Androgen deprivation therapy (ADT)

The mainstay of systemic therapy for advanced prostate cancer with the principal form of treatment leuteinizing hormone-releasing hormone (LHRH) agonists leuprolide, goserelin or triptorelin.

Resistance almost invariably develops to ADT leading to state of castration resistant prostate cancer (CRPC), defined as disease that progresses despite serum testosterone level in the castrate range.

ADT alone is no longer the standard of care for metastatic hormone sensitive prostate cancer and should be combined with other treatments such as doctaxel, abiraterone acetate, enzalutamide , apalutamide, and  daralutamide (2020).

Androgen receptor function inhibitors including abiratone, enzalutamide,  apalutamide,   and daralutamide are first line therapy for patients with metastatic castration resistant prostate cancer- 60-70% of patients will benefit for a median of 12-18 months, but 30-40% of patients will not have a favorable response.
Patients with metastatic hormon sensitive prostate cancer I never treated upfront with agents that target the androgen receptor along with ADT.

In the CARD trial cabitaxel was the preferred therapeutic option over second line androgen signaling inhibitors in patients  with metastatic castration resistant prostate cancer with rapid disease progression while receiving first line androgen signaling inhibitors.

Androgens are synthesized from cholesterol the multiple enzymatic steps.

Cytochrome P450 (CYP)17 is the key enzyme in androgen synthesis and has both 17 alpha-hydroxylase and C17, 20 lyase activity.

Continuous androgen deprivation is the standard therapy for metastatic hormone sensitive prostate cancer and despite a high initial response, occurs in most patients with a median survival of 2 1/2-3 years.

Androgen deprivation therapy (ADT) either by bilateral orchidectomy or by testicular androgen synthesis suppression using luteinizing hormone-releasing hormone agonists or antagonists are the cornerstones of initial treatment of hormonal naive metastatic prostate cancer.

ADT treatment is usually initially responsive to metastatic prostate cancer, but most patients become castration resistant within 11 months to two years, and will have a higher symptomatic burden associated with disease progression.

Conventional surgical or medical castration for the management of metastatic prostate cancer has an initial response rate greater than 60 to 70% and a median duration of initial response of less than three to five years.

ADT of the above modalities reduces serum testosterone levels to less than 50 ng/dL and results in PSA and/or radiographic responses as well as symptomatic improvement in most metastatic prostate cancer patients.

Prostate cancer cells must regulate and degrade the androgen receptor if they are to proliferate.

In a low testosterone environment of androgen deprivation therapy, prostate cancer cells adapt to produce far more androgen receptor, allowing them to capture every possible molecule of testosterone.

Androgen receptors mutate so they function even in the absence of testosterone.

Combined androgen blockade by the addition of first-generation anti-androgens to ADT as initial therapy demonstrates minimal clinical benefit at the expense of increased toxicity and high of course compared to ADT alone.

Androgens are synthesized from cholesterol via multiple enzymatic steps including cytochrome P450 and has both 17 alpha-hydroxylase and C17, 20 lease activity.

Gonadotropin releasing hormone agonists are the most common form of ADT today.

Gonadotropin releasing hormone agonists are easy to administer, avoid cardiovascular risks of estrogens, and the psychological trauma surgical castration, and allow for the potential of androgen blockade to be reversed.

LHRH agonists exert a non-pulsatile constant stimulation to the anterior pituitary gland, which in turn decreases luteinizing hormone (LH) and testosterone production.

In men with bone metastases androgen deprivation therapy (ADT) is associated with a greater than 80% response rate, and a response duration of approximately 2 years.

Synthetic LHRH agents are approximately 100 times more potent than the natural LHRH.

LHRH agonists transiently increase LH and may cause a testosterone flare increasing testosterone levels.

Ultimately LHRh agonists decrease LH and FSH production and inhibits testosterone production.

Castrate levels of testosterone with LHRh agonist treatment is typically achieved by day 21 (Kuber W et al).

Guidelines recommend that patients on ADT should be supplemented with calcium and vitamin D.

Toxic affects from ADTs include loss of bone mineralization, and cardiometabolic syndrome.

Very few patients on ADT undergo bone density testing.

