Therapie des fortgeschrittenen Prostatakarzinom

Präsentation zum Thema: "Therapie des fortgeschrittenen Prostatakarzinom"—  Präsentation transkript:

1 Therapie des fortgeschrittenen Prostatakarzinom
45 Minuten inkl. Kasuistik und Diskussion Prof. Dr. Axel S. Merseburger

2 Agenda Fakten Prostatakarzinom Definition CRPC Neue Substanzen
Optimale Sequenz Ref. Merseburger, Oncologist

3 Klinischer Verlauf der Prostatakarzinomerkrankung
Zeit Initiale Diagnose und Therapie Einleitung der ADT Tod Knochenmetastasen M0 kastrationsresistent PSA-Spiegel/Tumorlast Hormonsensitiv ADT mCRPC Nach Abrahamsson PA. Eur Urol Suppl 2009;8:821–38. 3

4 Ziele und Erwartungen an die Therapie des CRPC
Palliation Symptome Palliation Gesamtüberleben Survival Prävention von Komplikationen (SRE) Prävention M1 symptomatisch (Knochenschmerz) M0 Steigendes PSA M1 asymptomatisch 4 4

5 Überlebensdaten beim CRPC
Stadium Mittleres Überleben Asymptomatisch PSA Anstieg Keine Metastasen 24-27 Monate Minimal Metastasen 16-18 Monate Extensive Metastasen 9-12 Monate Symptomatisch PSA Anstieg Minimale Metastasen 14-16 Monate Clark N. et al. Eur Urol. Suppl. 2013

6 Agenda Fakten Prostatakarzinom Definition CRPC Neue Substanzen
Optimale Sequenz Ref. Merseburger, Oncologist

7 Definition des kastrationsresistenten Wachstums
Kastrationswerte für Testosteron im Serum (< ng / dl) 3 konsekutive PSA - Anstiege im Abstand von je Wochen, wobei 2 Werte mit Zunahme von ≥ 50 % oberhalb des Nadirs liegen PSA - Progression trotz sekundärer Hormonmanipulation Progression von Knochen - oder Weichteilmetastasen

8 Mechanismen der CRPC Entstehung

9 Angriffspunkte der Systemtherapie beim CRPC

10 Agenda Fakten Prostatakarzinom Definition CRPC Neue Substanzen
Optimale Sequenz

11 2,4 Monate 4,1 Monate 4,6 Monate 3,6 Monate Post-Chemo Chemo-naive
Sipuleucel T, Kantoff PW, NEJM 2010 Post-Chemo Cabazitaxel, De Bono J, Lancet 2010 2,4 Monate 4,1 Monate mCRPC Alpharadin, Parker C, NEJM 2013 Post-Chemo Abiraterone, De Bono J, NEJM 2011 4,6 Monate 3,6 Monate OS Sip-T: 4,1 Monate; Abiraterone 11,2 vs. 15,8 =4,6 Monate, Cabazitaxel: 12,7 vs. 15,1 =2,4 Monate; MDV 13,6 vs. 18,4 =4,8 Alpha-Strahler mit ganz kurzer Reichweite von 2-10 Zellen und eine Halbwertszeit von 11,4 Tagen. Die Behandlung umfasst 6 Injektionen, die im Abstand von 4 Wochen gegeben wurden. SRE Hinauszögerung um 4,9 Monate und OS Verbesserung um 2,8 Monate.

