By Prof. Federico Guercini / January 12, 2026
Edited by Prof. F. Guercini
The treatment of prostate cancer is based on three possible therapeutic pillars:
- Ablative surgery
- Radiotherapy
- Androgen deprivation (ADT), also known as antiandrogen therapy.
In this article we will focus exclusively on antiandrogen therapy, with particular attention to a mode of administration that is not continuous but, precisely, intermittent.
Let us begin by explaining why androgen deprivation (ADT) is used in prostate cancer.
Why must testosterone be inhibited in prostate cancer?
Prostate cancer is hormone-dependent (just as ovarian cancer or breast cancer are in women), because prostate carcinoma cells express androgen receptors (AR) and therefore use testosterone and dihydrotestosterone as true growth factors. In practice, testosterone enters the tumor cell, binds to the androgen receptor, and activates the transcription of genes that stimulate proliferation, survival, and above all the invasiveness of tumor cells.
Therefore, inhibiting plasma testosterone levels is an upstream strategy. In practice, even though we do not act directly on tumor DNA, we switch off within neoplastic cells the main biological signal that fuels tumor replication and makes it more aggressive.
👉 Without androgens, many tumor cells undergo death (apoptosis) or enter a state of quiescence.
Why testosterone specifically (and not other hormones)?
The prostate is an androgen-dependent organ from embryonic development onward; therefore, testosterone and DHT stimulate both the growth of the gland and its secretory function—in other words, the life of its normal cells as well as neoplastic ones. Let us remember that both normal and neoplastic cells produce PSA, and this explains why androgen deprivation leads, within a few weeks, to a rapid and dramatic drop in PSA levels.
👉 Testosterone production is therefore inhibited because, for prostate cancer, testosterone is not just a hormone: it is an essential growth factor.
How and where testosterone is produced
Explaining the cascade of events that leads to testosterone production in men is extremely complex and certainly of little interest for the purpose of this article (experts will forgive me!).
Broadly speaking, we can say that testosterone in men is produced mainly by the testes (with a very small amount also produced by the adrenal glands), and the regulation of its production occurs under the stimulus of a hormone secreted by the pituitary gland, called LH, which in turn is regulated upstream by another hormone secreted by the hypothalamus called GnRH. For GnRH to stimulate the production of pituitary LH, it must be released by the hypothalamus in a pulsatile manner. If, on the other hand, it is produced continuously, it halts its stimulating effect on the pituitary and consequently on LH production.
In prostate carcinoma, from a functional point of view, there are several biological lines defined by their relationship with the androgen receptor (AR), namely:
🔹 1. Hormone-sensitive prostate cancer (HSPC)
- Depends on androgen stimulation
- Grows in the presence of testosterone/DHT
- Responds to androgen deprivation therapy (ADT)
- Represents the initial phase in the vast majority of cases
🔹 2. Hormone-resistant / castration-resistant prostate cancer (CRPC)
- Progresses despite castrate levels of testosterone
- Is not truly “androgen-independent,” but rather adapted
- Shows amplification of the AR receptor
- AR mutations (hypersensitivity)
- AR-independent activation
- Intratumoral androgen production
🔹 3. AR-independent phenotypes
(a minority, but clinically crucial)
Prostate cancer almost always originates as hormone-sensitive and remains an androgen-receptor–driven disease much longer than previously thought. So-called “hormone resistance” is almost always an adaptive resistance rather than true androgen independence. Over time and under therapeutic pressure, clones capable of growing even in the absence of androgens are selected.
Biological limit: resistance
Unfortunately, over time some tumors evolve toward castration-resistant prostate cancer (CRPC). As will be discussed later, this occurs because androgen receptor sensitivity increases (amplification), cellular mutations associated with androgen resistance develop, intracellular androgens are produced autonomously, and alternative growth pathways are activated:
- Androgen receptor amplification
- Activating AR mutations
- Intracrine androgen synthesis
- Activation of alternative growth pathways
However, at disease onset, in the overwhelming majority of cases, inhibiting testosterone remains the most rational and effective therapeutic strategy.
