Διαχείριση mcrpca: Η επιλογή της θεραπείας για τον κάθε ασθενή χωριστά

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1 Διαχείριση mcrpca: Η επιλογή της θεραπείας για τον κάθε ασθενή χωριστά Δέσποινα Νάση Παθολόγος Ογκολόγος Α Παθολογική Ογκολογική Κλινική Γ.Α.Ο.Ν.Α. «Ο Άγιος Σάββας»

2 Disclosures Advisory: Novartis, Roche, Merck Investigatory protocols: Amgen, Astellas, Novartis, Pfizer, Roche Satelite Lectures: Janssen- Cilag Studies to be announced in ASCO 2017

3 Epidemiology 2ος συχνότερος συμπαγής όγκος στους άνδρες Ο συχνότερος καρκίνος σε άνδρες στην Ευρώπη 4ος συχνότερος ανάμεσα σε όλους τους τύπους καρκίνου: 1 στους 6 στην Αμερική και 1 στους 8 στο UK θα εμφανίσουν Ca προστάτη 5η αιτία θανάτου λόγω κακοήθειας παγκόσμια GLOBOCAN 2012 (IARC) Section of Cancer Information

4 Prostate Cancer Disease States Hormone-Sensitive (Castration-Sensitive) Newly diagnosed localized disease Non-metastatic, biochemical relapse ADT Metastatic, hormone-naive ADT Castration-Resistant

5 CRPC Definition European Association of Urology (EAU) Castrate-resistant prostate cancer Serum castration levels of testosterone <50 ng/dl or <1.7 nmol/l Three consecutive rises of PSA, 1 week apart, resulting in two 50% increases over the nadir, with a PSA >2 ng/ml Anti-androgen withdrawal for at least 4 weeks a PSA progression despite secondary hormonal manipulations or Progression of osseous lesions: progression or appearance of two or more lesions on bone scan or soft tissue lesions using the Response Evaluation Criteria In Solid Tumours (RECIST) criteria and with nodes 2 cm in diameter

6 Targets of mcrpc therapies Cell trafficking Taxanes AR targeting Enzalutamide Abiraterone mcrpc Bone targeting Radium-223 Immunotherapy Sipuleucel-T Embarrassment of riches

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8 The Advanced PCa Landscape in 2015 ADT M + HNPC PSA Prog. RX progr. SRE PAIN ± 2-4 years (1-2) Docetaxel Cabazitaxel Abiraterone Enzalutamide HR localized PCa PSA Prog. M O CRPC space RX progr. SRE PAIN ± 7-15 years (3-5) Local therapies ADT HN PC: hormone naïve PCa; CRPC: Castration-Resistant Prostate Cancer; M0, non-metastatic; RX progression: radiological progression; SRE skeletal related events. 1. Gravis G, et al. Lancet Oncol 2013;14:149-58; 2. James ND, Eur Urol Oct 6. pii: S (14) ; 3. Joniau S for EmPACT, Eur Urol Jan 25. epub; 4. Widmark A, SPCG-7, Lancet :301-8; Warde P, SPCG-7, Lancet :

9 Mechanisms of evolution to Castration Resistance

10 Sequential administration of new agents Few clinical trials (approximately 25) Retrospective uncontrolled post hoc analysis (inherent bias) Small sample size Short follow up Evaluation of objective responses not always comparable Evaluation of cumulative results and not patients individual data Prognostic variables that may influence the clinical outcomes Not always available (PFS, OS, Rerponse to prior therapy) OS since the first exposure to Docetaxel almost never reported Maines et al, Crit Rev Hem Oncol 96(2015)

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12 Ongoing Trials Testing Sequencing or Combinations Maughan et al The prostate (2016); DOI /pros23246

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14 N=1006 men with chemotherapy-naive m CRPC were randomly assigned to docetaxel (75 mg/m 2 q 3 weeks), docetaxel (30 mg/m 2 weekly) or mitoxantrone (12 mg/m 2 q 3 weeks) All patients received prednisone 5 mg orally twice a day HR for death=0.76 (95% CI, ; P=0.009) OS = +2,9 m -Benefit persisted across Older and younger pts Symptomatic pts with pain Pts with higher PSA values -Most pts had PS: % had bone meta 25% had visceral meta SWOG Antonarakis et al, Curr Treat Options in Oncol, Nov 2016 Docetaxel improved rates of response in terms of pain, serum PSA level, and quality of life

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16 Median OS was longer for (exploratory analysis with predefined factors): -ALP< UNL -Hb> 10 gr/dl -PS:0 -Asymptomatic patients -Radium 223+ AA/Enzalutamide -Radium 223+ Denosumab Radium 223 can be safely combined with AA or Enza- Prolonged survival need further validation Saad et al, Lancet Oncol 2016

