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

MALATTIA METASTATICA ORMONOSENSIBILE

Nel paziente in trattamento ormonale c'è una relazione

fra livelli circolanti di testosterone raggiunti e risposta alla terapia?

BJU Int. 2010;105(5):648-51 

J Urol 178: 1290-1295, 2007

<20 ng/dl

20-50 ng/dl

>50 ng/dl

<32 ng/dl

>=32 ng/dl

Clin Genitourin Cancer 3: 325-330, 2013

Metastatic patients Non metastatic patients

>=0.30 ng/ml

<0.30 ng/ml

Overall survival from PSA progression

Prognostic role

=

Surrogacy

PRENTICEPRENTICE’’s criterias criteria

1.1. Treatment effect on the surrogateTreatment effect on the surrogate

2.2. Treatment effect on the primaryTreatment effect on the primary

3.3. Correlation between primary and surrogateCorrelation between primary and surrogate

4.4. Treatment effect on the primary disappears when the Treatment effect on the primary disappears when the surrogate is adjusted forsurrogate is adjusted for

Armstrong, A. J. et al. J Clin Oncol; 25:3965-3970 2007

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

0 0.25 0.50 0.75 1 1.25

Hazard ratio (HR) and (95% CI)

P value

PSA as a surrogate parameter of docetaxel efficacySWOG study

docetaxel /E 0.052Vs mitox/P

HR 0.86 (0.69-1.07)

HR 0.76 (0.49-0.98)

Docetaxel/E 0.16Vs mitox/P

Univariate

analysis

Multivariate

analysis

PSA decline >30% <0.001Vs no decline

HR 0.43 (0.34-0.55)

Patrylack DP et al JNCI 98: 516-521, 2006.

Proportion of Treatment effect Esplained (PTE): 1 (0.73-1)

J Clin Endocrinol Metab 95: 4542–4548, 2010

Mass spectrometry as reference method forassessment of circulating testosterone inlower range

MALATTIA METASTATICA ORMONOSENSIBILE

La terapia intermittente IAD: quali farmaci,quali indicazioni e quali vantaggi ?

ConclusionThere is fair evidence to recommend use of IAD instead of CAD for the treatment of men with relapsing, locally advanced, or metastatic prostate cancer who achieve a good initial response toandrogen 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.

Overall survival

Time to progression

Cancer specific survival

Quali farmaciLHRH-A + antiandrogeni?

Quali indicazioniPaziente asintomatico con incremento di PSA specie se in

assenza di metastasi

Quali vantaggi Migliore tollerabilita?

Minori costiDurata del periodo off come fattore prognostico aggiuntivo

MALATTIA METASTATICA ORMONOSENSIBILE

Confronto LHRH analoghi ed antagonisti:chi e’ il vincitore ? O esistono diverse indicazioni

e sequenzialita ?

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)

Klotz L, Boccon-Gibod L, Shore ND, et al. The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer. BJU Int 2008;102:1531–8

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)

FSH

Clin Oncol 2013 in press

Degarelix non inferiore in termini diefficacia rispetto a Leuprolide + antiandrogeno

Potenzialità di Degarelix

In pazienti con malattia ossea estesa

In pazienti con LUTS

MALATTIA METASTATICA ORMONOSENSIBILE

Esiste ancora un ruolo per gli estrogeni ?

Reduction of luteinizing hormone, testosterone and androgenic steroid levels1 Inhibition of telomerase activity2 direct binding of the androgen receptor (AR)3 Suppression of b-tubulin isotypes4

Mechanisms of action of DES

1Bosset PO et al BJU Int 2012; 110: E826–E8292Geier R et al Prostate 2012; 70(12): 1307–1312.3Wang H et al Asian J Androl 2010; 12(4): 535–547.4Montgomery RB, et al: Prostate 2005; 65: 141–150.

BJC: 2013; 109: 1079-1084

Lancet Oncol 2007; 8: 994–1000

MALATTIA METASTATICA ORMONOSENSIBILE

Quale follow-up nel paziente sottoposto ad ormonoterapia ?

Main objectives of following-up during ADT

• monitor the response to treatment;• 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

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 0.2-4.0 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):3984-90.

2,D’Amico AV et al J Natl Cancer Inst 2004 ; 96 (7) :509-15.3 Stewart AJ et al J Clin Oncol 2005; 23 (27): 6556-60

Biochemistry: hemocrome, liver function tests, testosterone, Vitamin D

Monitoring metabolic complications

Imaging techniques

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

Dexa scan