To prevent testosterone flare nonsteroidal anti-androgens flutamide, nilutamide and bicalutamide, can be used concomitantly with LHRH agonists.

When anti-androgens are used as monotherapy for metastatic prostate cancer, serum testosterone levels remained stable or increase, and such therapy is not useful when rapid castrate levels of testosterone are required.

Androgen deprivation therapy may be through bilateral orchidectomy or treatment with gonadotropin releasing hormone (GnRH) agonists.

Combining three years of androgen suppression with external radiation improves survival in patients with locally advanced prostate cancer.

Long-term androgen deprivation compined with external beam radiation therapy for unfavorable prostate cancer is associated with a better disease free survival and 15 year overall survival than  short term androgen deprivation therapy.

Among patients with locally advanced disease phase 3 trials showed that when androgen deprivation treatment added to radiotherapy long-term treatment, of two years or greater, improved overall survival but also increases erectile dysfunction and the rate of myocardial infarction.

Short-term androgen deprivation therapy (phase 3 clinical trials) for four months before and during radiation significantly improves local control and disease free survival among patients with bulky stage to T2c-T4 tumors.

Addition of 6 months of androgen suppression therapy to external radiation improves survival in patients with clinically localized prostate cancer.

Multiple randomized controlled trials show androgen deprivation therapy (ADT) improved outcomes for men with intermediate or high risk prostate cancer treated with radiation therapy.

In men receiving definitive radiation for intermediate or high-risk prostate cancer, combined androgen blockade with a gonadotropin releasing hormone agonist and a non steroidal antiandrogen is not associated with improved prostate cancer specific mortality or overall survival compared with GnRH alone (Vitzhum LK).

Utilized in newly diagnosed patients, patients with metastatic disease and in patients with rising PSA levels.

Important to achieve the lowest serum testosterone levels as possible to minimize prostate cancer cell stimulation.

Initially decreases cell proliferation and increases apoptosis.

Associated with hot flashes, loss of libido and erectile dysfunction.

Sleep disorders commonly associated with hot flashes.

Significant weight gain over 6-9 months is typical.

2-3% lean body muscle mass loss and impaired muscle strength frequent.

There is an increase in subcutaneous fat mass by 3.5 kg and a decrease in lean mass of 1.5 kg after 12 months of ADT.



Insulin sensitivity declines by 13% following ADT.



It is assumed that the increase in fat mass or decrease in lean mass that occurs after ADT accounts for the change in insulin sensitivity.



Such adverse effects of ADT are the probable reason for the increased incidence of diabetes in men receiving ADT. 


ADT had a 60% higher relative risk of developing diabetes over 5 years.

The absolute risks for developing diabetes with ADT were 2.5 versus 1.6 events per 100 person‐years.

Androgen deprivation therapy leads to sarcopenia in elderly patients with prostate cancer (Mauras N).

Associated with fatigue and lowered physical activity.

ADT therapy leads to hypogonadal condition marked by metabolic changes to include dyslipidemia, hyperglycemia and increased fat mass.

10-20% increase in total body fat often accompanies use of such agents.

Associated with a decline in lean body mass.

Addition of androgen deprivation accelerates bone loss in men by 17% compared to aged-matched normal controls.

Castration levels of serum testosterone generally set at less than 50 ng/dL, although most orchiectomized men have levels below 20 ng/dL.

Rate of bone fractures is up to 12% higher in orchiectomized men compared to non orchiectomized men.

ADT (androgen deprivation therapy) is associated with poorer quality of life, sexual dysfunction, anemia, fatigue, loss of bone density, muscle atrophy, alterations in myocyte contraction, endurance, and upper extremity strength (Shabir MH et al).

Adverse effects include: loss of libido, hot flashes, weight gain, alterations in lipids, osteopenia, and a metabolic syndrome, increased cardiovascular disease and mortality.

Associated with increased in venous thromboembolism.

Studies have suggested ADT may increase risk of death from cardiovascular causes among patients with localized prostate cancer from the Prostate Strategic Urologic Research Endeavor (CaPSURE) (Tsai HK et al).

Increased risk of incident coronary heart disease, myocardial infarction, and sudden cardiac death (Keating NL et al Saigal CS et al).

Androgen deprivation therapy associated with a 2.6 times increased and cardiovascular death, than a man receiving radical prostatectomy (Tsai HK).