12 Androgen Biosynthese Erklärung – MOA: AR – Binding (Date),
Ketoconazole Orteronel (TAK-700) Galeterone (TOK-001) VT-464 CFG920 T/DHT Erklärung – MOA: AR – Binding (Date),

13 AFFIRM: Enzalutamide vs Placebo
R A N D O M I Z E D 2:1 Primärer Endpunkt: Gesamt- überleben Enzalutamide 160 mg Tag n = 800 Placebo n = 399 Patient Population*: 1199 Pat. mit progressiven mCRPC ** Nach Versagen einer Docetaxel Chemotherapie *Stratifikation Variablen: ECOG Performance Status (0-1, 2) Mean Brief Pain Inventory (<4, ≥ 4) Get Vollpublikation **Glucocorticoids waren erlaubt aber nicht notwendig Scher et al. NEJM, 2012 13

14 Enzalutamide verlängert das Überleben signifikant
37% Risikoreduktion für Versterben 18,4 Monate (95% CI: 17.3, NYR) Placebo: 13,6 Monate (95% CI: 11.3, 15.8) Scher et al. NEJM, 2012 14

15 Enzalutamide verlängert die Zeit bis zum ersten SRE im Median um 3,4 Monate
HR = P <0.0001 Enzalutamide: 16,7 Monate (95% CI: 14.6, 19.1) Placebo: 13,3 Monate (95% CI: 5.5, NYR) Scher et al. NEJM, 2012 15

16 AFFIRM: Sekundäre Endpunkte
Enzalutamide (n = 800) Placebo (n = 399) Hazard ratio p-value Confirmed PSA response rates ≥50% reduction from baseline (%) 54 2 – p<0.001 ≥90% reduction from baseline (%) 25 1 PSA progression Median time to PSA progression (months) 8.3 3.0 0.25 Soft tissue response* Soft tissue response rate (%) 29 4 Progression-free survival Radiographic progression-free survival (months) 2.9 0.40 Skeletal-related events Time to first skeletal-related event (months) 16.7 13.3 0.69 Health-related quality of life Functional Assessment of Cancer Therapy - Prostate (FACT-P) quality of life response rate (%) 43 18

17 Abirateron Acetat Blockade der Androgen - Biosynthese
Androgens produced at all 3 sources lead to tumor proliferation Abiraterone inhibits production of androgens that fuel prostate tumor cell growth Persistence of intra-tumoral androgens despite castration T, DHT and AD levels sufficient to stimulate AR ↑ expression of androgen synthesis genes/enzymes in CRPC Intracrine and/or paracrine mechanisms Currently approved therapies do not fully ablate androgens Castration does not inhibit adrenal or intra-tumor androgen synthesis Affinity of anti-androgens to the AR is much lower that that of Testosterone and DHT Adaptive mechanisms allow AR signaling despite “castrate-level” androgen environment AR over-expression 2° gene amplification and ↑ mRNA expression AR mutations that ↑ AR transcriptional activity Usually in ligand-binding domain AR “promiscuity” Danila DC et al. J Clin Oncol

18 Studiendesign COU-AA-302 – Prä-Chemo
Endpunkte R A N D O M I Z E D 1:1 Co-Primäre Endpunkte: rPFS (Centraler Review) Gesamtüberleben Secondäre Endpunkte: Zeit bis zur Opiatgabe (cancer-related pain) Zeit bis zur Initiierung Chemotherapíe Zeit bis zum ECOG- PS deterioration Zeit zum PSA Progress Patienten AA 1000 mg tägl. Prednisone 5 mg BID (n = 546) Progressive chemo-naïve mCRPC Patienten (N = 1088) Asymptomatisch oder mild symptomatisch Placebo tägl. Prednisone 5 mg BID (n = 542) Get Vollpublikation Ryan et al. NEJM, 2013 18 18

19 Statistisch signifikante Verbesserung des primären Endpunktes rPFS
Ryan et al. NEJM, 2013

20 Primärer Endpunkt Gesamtüberleben
Pre-specified significance level by O’Brien-Fleming Boundary = Ryan et al. NEJM, 2013

21 Sigifikanter Vorteil in allen sekundären Endpunkten
AA + P Placebo + P Median (months) HR (95% CI) P Value Time to opiate use (cancer related pain) NR 23.7 0.69 (0.57, 0.83) 0.0001 Time to chemotherapy initiation 25.2 16.8 0.58 (0.49, 0.69) <0.0001 Time to ECOG PS deterioration 12.3 10.9 0.82 (0.71, 0.94) 0.0053 Time to PSA progression 11.1 5.6 0.49 (0.42, 0.57) Ryan et al. NEJM, 2013