17 Abiraterone Acetate steroid synthesis inhibition Cholesterol Desmolase Low-dose steroid replacement minimizes mineralocorticoid-related toxicity Hypokalemia Fluid retention Hypertension X CYP17 17α-hydroxylase 11β-Hydroxylase Aldosterone 17α-OHpregnenolone DHEA X CYP17 C17,20-lyase Androstenedione 17α OHprogesterone Pregnenolone Progesterone Deoxycorticosterone Corticosterone 11-Deoxycortisol Testosterone Cortisol 5α-reductase DHT CYP19: aromatase ACTH AA inhibits biosynthesis of androgens produced at testes, adrenals, prostate tumor cells Estradiol Attard et al. J. Clin. Oncol. 2008

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22 Ενζαλουταμίδη και μηχανισμός δράσης o o Androgen Receptor Signaling Inhibitor (ARSI) Η Ενζαλουταμίδη καθυστερεί την ανάπτυξη και προκαλεί κυτταρικό θάνατο σε προχωρημένους καρκίνους: o o o Προκαλεί αποκλεισμό της πρόσδεσης της τεστοστερόνης στον AR Εμποδίζει τη μετακίνηση του AR στον πυρήνα των καρκινικών κυττάρων(nuclear translocation) Αναστέλει την πρόσδεση στο DNA

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24 40% enzalutamide group: received subsequent chemotherapy 70% of those in the placebo group: received subsequent chemotherapy Docetaxel : 33% (Enza) and 57% (placebo) AA: 21%(Enza) and 46% (Placebo)

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27 Abiraterone and Enzalutamide in mcrpc Phase III studies Pre-docetaxel Oligosymptomatic or asymptomatic mcrpca PREVAIL: 12% with visceral disease Presence of visceral meta 50% with was not Lymph predictive Node of Disease response and duration of treatment COU-AA-302: No visceral disease Procopio but et al, Oncotarget 49%: 2016 > 10 bone meta 49%: LN or Soft tissue disease PREVAIL post hoc: r PFS ss improvement in all subgroups of pts OS not ss improved in pts with liver meta and > 4+ bone meta Evans et al, Europ Urol 2016

28 Abiraterone and Enzalutamide in mcrpc Phase III studies Pre-docetaxel Grade 3-4 AEs ABIRATERONE Cardiac disorders (up to 8%) Increased ALT Hypertension (up to 24%) To be announced Ph II study comparing QoL, cognitive function and depression in mcrpca pts on AA vs Enza: 202 pts Significant differences related to QoL, mood, cognitive function in pts receiving AA Enzalutamide Hypertension ( up to 14%) Fatigue or asthenia Back pain Hot flushes Falls Seizure (0,1%) ASCO 2017, Abstract 5036 Ryan et al. Lancet Oncol 2015;16: Beer et al. N Engl J Med 2014; 371(5):424-33

29 ? Secondary endpoints difference?: Concomitant use of prednisone in AA treatment Agonistic effect of glucocorticoids on mutated AR OS was not significantly different between Enza and AA both in chemotherapy pretreated (HR 0,85) and naïve (HR 0,90) patients OS identical in pts with visceral disease and >75 yo Still a controversial notion Enz provides a signifficantly longer time without PSA progression Enz provides a signifficantly better radiografic PFS

30 AA vs Enza pre TXT Retrospective study- routine clinical practice 280 Japanese pts (113 AA- 167 Enza)-8,4 m f/u PS Limitations: -Only Japanese -Retrospective -Indication for NAA not determined according to a strict criterion -Short follow-up PSA value % Lymph node meta PSA RR PSA PFS were significantly higher in Enza group Only PS was an independent predictor of PSA PFS in multivariate analysis Enza-Not group r PFS more assessed grade 3 AEs Median PSA PFS: 9 m (AA) vs 11,6 m (Enz) (ss) OS: NR Significantly favoring Enza group Only PS and not AA vs Enza is an independent predictor of PSA PFS Miyake et al Clinical Geritourinary Cancer (2016) DOI: /j.clgc

31 Retrospective study 108 Japanese chemonaive mcrpc pts Endpoints: PSA decline of 50% Combined PSA-PFS OS Miyake et al. Clin Genitourin Cancer Dec 22. [Epub ahead of print]

32 Το PSA RR στη νέα ορμονική θεραπεία πρώτης γραμμής, στον συνολικό πληθυσμό, ήταν σημαντικά μεγαλύτερο από αυτό της θεραπείας δεύτερης γραμμής Δεν υπήρξε στατιστικά σημαντική διαφορά ξεχωριστά στα PSA response rates των group AA-ENZ και ENZ-AA Το ποσοστό των ασθενών που εμφανίζουν PSA response και στις δυο θεραπείες διαδοχικά ήταν σημαντικά μεγαλύτερο στο γκρουπ AA-ENZ απο οτι στο ENZ-ΑΑ Miyake et al. Clin Genitourin Cancer Dec 22. [Epub ahead of print]

33 Συμπέρασμα: Combined PSA-PFS Cross-resistance μεταξύ των νέων ορμονικών παραγόντων Το combined PSA-PFS ήταν σημαντικά ευνοϊκότερο Ωστόσοστο εάν γκρουπ χρειαστεί AA-ENZ αυτοί από οι ασθενείς ότι στο ENZ-AA. για οποιοδήποτε λόγο να λάβουν διαδοχικά ορμονικές θεραπείες η αλληλουχία AA-ENZ αναμένεται να έχει ευνοϊκότερα αποτελέσματα Univariate and Multivariate Analyses of Associations Between Various Parameters and Combined PSA-PFS Miyake et al. Clin Genitourin Cancer Dec 22. [Epub ahead of print]

34 Endpoints: Combined PSA-PFS OS Univariate and multivariate Cox proportional hazard analyses Terada N, et al. J Clin Oncol 2017;35 (suppl 6S): Abstract 219.

