MALATTIA METASTATICA. Nel paziente in trattamento ormonale c'è una relazione fra livelli circolanti di testosterone raggiunti e risposta alla terapia?

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1 MALATTIA METASTATICA ORMONOSENSIBILE Nel paziente in trattamento ormonale c'è una relazione fra livelli circolanti di testosterone raggiunti e risposta alla terapia?

2 MALATTIA METASTATICA ORMONOSENSIBILE Nel paziente in trattamento ormonale c'è cè una relazione fra livelli circolanti di testosterone raggiunti e risposta alla terapia?

3 BJU Int. 2010;105(5):648-51

4 J Urol 178: , 2007 <20 ng/dl <32 ng/dl ng/dl >50 ng/dl >=32 ng/dl

5 Clin Genitourin Cancer 3: , 330, 2013 Mt Metastatic tti patients t Non metastatic patients

6 Overall survival from PSA progression <0.30 ng/ml >=0.30 ng/ml

7 Prognostic role = Surrogacy

8 PRENTICE s criteria 1. Treatment effect on the surrogate 2. Treatment effect on the primary 3. Correlation between primary and surrogate 4. Treatment effect on the primary disappears when the surrogate is adjusted for

9 Fig 1. Kaplan-Meier estimates of overall survival in TAX327 according to >= 30% prostate-specific antigen (PSA) decline status within first 3 months of treatment initiation antigen (PSA) decline status within first 3 months of treatment initiation Armstrong, A. J. et al. J Clin Oncol; 25:

10 PSA as a surrogate parameter of docetaxel efficacy SWOG study Univariate HR 0.76 ( ) docetaxel /E Vs mitox/p analysis P value HR 0.43 ( ) 0.55) PSA decline >30% <0.001 Vs no decline Multivariate HR 0.86 ( ) analysis Docetaxel/E 0.16 Vs mitox/p Hazard ratio (HR) and (95% CI) Proportion of Treatment effect Esplained (PTE): 1 (0.73-1) Patrylack DP et al JNCI 98: , 2006.

11 J Clin Endocrinol Metab 95: , 2010 Mass spectrometry as reference method for assessment of circulating testosterone in lower range

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13 MALATTIA METASTATICA ORMONOSENSIBILE La terapia intermittente IAD: quali farmaci, quali indicazioni e quali vantaggi?

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15 Conclusion There is fair evidence to recommend use of IAD instead of CAD for the treatment t t of men with relapsing, locally ll advanced, d or metastatic t ti prostate cancer who achieve a good initial response to androgen deprivation. This recommendation is based on evidence against superiority of either strategy for time-to-event outcomes and substantial decrease with IAD in exposure to androgen deprivation, resulting in less cost, inconvenience, and potential toxicity.

16 Overall survival Time to progression Cancer specific survival

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18 Quali farmaci LHRH-A + antiandrogeni? Quali indicazioni Paziente asintomatico con incremento di PSA specie se in assenza di metastasi Quali vantaggi Migliore tollerabilita? Minori i costi Durata del periodo off come fattore prognostico aggiuntivo

19 MALATTIA METASTATICA ORMONOSENSIBILE Confronto LHRH analoghi ed antagonisti: chi e il vincitore? O esistono diverse indicazioni e sequenzialita?

20 GNRH antagonists: Advantages immediate reduction of serum testosterone - 72 h: 96% <0.5 ng/ml absence of testosterone initial flare up rapid reduction in PSA levels reduction in prostate volume already at 30 days reduction and stability on FSH limited half-life (10 days approximately)

21 Klotz L, Boccon-Gibod L, Shore ND, et al. The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label,,parallel-group pphase III study in patients with prostate cancer. BJU Int 2008;102: Primary aim: to demonstrate the non inferiority of degarelix versus leuprolide for the primary end point (probability of patients having testosterone 0.5 ng/ml at each monthly measurement for 1 yr)

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23 FSH

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25 Clin Oncol 2013 in press

26 Degarelix non inferiore in termini di efficacia rispetto a Leuprolide + antiandrogeno Potenzialità di Degarelix In pazienti con malattia ossea estesa In pazienti con LUTS

27 MALATTIA METASTATICA ORMONOSENSIBILE Esiste ancora un ruolo per gli estrogeni?

28 Mechanisms of action of DES Rd Reduction of fltiii luteinizing hormone, testosterone t t and androgenic steroid levels 1 Inhibition of telomerase activity 2 direct binding of the androgen receptor (AR) 3 Suppression of b-tubulin isotypes 4 1 Bosset PO et al BJU Int 2012; 110: E826 E829 2 Geier R et al Prostate 2012; 70(12): Wang H et al Asian J Androl 2010; 12(4): Montgomery RB, et al: Prostate 2005; 65:

29 BJC: 2013; 109:

30 Lancet Oncol 2007; 8:

31 MALATTIA METASTATICA ORMONOSENSIBILE Quale follow-up nel paziente sottoposto ad ormonoterapia?

32 Main objectives of following-up during ADT monitor the response seto treatment; e t; ensure compliance with treatment; detect potential complications of endocrine therapy; guide the modalities of palliative symptomatic treatment at the time of CRPC EAU guidelines 2013

33 Prognostic role of serum PSA levels Patients with the lowest absolute value of serum PSA (< 0.2 ng/ml) have been shown to have the best survival compared to patients with a value of ng/ml or > 4.0 ng/ml 1 The PSA response in patients treated with hormonal therapy, following a rising PSA after treatments with curative intent (radical prostatectomy, radiation therapy) correlates with the best survival 2,3 1 Hussain M, et al J Clin Oncol 2006; 24(24): , D Amico AV et al J Natl Cancer Inst 2004 ; 96 (7) : Stewart AJ et al J Clin Oncol 2005; 23 (27):

34 Biochemistry: hemocrome, liver function tests, testosterone, Vitamin D Monitoring metabolic complications

35 Imaging techniques Bone scan, ultrasonography. CT (?) on the basis of PSA changes and or clinics Dexa scan