22 Zulassung Abiraterone mit 10mg Prednison bei Pat. mit:
mCRPC mit asymptomatischen oder mild symptomatischen Verlauf der Erkrankung nach Versagen der Androgenentzugstherapie, bei denen eine Chemotherapie noch nicht klinisch indiziert ist. mCRPC bei Progress während oder nach einer Docetaxel Chemo. Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation) 22

23 Überlebensverlängernde Therapieansätze 2013
Prä-Chemo: Sipuleucel-T (Provenge) Abirateron (Zytiga + Prednison) Alpharadin (Xofigo) Docetaxel (Taxotere) Post-Chemo: Cabazitaxel (Jevtana) Enzalutamid (Xtandi)

24 Sekundäre/tertiäre Hormonmanipulation beim mCRPC
Enzalutamide EMA approved in 2013 for treatment of men with mCRPC previously treated with docetaxel1 ODM-201 Phase 1/2 trial for treatment of chemotherapy-naïve men with mCRPC2 ARN-509 Phase 3 trial for treatment of chemotherapy-naïve men with mCRPC3 2011 2012 2013 2014 2015 2016 2017 Abiraterone EMA approved for treatment of men with mCRPC previously treated with docetaxel4 Abiraterone EMA approved for treatment of men with mCRPC not previously treated with docetaxel4 Orteronel Phase 3 trial for treatment of chemotherapy-naïve men with mCRPC5 EMA=European Medicines Agency; FDA=Food and Drug Administration; mCRPC=metastatic castration-resistant prostate cancer. Xtandi (enzalutamide). Summary of product characteristics. July 2013. NCT Available at Last accessed September 2013. NCT Available at Last accessed September 2013. Zytiga (abiraterone). Summary of product characteristics. August 2013. NCT Available at Last accessed September 2013.

25 Enzalutamide Prä-Chemotherapie (mCRPC): PREVAIL Studie
Phase 3 1717 patients with mCRPC Asymptomatic or mildly symptomatic progression after ADT Enzalutamide 160 mg QD Placebo

26 Enzalutamid verlängert das rPFS
3 6 15 18 21 12 100 80 60 40 20 rPFS (%) Months 9 514 256 5 1 34 832 128 Enzalutamide, n 305 79 801 Placebo, n Placebo Enzalutamide HR=0.186 (95% CI: 0.15–0.23); p<0.0001 Estimated median rPFS, months (95% CI): Enzalutamide: NYR (13.8, NYR); Placebo: 3.9 (3.7, 5.4) Beer TM, ASCO-GU, 2014 NYR = Not Yet Reached

27 Die mediane Behandlungsdauer für Enzalutamid war 3 mal länger als für Plazebo
Enzalutamide (n=872) Placebo (n=845) Duration of treatment, median, months 16.6 4.6 Patients with ≥ 12-months duration 67.9% 18.0% Treatment ongoing at data cutoff date 42.1% 7.2% Median OS follow-up, months 22.2 22.4 Beer TM, ASCO-GU, 2014

28 Enzalutamid reduziert das Todesrisiko um 29%
100 HR=0.706 (95% CI: 0.60–0.84); p<0.0001 80 Placebo Enzalutamide 60 Survival (%) 40 20 3 6 9 12 15 18 21 24 27 30 33 36 Months 863 850 33 2 797 872 824 Enzalutamide, n 835 781 27 701 845 744 Placebo, n 745 644 566 484 395 328 244 213 128 102 Estimated median OS, months (95% CI): Enzalutamide: 32.4 (30.1, NYR); Placebo: (28.0, NYR) Beer TM, ASCO-GU, 2014 NYR = Not Yet Reached

29 Mehr nachfolgende Therapien im Plazeboarm
Enzalutamide (n=872) Placebo (n=845) Patients with at least one subsequent life-extending therapy 40.3% 70.3% Percentage of patients receiving subsequent therapies Docetaxel 32.8% 56.7% Abiraterone 20.5% 45.6% Cabazitaxel 5.8% 13.0% 1.0% 4.4% Sipuleucel-T 1.4% 1.2% Beer TM, et al. ASCO-GU 2014; Oral presentation.