TO INHIBIT THE EFFECT OF TESTOSTERONE ON PROSTATE CANCER, TWO GROUPS OF DRUGS ARE AVAILABLE:
- Drugs that directly reduce or suppress testosterone production by blocking LH
- Drugs that prevent testosterone from binding to its specific receptors inside neoplastic prostate cells
With the first group, circulating hormone levels are extremely low or nearly absent; with the second group, testosterone levels in the bloodstream remain almost normal but are inactive with respect to tumor cells.
Drugs of the first group (testosterone suppression)
These include two types: GnRH analogues and GnRH antagonists.
The common goal of both is to suppress testicular testosterone production to achieve castrate levels. Their difference lies in how they block LH production, which in turn suppresses testosterone production in the testes.
- GnRH analogues continuously (non-pulsatile) stimulate the pituitary GnRH receptor, ultimately suppressing LH production. They are administered via monthly, quarterly, or semiannual intramuscular or subcutaneous injections. The most commonly used are Goserelin (Zoladex), Leuprorelin (Enantone, Eligard), Buserelin (Suprefact), and Triptorelin (Decapeptyl).
- GnRH antagonists block the GnRH receptor at the pituitary level, leading to suppression of LH and consequently testicular testosterone. They cause an almost immediate decrease in PSA levels. On the downside, they require more frequent administration and may cause local reactions. The most common injectable agent is Degarelix (Firmagon), while the oral agent is Relugolix (Orgovix).
Drugs of the second group (antiandrogens)
These drugs prevent testosterone from binding to prostate cancer cells and are called antiandrogens. They selectively compete at the prostatic level with testosterone/DHT by binding to proteins on the surface of tumor cells, thereby preventing testosterone from entering the cell. Blood testosterone levels remain normal or increased, but the signal is not transduced and therefore cannot exert its effect.
The most commonly used are Bicalutamide (Casodex) and Flutamide (Drogenil, Eulexin), while newer-generation agents include Enzalutamide (Xtandi), Apalutamide (Erleada), and Darolutamide (Nubeqa).
Unfortunately, both groups of drugs are associated with significant side effects such as hot flashes, joint pain, osteoporosis, breast enlargement and pain (gynecomastia and mastodynia), with an impact on the psychological sphere, including fatigue, lack of motivation, and in some cases the development of a true depressive syndrome. Although drugs from the second group often allow a better quality of life, with preservation (at least partial) of libido and a lesser impact on general and bone metabolism, their oncological efficacy is lower. Therefore, they are not indicated (except in combination with GnRH analogues) in metastatic disease or in very aggressive cancer.
WHY USE INTERMITTENT THERAPY (IADT) AND WHAT ARE THE ADVANTAGES COMPARED WITH CONTINUOUS THERAPY (ADT)?
The reasons are multiple:
- Androgen deprivation therapy, regardless of the type used, significantly worsens quality of life, which is instead rapidly recovered during periods of treatment suspension.
- The same applies to metabolic and bone-related symptoms.
- Most importantly, intermittent therapy, in all selected patients, helps prevent neoplastic cells from transitioning from a hormone-sensitive stage to a hormone-resistant one.
This is because androgen-dependent cells inhibit the emergence of androgen-independent cells.
Androgen-dependent cells, when dominant, tend to restrain the emergence and expansion of androgen-independent clones. When hormonal therapy eliminates or drastically reduces them, this “competitive pressure” is also removed, favoring the selection of resistant clones.
Why this happens: the main mechanisms
1️⃣ Clonal (Darwinian) competition
In prostate cancer, multiple clones coexist:
- AR-dependent clones → more numerous and more efficient in an androgen-rich environment
- AR-independent clones → initially few and less competitive
As long as androgens are present:
- AR-dependent clones grow better
- they occupy space, nutrients, and growth signals
- AR-independent clones remain “silent” or minority populations
👉 They are not eliminated, but kept under control.