In two randomized trials androgen deprivation therapy associated with a shorter time to fatal MI in the subgroup of men older than 65 years of age(D’Amico AV et al).

GnRH agonist use associated with a 44% increase incidence of diabetes, 16% increase in coronary heart disease, 11% increase in myocardial infarction, and a 16% increase in sudden cardiac death in Seer data (Keating NL et al).

ADT associated with worsening of physical functions, and can slow walking.

In a prospective matched cohort study of men initiating ADT endurance, upper extremity strength and physical components of quality life were affected within three months of starting treatment, and exercise interventions are warranted (Shabbir MH et al).

Weight lifting in men with prostate cancer receiving androgen deprivation therapy improves body composition, physical function, and quality of life, and experience reductions in fatigue.

The risk of fracture doubles after 2-3 years of such treatment.

Skeletal effects include high bone turnover, osteopenia and osteoporosis.

Therapy leads to increases in fracture risk with increasing duration, and is an important cause of morbidity associated with this treatment.

Results in a loss of 2-4% bone loss in the first year of treatment and by 10 years up to 20% of bone loss may occur in older men.

Accelerates bone loss as annual bone loss of 0.5% occurs in healthy men and 1.0% in postmenopausal women, but men with undergoing ADT lose bone mineral density at 4.6% per year.

Bone loss increases with the duration of such treatment.

Risk of bone fractures in 50,613 prostate cancer patients correlates with the use of gonadotropin-releasing hormone agonist therapy: at 5 years risks of fracture 12.6% for men who received no GnRH agonist therapy and 19.4% for men who did (SEER), and the rate of fractures requiring hospitalization was double in the ADT group compared to those who did not.

Bisphosphonates prevent bone loss associated with such therapy.

Randomized controlled trials with bisphosphonates, and selective estrogen receptor modulators associated with increases in bone mineral density of the hip and spine and decreases bone turnover in men on androgen deprivation therapy for prostate cancer.

Therapy with Denosumab associated with increased bone mineral density at all sites and a reduction in incidence of new vertebral fractures among men receiving androgen deprivation therapy for nonmetastatic prostate cancer.

Should have bone density evaluation at the time of initiation of androgen deprivation therapy.

Anemia seen in up to 90% of patients so treated and it usually responds to erythropoeitin treatment.

Can lead to an insulin syndrome with increased insulin levels, hypertension, increased cardiovascular risk and central obesity.

Androgen deprivation therapy (ADT) in prostate cancer associated with an increased risk of cardiovascular events including myocardial infarction, and cardiac death.

ADT decreases lean body mass and increases fat mass.

ADT increases subcutaneous fat rather than visceral fat.

ADT lowering testosterone to castration levels and may antagonize the vasodilating effects of testosterone on renal vessels and creating estrogen deficiency which can negatively affect renal tubular function.

In patients with newly diagnosed non-metastatic prostate cancer the use of ADT was associated with an increased risk of acute kidney injury (Lapi F et al).

Most treatment related changes with androgen deprivation in fat and lean body mass occur within the first few months of treatment.

Ketoconazole a synthetic antifungal agent that inhibits cytochrome P-450 enzymes required for adrenal androgen synthesis, and when used at high doses inhibit adrenal androgen precursors and results in lowering of serum testosterone levels.

Ketoconazole at 400 mg Q8 hours can cause castrate levels of serum testosterone at 24 hours(Trachtenberg J).

Studies have suggested such treatment in prostate cancer associated with deleterious changes in lipid profiles, decreases in insulin sensitivity, increased arterial stiffness and impaired arterial compliance.

Androgen deprivation therapy-RTOG 92-02 study of 1554 patients with locally advanced prostate cancer (T2c-T4N0-X and PSA less than 150 ng/mL treated with combined androgen blockade for 2 months before and 2 months after radiation therapy of 65-70 Gy, with subsequent randomization of monthly ADT for 2 additional years or no further treatment-resulted in an absolute 10% improvement in disease free survival, from 40 to 50%, in patients with extended ADT therapy, at 5 years.

10 year analysis of the RTOG 92-02 study revealed disease free survival higher for patients receiving 2 additional years of ADT 22.5% vs. 13.2%, while the overall survival was similar at 53.9% vs. 51.6%.

