Castraatresistent prostaatcarcinoom - waar staan we nu? Martijn Lolkema, MD/PhD Medical Oncologist ErasmusMC Cancer Center

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1 Castraatresistent prostaatcarcinoom - waar staan we nu? Martijn Lolkema, MD/PhD Medical Oncologist ErasmusMC Cancer Center

2 Disclosures Research funding from Astellas/ JnJ/ MSD and Sanofi Consultancy fees from Novartis, Bayer and JnJ

3 Inhoud van de presentatie Focus op mhspc behandeling: Docetaxel vs abiraterone Hoog risico: wat is dat? Toekomst: MSI: is dat relevant voor prostaatca DNA repair: het komt eraan PTEN loss of function en AKT inhibitors

4 Waar komen we vandaan?

5 PLATO: Novel Trial Design Randomized Treatment - Period 2 Open-Label Enzalutamide - Period 1 Primary and Secondary Endpoints of the Trial Treatment Enzalutamide initiation PSA evaluation (week 13 and week 21) Follow for PSA progression 1:1 randomization* at confirmed PSA progression Enzalutamide + abiraterone/ prednisone Placebo + abiraterone/ prednisone Radiographic or unequivocal clinical progression Total 16 weeks of follow-up Safety follow-up and survival Subsequent therapy PSA rise Safety follow-up *Randomization stratified by confirmed PSA response at week 13 in period 1 ( 0% to < 30% vs 30%): 9 patients ( 0% to < 30%) and 242 patients ( 30%) Enrolled n = 509 (Target n = 500) PSA Responders n = 412 (Target n = 415) Randomized n = 251 (Target n = 250) PFS Events n = 175 (Target n = 175) Period 1 results presented by Attard G et al, at the European Cancer Congress; September 25-29, 2015; Vienna, Austria. Patients enrolled in 51 study centers in North America, Europe, and Australia. Abbreviation: PFS, progression-free survival. NCT ; Presented by: Gerhardt Attard 5

6 Progression-Free Survival, % Primary Endpoint: PFS Event/Cumulative Events ENZA + Abi/Pred Placebo + Abi/Pred 27/27 33/33 Abbreviations: CI, confidence interval; mo, months. 30/57 26/59 10/67 13/72 Time, mo 9/76 8/80 ENZA + Abi/Pred (n = 126) Median (95% CI) 5.7 ( ) mo Stratified hazard ratio (95% CI) ( ) 5/81 6/86 Placebo + Abi/Pred (n = 125) 1/82 4/ ( ) mo Stratified log-rank test /83 2/92 Presented by: Gerhardt Attard 6

7 PSA Change From Baseline, % Best PSA Change From Baseline: Period ENZA + Abi/Pred Placebo + Abi/Pred Presented by: Gerhardt Attard 7

8 Overzicht mcrpc Anti-hormonale therapie?? Docetaxel Docetaxel Anti-hormonale therapie Cabazitaxel

9 Hormoon Sensitief Prostaat Carcinoom (HSPC) HSPC Subgroepen: Recurrence na eerdere locale behandeling Bij diagnose gemetastaseerde ziekte Indolent vs agressief beloop

10 ECCO 2015: meta-analyse Results based on 2993 men / 1254 deaths 10% absolute improvement in survival (from 40% to 50%) at 4 years

11 CHAARTED Update ESMO 2016 High volume Low volume

12 QL ADT +/- docetaxel FACT-P high volume FACT-P low volume

13 Lattitude en Stampede: abiraterone

14 Overall Survival by Subgroup The treatment effect of ADT-abiraterone-prednisone on OS was consistently favorable across nearly all prespecified subgroups