2️⃣ Paracrine and microenvironmental pressure
AR-positive cells:
- secrete factors that maintain a differentiated luminal phenotype
- contribute to a microenvironment that is unfavorable to cellular plasticity
When ADT:
- drastically reduces these cells, the microenvironment changes and cellular plasticity increases.
3️⃣ Role of androgen receptors as a “differentiation factor”
This is a key and often underestimated point.
The androgen receptor:
- is not only an oncogene
- it also acts as a stabilizer of the luminal phenotype
Prolonged suppression:
- promotes dedifferentiation
- activates stem-like programs
- facilitates lineage plasticity
👉 4️⃣ Experimental and clinical evidence
As shown in an important 2024 study (Salsiccia G; Carbone A. et al., Clin Genitourin Cancer. 2024;22(2):74–83):
“Androgen-dependent cells do not ‘protect’ the patient, but biologically delay the selection of more aggressive and independent clones. In this real-world retrospective study, intermittent androgen deprivation therapy was associated with a significant delay in progression to non-metastatic castration-resistant prostate cancer compared with continuous therapy [1], supporting the biological hypothesis that sustained androgen suppression may favor earlier selection of resistant tumor clones in hormone-sensitive disease.”
How intermittent hormonal therapy (IADT) is administered
Intermittent therapy consists of cycles of hormonal treatment followed by periods of suspension, rather than continuous treatment without breaks.
The goal is not to “give less therapy,” but to use it in a biologically smarter way, when possible.
Biological rationale (the key point)
IADT is based on the following observation:
👉 Androgen-dependent cells, when present, compete with and restrain androgen-independent clones.
With continuous and prolonged androgen suppression:
- androgen-dependent clones are rapidly eliminated
- evolutionary space is freed for more aggressive and adaptable clones
With intermittency:
- during “off” periods, androgens return
- androgen-dependent clones regrow
- they resume exerting competitive pressure on resistant clones
📌 In other words, it is not just a break for the patient, but a break that keeps the tumor ecosystem more “controllable.”
How intermittent therapy works in practice
Typical (simplified) scheme
ON phase
ADT until:
- normalization or marked reduction of PSA
- stable clinical response
OFF phase
- complete suspension of therapy
- close monitoring of PSA and clinical status
Restart threshold (beginning of the next ON phase)
- when PSA exceeds a predefined threshold
- or when clinical/radiological signs appear
Main advantages
🟢 Quality of life
Recovery of:
- libido
- (partial) sexual function
- energy
- mood tone
Better:
- bone health
- metabolic health
- cardiovascular health
🧬 Biological rationale
- Reduced continuous selective pressure
- Potential delay in resistance
- Maintenance of AR-dependent control
Limitations and critical points
It is essential to be clear: not all patients are candidates.
Not indicated in:
- aggressive disease
- high-volume metastatic disease
- rapid PSA kinetics
It requires:
- a reliable patient
- rigorous follow-up
- good physician–patient communication
📌 Studies show:
- overall survival similar to continuous therapy in selected patients
- superior quality of life with intermittent therapy
Minimum duration of the ON phase
Even if PSA decreases rapidly:
- at least 6–9 months
to achieve: - clonal stabilization
- true biological control
Stopping too early → risk of rapid rebound.
A very important point (often misunderstood)
👉 Intermittent therapy is not a “weak” strategy
👉 It is a strategy of biological precision
It should be viewed as:
- dynamic disease management
- not as therapeutic renunciation
References
- Akakura K, Bruchovsky N, Goldenberg SL, Rennie PS, Buckley AR, Sullivan LD.
Effects of intermittent androgen suppression on androgen-dependent tumors: apoptosis and serum prostate-specific antigen.
Cancer 1993;71(9):2782–2790. PMID: 7682149 DOI: 10.1002/1097-0142(19930501)71:9<2782::AID-CNCR2820710916>3.0.CO;2-Z - Crook J, O’Callaghan CJ, Duncan G, et al.
Intermittent androgen suppression for rising PSA after radiotherapy.