35 Terada N, et al. J Clin Oncol 2017;35 (suppl 6S): Abstract 219.

36 Χωρίς στατιστικά σημαντικές διαφορές στο OS, με trend ωστόσο υπέρ της διαδοχής ΑΑ- Enza Terada N, et al. J Clin Oncol 2017;35 (suppl 6S): Abstract 219.

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38 Αλληλουχία θεραπειών: Ταξάνη μετά από 1 ης γραμμής abiraterone Χαρακτηριστικά ασθενών Mezynski et al. 1 Abi» Doc (n=35) Saad et al. 2 Abi» Doc/Cab (n=265) Doc (n=95) Schweizer et al. 3 Abi» Doc (n=24) ECOG PS 2, % PSA, διάμεσο, ng/ml ,7 269,2 Σπλαγχνικές μεταστάσεις, % Αποτελεσματικότητα 50% μείωση PSA Διάμεσος χρόνος μέχρι την υποτροπή του PSA, μήνες 4,6 7,6 4,1 6,7 Διάμεση PFS, μήνες 7,6 4,4 Διάμεση OS*, μήνες 12,5 Abi=abiraterone; Cab=cabazitaxel; Doc=docetaxel; ECOG PS=Eastern Cooperative Oncology Group performance status; OS=overall survival; PFS=progression-free survival; PSA=prostate-specific antigen. 1. Mezynski J, et al. Ann Oncol 2012;23: Saad F, et al. EAU 2015; Abstract Schweizer MT, et al. Eur Urol 2014;66: Suggestion of lower efficacy of subsequent taxanes

39 Αλληλουχία θεραπειών: Ταξάνη μετά από 1 ης γραμμής abiraterone Retrospective study of the Royal Marsden Hospital (COU-AA-301) 35 pts- median of 6 cycles of DCT All pts refractory to AA are refractory to DCT 50% PSA decline rate of 26% Median time to PSA progression of 4.6 months Men receiving AA before DCT were more likely to OS progress from commencement on DCT and less of likely to achieve PSA responses docetaxel of only 12.5 months 30% non AA responders achieved PSA responses Cross-resistance??? to DCT [ preclinical Schweizer et al Eur Urol evidence 2014, 66: that the antitumour activity of docetaxel may be related to its impact on AR signalling] Mezynski et al Ann Ocol 2012; 23: Lebdai et al World J Urol 2015

40 Docetaxel after AA Post hoc analysis of COU-AA % men treated with AA were then treated with chemotherapy (261 received Docetaxel and 4 received Cabazitaxel) In these men there was a reasonable activity of Docetaxel: PFS 7,6m- PSA RR: 50% De Bono et al, JCO 2015

41 Impact of Prior Response to AA on Doc Efficacy 86 pts (37 DCT naïve) PSA Response Rates were not linked to prior response to AA No differences in pts receiving DCT for PSA Response Rates Median PFS (4 m) Median OS (11.7 m) While the efficacy of Doc may potentially be somewhat blunted when given after NAA, it still retains sufficient clinical activity to justify its use as the secondline systemic therapy for m CRPC Azad et al Prostate 2014;74: Antonarakis et al Curr. Treat. Options in Oncol :64

42 Αλληλουχία θεραπειών: Ταξάνη μετά από 1 ης γραμμής enzalutamide Gizzi et al. Χαρακτηριστικά ασθενών No prior enzalutamide (n=57) Prior enzalutamide (n=39) ECOG PS 2, % 12,2 20,6 PSA, διάμεσο, ng/ml Σπλαγχνικές μεταστάσεις, % 17,6 15,4 Efficacy endpoints 50% μείωση PSA 53% 34% Διάμεση PFS, μήνες 4,8 6,7 ECOG PS=Eastern Cooperative Oncology Group performance status; PFS=progression-free survival; PSA=prostate-specific antigen. Gizzi M, et al. ASCO-GU 2015; Poster presentation