30 Abiraterone vs. Enzalutamid

31 Therapieübersicht mPCa
 Enzalutamid (PREVAIL) vs. PLC Sipuleucel T vs. PLC mOS 21,7 vs. 25,8 Mo. (s) Abiraterone (COU-AA-302) vs. PLC mrPFS: 16,5 vs. 8,3 Mo. (s) mOS: NR vs. 27,2 Mo. (trend) Docetaxel (TAX327) vs. Mitoxantron mOS: 18,9 vs. 16,5 Mo. (s) Enzalutamid (AFFIRM) vs. PLC mOS: 18,4 vs. 13,6 Mo. (s) Cabazitaxel (TROPIC) vs. PLC mOS: 15,1 vs. 12,7 Mo. (s) Abiraterone (COU-AA-301) vs. PLC mOS: 15,8 vs. 11,2 Mo. (s) Alpharadin (ALSYMPCA) vs. PLC mOS 14,9 vs. 11,3 Mo. (s) () Abkürzungen: mPCa, metastatic Prostate Cancer (metastasiertes Prostatakarzinom; LHRHa/aa, LH Relea-sing Hormon (LH freisetzendes Hormon, Agonist/Antagonist); CAB, Complete Androgen Blockade (kom-plette Androgen-blockade; NSAA, nicht-steroidaler Androgen-Antagonist, PLC, Placebo; mOS, median Over-all Survival (medianes Gesamtüberleben); mrPFS, median radiological Progression-Free Survival (medianes radiologisches progressions-freies Überleben), s, signifikant Modifiziert nach: Heidenreich et al. EAU-Leitlinien Prostata-Karzinom; 2013 31

32 Sequenzoptionen 2014 … Abiraterone / Enzalutamide Docetaxel
Radium-223 / Alpharadin Cabazitaxel

33 Optimale Therapie Sequenz?
2012: Abiraterone Docetaxel  Cabazitaxel 2013: Cabazitaxel Abiraterone Docetaxel  Enzalutamide Alpharadin 33

34 Osteoprotektion +/- Alpharadin
Sequenz Ende 2014? Abiraterone Cabazitaxel Docetaxel Enzalutamide ADT Osteoprotektion +/- Alpharadin Carbo 34