N Engl J Med. 2012;367(10):895–903. DOI: 10.1056/NEJMoa1201546 - Hussain M, Tangen CM, Berry DL, et al.
Intermittent versus continuous androgen deprivation in metastatic prostate cancer (SWOG 9346).
N Engl J Med. 2013;368:1314–1325. DOI: 10.1056/NEJMoa1212299 - Calais da Silva FE, Bono AV, Whelan P, Brausi M, Queimadelos AM, Portillo Martin JA, Kirkali Z, Calais da Silva FMV, Robertson C.
Intermittent androgen deprivation for locally advanced and metastatic prostate cancer: results from a randomised phase 3 study of the South European Uroncological Group.
Eur Urol. 2009 Jun;55(6):1269-1277. doi: 10.1016/j.eururo.2009.02.016 PMID: 19249153 - Niraula S, Le LW, Tannock IF.
Treatment of prostate cancer with intermittent versus continuous androgen deprivation: a systematic review of randomized trials.
J Clin Oncol 2013;31:2029–2036. - Tsai HT, Penson DF, Makambi KH, Lynch JH, Van Den Eeden SK, Potosky AL.
Efficacy of intermittent androgen-deprivation therapy vs conventional continuous androgen-deprivation therapy for advanced prostate cancer: a meta-analysis.
Urology 2013;82(2):327–334. - Bruchovsky N, Klotz LH, Sadar M, Crook JM, Hoffart D, Godwin L, Warkentin M, Gleave ME, Goldenberg SL.
Intermittent androgen suppression for prostate cancer: Canadian prospective trial and related observations.
Mol Urol. 2000 Fall;4(3):191–199; discussion 201. PMID: 11062374 - European Association of Urology.
EAU Guidelines on Prostate Cancer.
EAU Guidelines, latest update. - National Comprehensive Cancer Network.
Prostate Cancer (Version current).
NCCN Clinical Practice Guidelines in Oncology. - Bonfill-Cosp X, Auladell-Rispau A, Gich I, Saiz LC, Cordero JA, et al.
Prevalence study of intermittent hormonal therapy of prostate cancer patients in Spain.
F1000Research. 2022;10:1069. doi:10.12688/f1000research.53875.2. - EORTC 2238 “De-Escalate” (2024)
Trial pragmatica che riesamina ruolo di terapia intermittente in contesto di maximal androgen blockade (MAB), con obiettivi di QoL, riduzione tossicità e mantenimento di efficacia oncologica. (2024) - Bahl A, Hellmis E, Gabriel A, et al.
The androgen deprivation therapy landscape in 2024: navigating the available options with prostate cancer patients.
EMJ Urol. 2024; 12(Suppl):S18–S24. - Grisay G, Turco F, Litiere S, Fournier B, Patrikidou A, Gallardo Díaz E, McDermott R, Alanya A, Gillessen S, Tombal B.
EORTC 2238 “De-Escalate”: a pragmatic trial to revisit intermittent androgen deprivation therapy in the era of new androgen receptor pathway inhibitors.
Front Oncol. 2024;14:1391825. doi:10.3389/fonc.2024.1391825 - Salciccia S, Frisenda M, Tufano A, Di Pierro G, Bevilacqua G, Rosati D, Gobbi L, Basile G, Moriconi M, Mariotti G, Forte F, Carbone A, Pastore A, Cattarino S, Sciarra A, Gentilucci A.
Intermittent versus Continuous Androgen Deprivation Therapy for Biochemical Progression After Primary Therapy in Hormone-Sensitive Nonmetastatic Prostate Cancer: Comparative Analysis in Terms of CRPC-M0 Progression.
Clin Genitourin Cancer. 2024;22(2):74–83. - Trial Libertas (in corso):
Peter MacCallum Cancer Centre, Melbourne, Australia
Memorial Sloan Kettering Cancer Center, New York, USA
University of Texas Southwestern Medical Center, Dallas, USA
West China Hospital of Sichuan University, Sichuan, Cina
University of Utah Health Hospitals and Clinics, Salt Lake City, USA