43 Αλληλουχία θεραπειών: Enzalutamide ή docetaxel μετά από 1 ης γραμμής abiraterone Χαρακτηριστικά ασθενών Abi» Enz (n=30) Suzman et al. 1 Zhang et al. 2 Abi» Doc (n=31) Abi» Enz (n=9) Abi» Doc (n=13) ECOG PS 2, % 3 5 Doc» Abi» Enz (n=19) PSA, διάμεσο, ng/ml Σπλαγχνικές μεταστάσεις, % Αποτελεσματικότητα Ανταποκρίσεις PSA, % 50% μείωση PSA 30% μείωση PSA Διάμεση PFS, μήνες 4,7 4,4 3,7 5,1 2,8 Διάμεση OS, μήνες 8,5 Δ/Ε 9,6 Modest PSA Responses and PFS intervals Abi=abiraterone; Cab=cabazitaxel; Doc=docetaxel; ECOG PS=Eastern Cooperative Oncology Group performance status; Enz=enzalutamide; OS=overall survival; PFS=progression-free survival; PSA=prostate-specific antigen. 1. Suzman DL, et al. Prostate 2014;13: Zhang T, et al. Clin Genitourin Cancer 2015;pii:S (15)

44 Patients progressing with ABI do not respond to ENZA and vice versa Zhang T et al. Expert Opin Pharmacotherap 2014;16:1-9

45 Resistance AA- Enzalutamide D4A Sequencing of AR therapies might Be beneficial Imamura et al Int J of Urol (2016)23;

46 AR splice variants (ARv) AR-FL AR-45 AR-V7 AR-V1 AR-V4 AR-V3 AR-V567 AR-FL: Full-Length Androgen Receptor NTD: N-Terminal Domain DBD: DNA-Binding Domain LBD: Ligand-Binding Domain U: Unique N- or C-terminal sequence AR-V7: x20 in CRPC ADT induces constitutively active splice variants which drive development of CRPC 1-2 ARv567 (43%) and ARv7 (24%) are the most prevalent 3 : Both lack ligand-binding domain AR-V7 also lacks Hinge domain Inhibition of ARv7 transcription by FOXO1 (potent AR suppressor) 4-5 May contribute to resistance to enzalutamide 6 & abiraterone 7 Taxanes inhibit nuclear translocation of ARv567, not ARv7 8 Associated to increased expression of N- cadherin 1. Guo Z et al. Int J Biol Sci 2011; 7: ; 2. Lu C & Luo J. Transl Androl Urol 2013;2: ; 3. Sun S et al. J Clin Invest. 2010;120: ; 4. Mediwala SN et al. The Prostate 2013; 73: ; 5. Bohrer LR et al. The Prostate 2013; 73: ; 6. Li Y. Cancer Res 2013; 73: ; 7. Mostaghel EA et al. Clin Cancer Res 2011; 17: ; 8. Thadani-Mulero M et al. Cancer Res. 2014; 74:

47 PSA-PFS, r PFS, OS: Negatively correlated with ARV-7 status AR-V7 and resistance to enzalutamide and abiraterone in men with mcrpc Enzalutamide cohort n=31 prevalence AR-V7(+): 12/31= 38.7% AR-V7 (-): 19/31= 61.3% Abiraterone cohort n=31 prevalence AR-V7(+):W 6/31= 19.4% AR-V7 (-): 25/31= 80.6%% Antonarakis et al. NEJM 2014 Bryce et al In J Urol (2016) 23,

48 PSA change, % Cross-resistance: CTCs: AR-V7 seems a promising predictor of treatment response * * * * Abiraterone 1 Enzalutamide 1 Taxanes 2 PSA response rate: AR-V7 positive: 0% (95% CI: 0-46%) AR-V7 negative: 68.0% (95% CI: 46-85%) P= AR-V7 positive * * * AR-V7 negative 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

49 rpfs according to AR-V7 status

50 AR V7 In ARV7 + pts taxane-based therapy should be preferred over AR inhibitors, but further validation is needed Small sample size (36 pts-34 pts) Lack of prospective randomization Is used as inclusion criterion for galeterone AR-V7 reversions with taxane therapy AR-V7- negative patients: AR targeting therapy is equivalent to taxanes Antonarakis et al, JAMA Oncol, 2015;1: Onstek et el, Eur Urol 2015; 68: Scher et al, JAMA Oncol; Epub aahead of print Nakazawa M. et al Ann Oncol 2015;26:

51 Abiraterone and Enzalutamide in mcrpc Phase III studies Post-docetaxel Studies design

52 Abiraterone and Enzalutamide in mcrcp Phase III studies Post-docetaxel Patients COO-AA-301 AFFIRM

53 COO-AA-301 Overall Survival median benefit 4.6 months

54 AFFIRM Overall Survival median benefit 4.8 months

55 AA vs Enza before and after Doc Retrospective single center [Johns Hopkins] Ασθενείς που έλαβαν διαδοχικά ENZ και AA, με οποιαδήποτε σειρά (χωρίς να λαμβάνεται υπ όψιν εάν ήταν pre- ή post-chemotherapy, χωρίς παρεμβολή άλλης θεραπείας ανάμεσα στους ορμονικούς χειρισμούς) Primary endpoint: Combined clinical/radiographic PFS (PFS: PFS1+PFS2) που ορίζεται από την πρώτη θεραπεία για mcrpc (π.χ. ENZ or AA) μέχρι το radiographic ή clinical progression PFS1 και PFS2 είναι τα progression-free διαστήματα του πρώτου και του δεύτερου παράγοντα θεραπείας, αντίστοιχα Secondary endpoints: OS: ορίζεται από την αρχή της πρώτης θεραπείας μέχρι τον θάνατο από οποιαδήποτε αιτία Combined PSA PFS: ορίζεται ως ο χρόνος από την έναρξη της πρώτης θεραπείας μέχρι το PSA progression (25% αύξηση από το baseline ή το nadir) κατά τη δεύτερη θεραπεία. Maughan et al. Prostate Jan;77(1):33-40

