherapy PSA surge syndrome» Def: Augmentation du PSA sérique au cours des premières semaines de chimiothérapie, suivie par une réponse Incidence: 20% des répondeurs! 250 1,0 0,8 Disease free survival p = ,6 0,4 0,2 No surge (n=33 pts) Surge (n=8 pts) Progression (n=11 pts) 100 0, M onths 50 At risk Thuret, Ann Oncol 2008; 19:

31 Q7 Finalement, on assiste à une diminution du PSA > 50% associée à une disparition des douleurs. Après 6 cycles de traitement, la tolérance reste bonne. Que proposez vous? A) Poursuite du docetaxel jusqu à progression ou intolérance B) Arrêt du docetaxel et reprise lors de la progression C) Traitement d entretien combinant chimiothérapie + irradiation métabolique

32 Q8: 4 mois après l arrêt du docetaxel, il existe de nouveau une progression. Que proposez vous? 1- Reprise du Docetaxel 2- Mitoxantrone 3- Cabazitaxel 4- Abiraterone 5- Irradiation métabolique par Radium Enzalutamide

33 Short response to ADT predicts poor response to Enzalutamide (post-docetaxel) PSA decrease 50% PFS 8% 58% P<0.001 TTCRPC Loriot Y et al., Eur J Cancer 2015

34 Personalize (biomarker)? Nuclear localization domain N-Terminal Domain DNA binding domain Ligand Binding domain AR splice variants (V7) Splice variant -> AR constitutively active (no need for androgens)

35 CTCs: AR-V7 seems a promising predictor of treatment response Abiraterone 1 Enzalutamide 1 Taxanes 2 AR-V7 positive AR-V7 negative PSA change, % * * * * PSA response rate: AR-V7 positive: 0% (95% CI: 0-46%) AR-V7 negative: 68.0% (95% CI: 46-85%) P= * * * PSA response rate: AR-V7 positive: 0% (95% CI: 0-26%) AR-V7 negative: 52.6% (95% CI: 29-76%) P= Docetaxel, n=30 Cabazitaxel, n=7 PSA response rate: AR-V7 positive: 41% (95% CI: 18-67%) AR-V7 negative: 65% (95% CI: 41-85%) P= Antonarakis ES et al. N Engl J Med 2014;371: ; 2. Antonarakis ES et al. JAMA Oncol 2015; 1:582-91

36 Q 379. Le patient reçoit de l abiraterone. Il bénéficie d une réponse tumorale, suivie 8 mois après d une nouvelle progression. Que proposez vous? 1- Reprise du Docetaxel 2- Mitoxantrone 3- Cabazitaxel 4- Irradiation métabolique par Radium Enzalutamide

37 Enzalutamide post-abiraterone (and post-docetaxel) n=35 pts PFS=3.1 months OS=7.5 months n=35 pts PSA resp: 29% PFS<4 months 1 partial resp (3%) n=61 pts PSA resp: 21% PFS=4 months OS= 7 months Schmid SC Adv Ther 2014 Schrader AJ, Eur Urol 2014; 65: 30-6 Badrising S, Cancer 2014; 120:

38 38 pts progressing on enzalutamide and docetaxel PSA decrease 50% in 8% Median PFS: 2.7 months Only 1 partial response (8%) 30 pts progressing on enzalutamide and docetaxel PSA decrease 50% in 3% Median PFS: 3.5 months No objective response Loriot Y et al. Ann Oncol 2013 Noonan KL et al. Ann Oncol 2013

39 Cabazitaxel post-abiraterone (and post-docetaxel) n=79 pts PSA response>30%: 62% PSA response>50%: 35% PFS: 4.4 mo OS: 11 mo In vitro: Caba active against both enza-s and enza-r cells PSA response Al Nakouzi N, Eur Urol 2015; 68:

40 Thank you!