35 ECOG-E3805: ADT plus Chemo im mPCa
ADT+Docetaxel 75mg/3Wo für 18 Wochen R N=790 M+PCa ADT Phase III randomisierte, Multicenterstudie zum Vergleich von früher Chemotherapie bei Patienten mit mPCA Embargoed for Release: Thursday, December 5, 2013, 4 p.m. EST NIH-funded study shows increased survival in men with metastatic prostate cancer who receive chemotherapy when starting hormone therapy Share on Share on facebook Share on twitter Men with hormone-sensitive metastatic prostate cancer who received the chemotherapy drug docetaxel given at the start of standard hormone therapy lived longer than patients who received hormone therapy alone, according to early results from a National Institutes of Health-supported randomized controlled clinical trial. The prostate gland rests below the bladder The independent Data and Safety Monitoring Committee overseeing the trial recommended to the National Cancer Institute (NCI), part of NIH, that the study results be made public because a recent planned interim analysis showed the prolongation in overall survival. Full details from this early analysis will be presented at a scientific meeting in 2014 and in a peer-reviewed publication. The study enrolled 790 men with metastatic prostate cancer between July 2006 and November 2012 in a trial known as E3805. All patients started treatment by receiving a form of hormone therapy known as ADT (androgen deprivation therapy). Androgens regulate male sex characteristics and can stimulate prostate cancer cells. Men received either ADT alone or ADT with the chemotherapy drug docetaxel every three weeks over a period of 18 weeks. In addition to examining whether the study participants lived longer with the addition of chemotherapy, investigators looked at whether the extent of a patient’s metastatic disease was high or low at the start of treatment. Approximately two thirds of patients had a high extent of disease which, according to the study, meant the disease had spread to major organs such as the liver, had a spread resulting in four or more bone lesions, or both. A significant improvement in the overall survival was noted favoring the participants who had received docetaxel chemotherapy in addition to the ADT compared to the ADT alone (three-year survival rates of 69.0 percent vs percent respectively). Further analysis showed that patients with a high extent of metastatic disease accounted for most of the benefit in the overall survival from docetaxel plus ADT (three-year survival rates of 63.4 percent vs percent for ADT alone). Median follow-up to date is two years. Since docetaxel has been shown in previous clinical trials to be beneficial in ADT-resistant disease and is approved by the U.S. Food and Drug Administration for treatment of late-stage prostate cancer, it is available for use now. However, because it is a chemotherapy drug associated with some toxicities, its use in combination with ADT at this time should be restricted to patients with high-extent metastatic prostate cancer who are candidates for treatment with docetaxel, according to the trial investigators. This is the group of patients who experienced the most benefit in the current analysis. Further follow-up will be performed on patients with less extensive metastatic disease who participated in E3805 in order to define the effect of this treatment combination on these patients. “The results of this study are practice-changing,” said lead investigator Christopher Sweeney, Dana Farber Cancer Institute, Boston. “We have strong scientific evidence that patients with the most advanced metastatic prostate cancer benefit from the early addition of docetaxel to ADT and not waiting until the cancer has progressed on hormonal therapy. The findings of this study are important both for improving the clinical care we deliver now and in designing new clinical trials as we strive to further improve the lives of men with metastatic prostate cancer.” E3805 was sponsored by NCI and was designed and conducted by the ECOG-ACRIN Cancer Research Group in collaboration with SWOG, Alliance for Clinical Trials in Oncology, and NRG Oncology. Sanofi, Paris, the drug manufacturer, provided the docetaxel and supported this study under a Clinical Trials Agreement with ECOG-ACRIN. “This trial would not have been done in the United States without a large national network of investigators brought together through the NCI-supported Cooperative Group program that was capable of rapidly enrolling many patients,” said Jeff Abrams, M.D., clinical director of NCI’s Division of Cancer Treatment and Diagnosis. “Additionally, these findings are an example of how combining two approved and available treatments can produce a significant improvement in clinical outcome. It is estimated that over 238,000 men will be diagnosed with prostate cancer in the United States in 2013 and over 29,000 men will die of the disease. NCI leads the National Cancer Program and the NIH effort to dramatically reduce the prevalence of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI website at or call NCI's Cancer Information Service at CANCER ( ). About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit NIH...Turning Discovery Into Health® Reference E3805: CHAARTED: ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer. The full protocol for this trial can be found at ### 3 Jahre Überlebensbenefit für ADT+Chemo: 69% vs. 52% Signifikanterer Benefit für Patienten mit hoher Metastasenlast: 63,4% vs. 43,9% Press release NIH:

36 Sequenz „Docetaxel – Abiraterone – Enzalutamid“
Author sequence n bRR mPFS Loriot ENZAABI 38 8% 2.7 m Noonan 30 3% 3.8 m Schrader ABIENZA 35 28.6% NR Bianchini 39 12.8% 2.8 m GWG-CRPC

37 Zusammenfassung mCRPC 2014
Vielzahl neuer Behandlungsoptionen beim mCRPC Datenlücken: M0 CRPC Viszerale Metastasen Ältere und comorbide Patienten Zeitpunkt Chemotherapie Optimale Sequenz unklar ADT kontinuierlich Osteoprotektion empfohlen •Older men in low/intermediate -risk group likely to benefit from active surveillance •Carefully balance benefits/harms of ADT for localized disease Increased diabetes, CV complications, osteoporosis and fractures