La scelta della terapia ormonale Intermittente o Continua ? To stop or not to stop? That is the question ! Vincenzo Serretta Section of Urology, Department of Surgical and Oncological Sciences University of Palermo, Italy No interest to disclose

La scelta della terapia ormonale Intermittente o Continua ? Surgical castration is still considered the ‘gold standard’ for ADT, against which all other treatments are rated The standard castrate level < 50 ng/dL defined more than 40 years ago. More appropriate level defined as below 20 ng/dL. Testosterone evaluation mandatory There is no level 1 evidence to choose between an LHRH analogue or antagonist, except in patients with an impending spinal cord compression. Systematic reviews CAB appears to provide a small survival advantage (< 5%) vs. beyond 5 years compared to LHRH analogue monotherapy Antiandrogen monotherapy compared with medical or surgical castrationon-steroidal n is less effective in terms of OS and PFS

Intermittent Androgen Blockade(IAD) La scelta della terapia ormonale Intermittente o Continua ? Intermittent Androgen Blockade(IAD) Theory PC inevitably relapses after a variable period (averaging 24 months) of hormonal treatment Hormone resistance may begin early, due to the lack of stem cells androgen-induced differentiation IAD could block androgen deprivation prior to progression of androgen-independent cells The stem cells should therefore be susceptible once again to androgen withdrawal. Thus, intermittent androgen blockade would delay the emergence of the androgen-independent clone.

Intermittent Androgen Blockade(IAD) PRO

La scelta della terapia ormonale Intermittente o Continua ? PRO

La scelta della terapia ormonale Intermittente o Continua ? G. Shaw, RTD Oliver Metanalysis 2009 10 studies 1446 patients “Fewer side effects” (p= 0.008) “Equal effectiveness” ...Not omogenous studies, M0 and M1 patients…short follow-up

Intermittent Androgen Blockade(IAD) IAB is currently widely offered to patients with PCa in various clinical settings, and its status should no longer be regarded as investigational (level of evidence: 2). Gleave, Urol Oncol 2009 ...IAD should be considered for use in routine practice... SEUG T3-4; M0-1

Intermittent Androgen Blockade(IAD) Still debatable? Curr Oncol. 2010 Sep;17 Suppl 2:S45-8. Intermittent versus continuous androgen suppression therapy: do we have consensus yet? Buchan NC, Goldenberg SL. 2015 Current evidence has led to the endorsement of ias by a few professional bodies. The European Association of Urology 2009 guidelines on pca state that IAD [intermittent androgen deprivation] is currently widely offered to patients with pca in various clinical settings, and its status should no longer be regarded as investigational”. The U.K. National Institute for Health and Clinical Excellence recommends that IAD be offered as a first-line hormonal therapy option to men with newly diagnosed or relapsing metastatic cancer, provided they are aware of the therapy’s unproven status. The American Urological Association has yet to acknowledge IAD in its treatment guidelines.

Intermittent androgen blockade

La scelta della terapia ormonale Intermittente o Continua ? No difference in terms of OS, CSS, PFS Progression to CRPC (bias) Drug Exposure: 43.9 vs 15.4 months Benefits in some aspects of QoL Results cannot be extrapolated

Quality of Life in favor of IAD up to 9-15 months The study failed in demostrating the non-inferiority (and the inferiority) of IAD vs CAD for survival IAD 20% relative increase risk of death From a statistical point of view, the results of the study are “inconclusive”

Intermittent Androgen Deprivation (IAD) Niraula S, et al "Treatment of prostate cancer with intermittent versus continuous androgen deprivation: A systematic review of randomized trials" J Clin Oncol 2013; 31 Nine studies with 5,508 patients No significant differences in for IAD compared with CAD: - time-to-event outcomes between the groups in any studies Pooled HR for OS was 1.02 for PFS was 0.96 More prostate cancer–related deaths with IAD More deaths not related to prostate cancer with CAD Pro: Superiority of IAD for sexual function, physical activity, and general well-being was observed in some trials Pro: Median cost savings with IAD was estimated to be 48%.

La scelta della terapia ormonale Intermittente o Continua ? 2014

Intermittente o Continua ? IAD Studies: Population

Intermittente o Continua ? IAD Studies: RESULTS

Intermittente o Continua ? IAD Studies: QoL and toxicity

Strategy planning Age/Co-morbilities Life expentancy La scelta della terapia ormonale Intermittente o Continua ? Strategy planning When to start IAD? In which patient? In which tumour? Which hormal therapy? When to abandon IAD? Age/Co-morbilities Life expentancy Quality of life Early and late complications Costs Correct patients’information

Intermittent androgen blockade EAU 2013 -2015 ….only drugs leading to castration are suitable for use in IAD …. It is unclear if an LHRH agonist may be used alone, as published experiences are based on CAB. An LHRH antagonist might be a valid alternative ….The initial (induction) cycle must last between 6 and 9 months, otherwise testosterone recovery is unlikely. ….CAB is stopped only if : - well-informed and compliant patient no clinical progression PSA response, empirically defined as a PSA < 4 ng/mL or 0.5 ng/mL in relapsing disease • Strict follow-up once treatment has stopped, with clinical examination every 3-6 months. The more advanced the disease, the closer the follow-up.

Intermittent androgen blockade When to re-start? A strict follow-up must then be applied, … with PSA measurements at the same time and always performed in the same laboratory. CAB is resumed when the patient reaches either a clinical progression, or a PSA value above a predetermined empirically fixed threshold (usually 4 ng/mL in non-metastatic, or 10-15 ng/mL in metastatic patients) The same treatment is used for at least three to six months. The next cycles are based on the same rules until the first sign of hormone refractory status. EAU 2013-15

La scelta della terapia ormonale Intermittente o Continua ?

CAB Intermittente o Continua ? "fair evidence to recommend use of intermittent androgen deprivation instead of continuous androgen deprivation for the treatment of men with relapsing, locally advanced, or metastatic prostate cancer who achieve a good initial response to androgen deprivation" Niraula S, et al "Treatment of prostate cancer with intermittent versus continuous androgen deprivation: A systematic review of randomized trials" J Clin Oncol 2013; 31 Linee Guida Aiom

Strategia terapeutica e terapia individualizzata La scelta della terapia ormonale Intermittente o Continua ? Strategia terapeutica e terapia individualizzata

Intermittente o Continua ? Eur. Urol. 2014 To stop or not to stop? That is the question !