European Organisation for Research and Treatment (EORTC) demonstrated an overall survival for patients with prostate cancer who received 3 years of androgen deprivation therapy plus radiotherapy.

In patients with locally advanced prostate cancer, rose with biochemical relapse, and those with metastatic disease ongoing androgen deprivation therapy (ADT) we’ll eventually resolved in increasing PSA levels within 3-5 years in patients progress to hormone refractory will castrate resistant disease (Saad F).

Neoadjuvant treatment with a GnRH agonist improves the rates of disease free and overall survival in patients receiving external beam radiation therapy for locally advanced or high risk non-metastatic prostate cancer.

Adjuvant therapy with a GnRH agonist improves the survival rate in men with node positive disease after prostatectomy (Messing EM et al).

In the study of 56 men with localized high-risk prostate cancer defined as Gleason score = or > than eight, PSA = or > 20 mg/mL, T3 or T4 bulky disease, a high PSA velocity score, slightly more than one-third of patients had lymph node involvement: patients were treated with either 3-6 months of preoperative leuprolide or abiraterone, leuprolide and low-dose prednisone and then had biopsy of the prostate: a pathological complete response was observed in 10% of those treated with six months of combination therapy versus 4% in those with three months of combination therapy and near pathologic complete response was 24% versus 11%, respectively (Taplin E et al)

The above study suggests neoadjuvant therapy can make cancer disappear in a percentage of high-risk patients.

Androgen deprivation therapy (ADT) for most men with localized PC who defer surgery or radiation, primary ADT offers no mortality benefit (Potosky AL et al).

In the above retrospective cohort study looking at 15,170 men with newly diagnosed, clinically localized prostate cancer: There was no difference between primary ADT and untreated patients all cause mortality.

Adding docetaxel to initial androgen deprivation therapy significantly prolongs overall survival among men with metastatic, hormone sensitive prostate cancer (Sweeney C et al).

In the above study the median overall survival was 57.6 months with docetaxel plus ADT compared with 44 months in the ADT arm alone.

Adding docetaxel to androgen deprivation therapy significantly improves recurrence free survival compared to a ADT alone in patients with high-risk localized prostate cancer with no apparent long-term toxicity: Whether this benefit translates into improved metastasis free survival is yet unknown (Fizazi K et al).

The above study suggests upfront chemo-hormonal therapy prolongs overall survival in men with metastatic prostate cancer beginning testosterone suppression.

Use of intermittent androgen deprivation as opposed to continued androgen deprivation has not been supported by clinical trials.

Short-term ADT improves radiation salvage after prostatectomy

Adding short-term androgen deprivation therapy (ADT) to radiotherapy as salvage treatment after radical prostatectomy was associated with significantly better metastasis-free survival at nearly 10 years compared with salvage radiation alone, long-term results of a randomized phase 3 trial show.

After a median follow-up of 9.3 years, the metastasis-free survival (MFS) rate for patients assigned to receive salvage radiation and short-term goserelin was 75%, compared with 69% for patients randomized to radiation alone.

There was no significant difference, however, in the secondary endpoint of overall survival at 10 years.

The patients were randomly assigned to receive standard salvage radiotherapy either alone or with hormonal therapy.

Progression-free survival (PFS), the primary endpoint, was significantly better with the combination than with radiation alone for both low-risk patients and high-risk patients.

Metastasis-free survival was also significantly better in the combination arm.

Biochemical control is improved, with testosterone suppression alone, making the conclusion that the combination therapy is more advantageous,

There is an increase in subcutaneous fat mass by 3.5 kg and a decrease in lean mass of 1.5 kg after 12?months of ADT.


Insulin sensitivity declines by 13% following ADT.


Insulin sensitivity declines by 13% following ADT.

It is assumed that the increase in fat mass or decrease in lean mass that occurs after ADT accounts for the change in insulin sensitivity.

Drugs targeting the androgen receptor such as abiratone, enzalutamide, apalutamide, and darolutamide show benefit in Patients  with castrate resistant prostate cancer, support the hypothesis that androgen receptors remain active and represent an important mechanism driving prostate cancer growth, even at low levels of testosterone.


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