56 Combined PFS Unadjusted Kaplan Meier analysis the median combined PFS was: AA-to-ENZ: 19.5 months (95%CI months) ENZ-to-AA: 13.0 months (95%CI months) Difference was statistically significant in the PSW univariate and multivariable analyses: Univariate PSW model: superior combined PFS AA-to-ENZ vs ENZ-to-AA HR 0.58, 95%CI ; P=0.03 Multivariable PSW model: superior combined PFS AA-to-ENZ vs ENZ-to-AA HR 0.37, 95%CI ; P<0.001 Maughan et al. Prostate Jan;77(1):33-40

57 Median OS Unadjusted Kaplan Meier analysis the median OS was: AA-to-ENZ: 33.3 months (95%CI 25.4 not reached) ENZ-to-AA 29.9 months (95%CI 18.8 not reached) No statistical differences were found in either the univariate or multivariable PSW Cox models Trend towards superior OS with the AA-to-ENZ sequence (HR 0.57, 95% CI ; P=0.098) Maughan et al. Prostate Jan;77(1):33-40

58 Combined PSA- PFS Unadjusted Kaplan Meier analysis the median combined PSA-PFS was: AA-to-ENZ: 17.5 months (95%CI months) ENZ-to-AA: 12.3 months (95%CI months) Difference was statistically significant in the PSW univariate and multivariable analyses: Univariate PSW model: decreased risk of PSA progression with AA-to-ENZ vs ENZ-to-AA HR 0.56, 95%CI ; P=0.02 Multivariable PSW model: decreased risk of PSA progression with AA-to-ENZ vs ENZ-to-AA HR 0.44, 95%CI ; P=0.002

59 Με βάση τις multivariable αναλύσεις αυτής της μελέτης, τα δεδομένα δείχνουν ότι μπορεί να υπάρχει διαφορά υπέρ της διαδοχικής χορήγησης AA-ENZ, σε ό,τι αφορά το PFS αλλά όχι το OS. Επίσης προτείνεται ότι μπορεί να αυξάνεται η πιθανότητα μεγαλύτερης απόκρισης PSA με την χορήγηση AA-ENZ για τους δυο παράγοντες, The chance of achieving a PSA response υποθέτοντας was μικρότερο significantly higher cross in the resistance AA Enza μέσω αυτού του συνδυασμού, group ώστε να εξηγηθεί η παρατηρούμενη διαφορά στο PFS Maughan et al. Prostate Jan;77(1):33-40

60 ΣΥΜΠΕΡΑΣΜΑΤΙΚΑ Πρώιμες ενδείξεις που προτείνουν την υπεροχή της διαδοχής θεραπειών AA-ENZ (σε σύγκριση με την αντίστροφη σειρά χρήσης θεραπειών) σε ότι αφορά το PFS αλλά όχι και το OS σε μη επιλεγμένους ασθενείς με mcrpc 1 Εάν υπάρχει ανάγκη διαδοχικής χορήγησης AA και ENZ, τότε η διαδοχή AA-ENZ αναμένεται να προκαλέσει ευνοϊκότερο έλεγχο της νόσου σε chemotherapy naïve mcrpc ασθενείς 2 Η διαδοχή AA από ENZ μπορεί να είναι πιο αποτελεσματική σε ό,τι αφορά στο combined PSA PFS σε σύγκριση με την διαδοχή ENZ από AA, σε chemotherapy naïve mcrpc, πιθανώς προσδίδοντας μεγαλύτερο PSA-PFS στην 2 η γραμμή ENZ αντί της AA 3

61 Logothetis et al Cancer Discov.2013;3(8):849-

62 Δεδομένα από: Truven Health MarketScan Research Databases 03/ / ασθενείς που ξεκίνησαν τη θεραπεία τους με AA και 807 με ENZ επιλέχθηκαν για αυτή τη μελέτη. Duration of Treatment: Από την εισαγωγή στον νέο ορμονικό χειρισμό έως την συντομότερη διακοπή (η οποία ορίζεται ως κενό > 60 days στη θεραπεία), είτε για 24 μήνες μετά την έναρξη, είτε λόγω διακοπής ασφαλιστικού συμβολαίου ή παύση παροχής δεδομένων Weighted Kaplan-Meier και Cox proportional hazard models χρησιμοποιήθηκαν για να συγκριθεί η συνδυασμένη διάρκεια θεραπειών του mcrpc (AA, ENZ, ΧΜΘ, sipuleucel-t και Radium-223) και οποιασδήποτε άλλης θεραπείας καρκίνου του προστάτη (mcrpc, ορμονικοί και κορτικοστεροϊδικοί χειρισμοί) μεταξύ ασθενών που ξεκίνησαν τις θεραπείες τους είτε με AA είτε με ENZ. Pilon et al. J Manag Care Spec Pharm Feb;23(2):