15 Subsequent Life-prolonging Therapy for Prostate Cancer ADT-Abiraterone- Prednisone (n = 597) ADT-Placebos (n = 602) Agent no of patients (%)* n = 314 n = 469 Abiraterone acetate plus prednisone 10 (3) 53 (11) Cabazitaxel 11 (4) 30 (6) Docetaxel 106 (34) 187 (40) Enzalutamide 30 (10) 76 (16) Radium (4) 27 (6) *Patients who discontinued treatment and were eligible for subsequent therapy. The numbers of patients receiving one or multiple life-prolonging therapies totaled 125 (21%) in the ADTabiraterone-prednisone group and 246 (41%) in the ADT-placebos group More patients in the ADT-placebos group received docetaxel, enzalutamide, abiraterone acetate plus prednisone, cabazitaxel, and radium-223 1

16 Patients without degradation in FACT-P total score (%) FACT-P total score ADT + AA + P Significantly Improved HRQoL per FACT-P 15% Risk Reduction for HRQoL Degradation ADT + AA + P, 12.9 mo 0.2 Better 40 ADT + Placebos, 8.3 mo Patients at risk ADT + AA + P ADT + Placebos *1 cycle = 28 days. HR 0.85 (95% CI, ) P = Months Cycle* ADT + AA + P ADT + Placebos Worse However: can we distinguish a true overall HRQoL difference?

17 Adding abiraterone plus prednisone for men with high-risk prostate cancer starting long-term androgen deprivation therapy: Survival results from STAMPEDE James ND, et al ASCO 2017 (Abstr LBA5003 and oral abstract session)

18 Abiraterone plus prednisone comparison: patients

19 Patient characteristics 1% WHO PS 2 [s] 21% WHO PS 1 [s] 67yr Median age [s] (min 39, max 85) 52% Metastatic [s] (88% Bony mets) 20% N+M0 28% N0M0 99% LHRH analogues [s] 41% Planned for RT [s] (96% of N0M0 pts; 62% of N+M0 pts) 5% Previous local therapy [s] = Stratification factors Also stratified on :: hospital :: NSAID/aspirin Balanced by arm

20 OS STAMPEDE abiraterone plus prednisone comparison

21 OS STAMPEDE abiraterone plus prednisone comparison Overall survival by metastatic status pre-planned analysis SOC vs SOC+AAP Mets SOC-only SOC+AAP Mets * treatment interaction P-value 0.37 Haz. Ratio status Dths/N Dths/N (95% CI) M0 44/455 34/ (0.48, 1.18) M1 218/ / (0.49, 0.75) Overall 0.63 (0.52, 0.76) Favours: abiraterone SOC-only 0.63 No good evidence of heterogeneity by metastatic status

22 Docetaxel/ Abiraterone bij HSPC patienten Een optie na goedkeuring ciebom Verschil is met name de behandelduur en dus het profiel van bijwerkingen over de tijd Wat betreft subgroepen en patienten is er geen goede stratificatie te maken Voor nu geldt: evidence voor vroege behandeling is met name sterk voor agressieve en grote ziekte last

23 De nabije toekomst

24 Genomic data on prostate cancer Cell, Volume 161, Issue 5, 21 May 2015, Pages

25 Wat is er beyond hormones?

26 Germline DNA repair deficits Pritchard et al NEJM 2016

27 MSI and prostate cancer About 10% of prostate cancer patients have MSI phenotype These patients have a higher infiltration of T-Cells

28 PI3K pathway in prostate cancer

29 Conclusies Prostaat kanker is ook in de gemetastaseerde setting een goed te behandelen aandoening De behandeling begint complex te worden met veel keuzes Er is beperkte biomarker data beschikbaar voor de behandelkeuzes: daar moet de toekomst liggen.

30 Take home messages Geef je therapie vorm op basis van echt bewijs Vergeet de chemotherapie niet Klinische stratificatie en de behandeling in HSPC heeft een echte meerwaarde De toekomst is het ontwikkelen van de 3 e dimensie: tumor kenmerken! Doe bij je patienten biopten in het kader van CPCT-02 daar zit voor de toekomst de echte verbetering.

31 Dank voor uw aandacht