63 Time from Index Date to Discontinuation of mcrpc Treatment At 3, 6, 9, 12, 18, and 24 months, lower proportions of AA patients had a discontinuation of any mcrpc treatment compared with ENZ patients Pilon et al. J Manag Care Spec Pharm Feb;23(2):

64 Time from Index Date to Discontinuation of Any PC Treatment Η AA ως πρώτη θεραπεία συνδέθηκε με μια μείωση 25%- 31% στην πιθανότητα παύσης θεραπείας καρκίνου του προστάτη σε σύγκριση με την έναρξη με ENZ Ασθενείς με mcrpc που ξεκινούν τη θεραπεία τους με ΑΑ έχουν πιο μακροχρόνια περίοδο συνδυασμένων θεραπειών PC, σε σύγκριση με ασθενείς που ξεκίνησαν τη θεραπεία τους με ENZ At 3, 6, 9, 12, 18, and 24 months, lower proportions of AA patients had a discontinuation of any prostate cancer treatment compared with ENZ patients Pilon et al. J Manag Care Spec Pharm Feb;23(2):

65 Predictors of duration of AA treatment Retrospective 143 pts Post Docetaxel Median Duration of treatment: 20 m (even in pts with high Gleason score, synchronous meta at dx, visceral metastases) Verzoni et al, Oncotarget 2016

66 Added value of cabazitaxel in mcrpc More active than AR-targeted agents in patients primary resistant to docetaxel 1 Cabazitaxel Retains its activity in patients progressing with an AR-targeted agent 2 Activity not influenced by ARv7 positivity in circulating tumor cells 3 Microtubule stabilization 1. Di Lorenzo et al. Eur Urol 2014; 65: Van Soest et al. Eur J Cancer 2015 (epub ahead of print) 3. Onstenk et al Eur Urol 2015 (epub ahead of print)

67 TROPIC study design

68 TROPIC Survival

69 Benefit of cabazitaxel according to previous docetaxel treatment. J. De Bono, Lancet 2010; 376:

70 AA vs Cabazitaxel post Doc Retrospective -350 pts AA was administered more frequently (85% vs 47%) Discontinuation due to progression was higher with AA- due to toxicity higher with Cabaz (ns) 52,3% DA 15,4% DC 22% DCA 10,3% DAC 1 st 2 nd line 2nd 3 rd line Sonpavde et al Clin Genitourin Cancer 2015;13: Sonpavde et al Clin Genitourin Cancer 2015;13:

71 AA vs Cabazitaxel post Doc OS and TTF in favor of DC but not statistically significant in multivariate analysis More cycles of Cabazitaxel administered in DCA (6 vs 4) Maybe DCA is more feasible Exclusion of pts participating in clinical trials Sonpavde et al Clin Genitourin Cancer 2015;13:

72 Sequential administration of new agents Different toxicity profiles Different modes of administration PS / Age Patient s Preference Activity profile Non single New Agent seems to be superior to another in third line setting However sequences including Cabazitaxel may lead to a possible advantage Maines et al, Crit Rev Hem Oncol 96(2015)

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74 AA post Enza post TXT Χαρακτηριστικά ασθενών de Bono et al. 1 (n=797) Noonan et al. 2 (n=30) Loriot et al. 3 (n=38) ECOG PS 2, % PSA, διάμεσο, ng/ml 128,8 232 Σπλαγχνικές μεταστάσεις, % 18, Αποτελεσματικότητα Ανταποκρίσεις PSA, % 50% μείωση PSA 30% μείωση PSA Διάμεση PFS, μήνες 5,6 3,5 2,7 Διάμεση OS, μήνες 14,8 11,5 7,2 ECOG PS=Eastern Cooperative Oncology Group performance status; mcrpc=metastatic castration-resistant prostate cancer; OS=overall survival; PFS=progression-free survival; PSA=prostate-specific antigen. 1. de Bono JS, et al. N Engl J Med 2011;364: Noonan KL, et al. Ann Oncol 2013;24: Loriot Y, et al. Ann Oncol 2013;24:

75 Post-hoc COU-AA-302 Limited clinical benefit of subsequent NAA 68% pts received intervening chemotherapy Prospective data but - high censoring (> 75%) -small sample size (55 AA/ 33 ENZ) -Investigator bias -incomplete data reporting -premature discontinuation of subsequent therapy - PSA response as the only response criterion Smith et al, Eur Urol, 2017

76 AA beyond 3rd line Francini et al, Anti-Cancer Drugs 25:

77 Enz post Doc and AA Suggestion that Enz and AA actions are not overlaping and are potentially synergistic 21% pts: PSA response >50% Median TTP (PSA): 17,4 w vs 36,1 w (AFFIRM) Median OS: 31,6 w vs 80 w (AFFIRM) PSA response to AA: Not predictive of PSA response to Enz

78 Enza post AA post Chemo Χαρακτηριστικά ασθενών Scher et al. 1 (n=800) Schrader et al. 2 (n=35) Bournakis et al. 3 (n=20) Bianchini et al. 4 (n=39) Thomson et al. 5 (n=23) Thomsen et al. 6 (n=24) Scholz et al. 7 (n=66) ECOG PS 2, % 8,8 35,8 34,8 33,3 PSA, διάμεσο, ng/ml 107, Σπλαγχνικές μεταστάσεις, % 26, ,3 17,4 16,7* Αποτελεσματικότητα Ανταποκρίσεις PSA, % 50% μείωση PSA 30% μείωση PSA 54 28,6 37, ,8 41, Διάμεση PFS, μήνες 8,3 4,0 2,8 2,7 Διάμεση OS, μήνες 18,4 7,1 Δ/Ε 4,8 *Ηπατικές μεταστάσεις. ECOG PS=Eastern Cooperative Oncology Group performance status; mcrpc=metastatic castration-resistant prostate cancer; OS=overall survival; PFS=progression-free survival; PSA=prostate-specific antigen. 1. Scher HI, et al. N Engl J Med 2012;367: Schrader AJ, et al. Eur Urol 2014;65: Bournakis E, et al. ECC Poster presentation P Bianchini D, et al. Eur J Cancer 2014;50: Thomson D, et al. J Clin Oncol 2014;32(Suppl 4): Abstract Thomsen FB, et al. Scand J Urol [Epub ahead of print]. 7. Scholz MC, et al. J Clin Oncol 2014;32(Suppl 4): Abstract 247.

79 Enza post AA post Chemo Χαρακτηριστικά ασθενών Scher et al. 1 (n=800) Cheng et al. 2 (n=122) Stevenson et al. 3 (n=57) Vera-Badillo et al. 4 (n=26) Røder et al. 5 (n=24) Badrising et al. 6 (n=61) ECOG PS 2, % 8, ,3 43 PSA, διάμεσο, ng/ml 107,7 109,5* Σπλαγχνικές μεταστάσεις, % 26,8 19* 16,7 21 Αποτελεσματικότητα Ανταποκρίσεις PSA, % 50% μείωση PSA 30% μείωση PSA Διάμεση PFS, μήνες 8,3 3,5 4,9 2,8 Διάμεση OS, μήνες 18,4 2,6 4,8 7,3 *Total population which included 28 patients who had not received prior docetaxel. ECOG PS=Eastern Cooperative Oncology Group performance status; mcrpc=metastatic castration-resistant prostate cancer; OS=overall survival; PFS=progression-free survival; PSA=prostate-specific antigen. 1. Scher HI, et al. N Engl J Med 2012;367: Cheng HH, et al. ASCO-GU 2014; Poster presentation Stevenson R, et al. ASCO-GU 2014; Poster presentation Vera-Badillo FF, et al. ASCO-GU 2014; Poster presentation Røder MA, et al. ASCO-GU 2014; Poster presentation Badrising S, et al. Cancer 2014;120:

80 Antitumour activity of enzalutamide in patients with mcrpc pre-treated with docetaxel and abiraterone Retrospective analysis of 39 CRPC patients treated with docetaxel and abiraterone prior to enzalutamide -Modest activity of Enzalutamide -No association with previous PSA Response and PFS on AA Bianchini D. et al. Eur J Cancer :78-84.

81 Enzalutamide in heavily pretreated patients with bone meta mcrpc resistant to AIs the Hellenic experience of the named patient access program Max. PSA decline 50% in 40% 4 patients (33%) self reported performance score improvements No grade 3 AEs reported Enzalutamide is well tolerated in a cohort of heavily pretreated mcrpc Preliminary report and further follow up is required Bournakis E et al. ECC 2013; Abstract 2906

82 Cabazitaxel Remains Active in Patients Progressing After Docetaxel Followed by Novel Androgen Receptor Pathway Targeted Therapies. A total of 79 patients who had progressive mcrpc after docetaxel (median: 8 cycles; range: 4 12 mo), and AA (median: 4.8 mo; range:1 55 mo) received cabazitaxel 25 mg/m 2 every 3 weeks (median: 6 cycles; range:1 15 cycles). Cabazitaxel and AR pathway inhibitors are not cross resistant 49% had 50% PSA response 20% had PR (RECIST, n=35) Al Nakouzi N. Eur Urol May 2 Pezaro et al. J Clin Oncol 2013; 31(Suppl 6): Waterfall plots of maximal prostate-specific antigen (PSA) changes on cabazitaxel therapy

83 Which drug for which patient

84 Primary resistance to AR-targeted agents

85 Who are the non responders to Abiraterone? 25% of pts exhibit primary resistance

86 How we can identify patients with primary resistance to hormone therapy? Physicians must admit that there is a lot of cross-resistance between AR pathways inhibitors They secure early identification of primary resistance to androgen targeted therapies They make an effort to identify the subset of patients that are probably true androgen-independent How? High-volume metastatic hormone naïve PrCa (CHAARTED) Rapid progression on ADT Rapid progression on docetaxel Visceral disease

87 Percentage of Patients Percentage of Patients Duration of Response to First ADT and Efficacy of Subsequent Endocrine Therapy and Docetaxel in mcrpc PSA Response 30% with first & subsequent ADT PSA Response 30% with Docetaxel p = % 90% Response to 1st ADT 61.8% 77.1% 45% 28% Retrospective analysis in 153 mcrpc patients treated with cabazitaxel Angelergues A, et al. J Clin Oncol. 2014;32(Suppl 4): Abstract 282. mcrpc: metastatic castration-resistant prostate cancer 98

88 Κριτήρια Επιλογής Εξατομικευμένης θεραπείας Pathology Gleason score Grade Neuroendocrine/ Anaplastic type PSA low and high tumor burden PSA very high NSE/ Chromogranine A CEA, CA 19.9, CA 125, NSE Serology Clinical course

89 Κλινικοί παράγοντες που μπορεί να επηρεάσουν τη θεραπευτική προσέγγιση σε ασθενείς μετά από υποτροπή από την θεραπεία ανδρογονικού αποκλεισμού Abiraterone Enzalutamide Docetaxel Καλή ανταπόκριση στην ADT (>12 μήνες) Καθόλου ή ήπια συμπτώματα Χαμηλό μέτριο φορτίο νόσου Αργά εξελισσόμενη νόσος Χωρίς σπλαγχνικές μεταστάσεις? Ακατάλληλοι για χημειοθεραπεία (ηλικιωμένοι, φτωχό PS, επιλογή ασθενούς) PSA DT> 4-6 m Docetaxel Μικρή διάρκεια ανταπόκρισης σε ADT (<12 μήνες) Συμπτωματικοί ασθενείς Υψηλό φορτίο νόσου Ταχέως εξελισσόμενη νόσος Σπλαγχνικές μεταστάσεις/ Οστεολυτικές μεταστάσεις Καταλληλότητα / καλό PS PSA DT< 4-6 m Νέοι?

90 Prognostic models in CRPrCa CALGB 90401: Men with CRPrCa receiving chemo For 1 st time +/- Bevacizumab Mainly disease dependent model- not treatment Validated in Ph III clinical trial Halabi et al, JCO 2014; 32:671-76

91 Prognostic models in CRPrCa The OS multivariate analysis showed statistically significant values for: -baseline performance status (PS) (patients with a PS >2) -baseline haemoglobin levels (haemoglobin levels <11 g/dl) -baseline alkaline phosphatase levels ( >278 IU/l) Group 1: Pts with a PS of 2 associated with one or both of the other 2 factors Group 2: Pts with only one of the prognostic factors or a combination of low haemoglobin and high alkaline phosphatase levels Group 3: patients without any negative factors Caffo et al, Eur Urol (68)

92 Liquid biopsy to guide therapy The blood of a proportion of pts can contain CTCs derived from the primary tumor and different metastatic sites (CellSearch) 75% of pts with advanced PrCa >= 5 CTCs in 7,5 ml has been validated as a prognostic marker in mcrprca receiving TXT or AA Increase in CTCs at any point under Tx was associated with reduced OS More prognostic than PSA CTCs with stem cell features contribute to metastases However lack of sensibility within CRPrCa Scher at al, Nat rev Clin Oncol 2013;10:225-34

93 Neuroendocrine differentiation Distinct morphological features in CTCs Clusters Low or absent AR expression Less keratin expression Smaller in size Small nucleus in pts at risk for visceral meta Distinct clinical phenotype Beltran et al, Clinical Cancer Res 2016; 22: Fizazi et al Annalsof Oncology 26: , 2015

94 DNA damage repair mutations 11,8% mcrpca patients had germline mutations (irrespectively to family history) 23% of PrCa harbor alterations in DNA repair genes Somatic mutations can occur in later stages Preliminary data suggest that men with tumors who harbor DNA damage repair defects may be more sensitive to platinum based chemotherapy BRCA 2mutated: independent negative prognostic factor Antonarakis et al Curr. Treat. Options in Oncol (2016) 17:64 Piritchard et al, NEJM 2016;375: Modena et al, Targ Onvol, 2016

95

96 Challenge of the next 5-10 years: How to best combine and sequence all of these agents in an evidence- based manner, with consideration of biomarker data Yap et al 2016 Nature Reviews Antonarakis et al Curr. Treat. Options in Oncol (2016) 17:64

97 Σας ευχαριστώ