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Home » Oncology » Oncology – Prostate » Androgen deprivation therapy

Androgen deprivation therapy

Classes of ADT include:

  • Surgical castration / orchidectomy
  • LHRH agonists
  • LHRH antagonist
  • Antiandrogens (steroidal cyproterone, and nonsteroidal -utamides)
  • Inhibitors of androgen synthesis (ketoconazole and abiraterone)

 

Orchidectomy

Very effective and very rapid castration (2 – 12 hours).

Subcapsular orchidectomy has the same efficacy and avoids an “empty scrotum”.

Pros: Cons:
·       Rapid castration

·       No issues with compliance

·       Cheap

 ·       Surgical risks + need for anaesthetic

·       Psychological impact

·       Irreversible

 

 

LHRH agonists

Goserelin (zoladex), leuprorelin (eligard/lucrin), triptorelin (diphereline).

Agonist to LHRH receptors -> surge in LH/FSH release -> triggers negative feedback loop on pituitary which stops LH and subsequent testosterone production.

Comparable efficacy and survival outcomes to orchidectomy.

Initial exposure associated with flare phenomenon with initial increase in testosterone levels first 1 – 2 weeks.

  • Worsening of pain from bony metastases (risk of cord compression), bladder outlet obstruction
  • Pre-treatment with antiandrogen or LHRH antagonist prevents this phenomenon.

 

Pros: Cons:
·       Variety of dose durations

·       Easy to administer

·       Good compliance

·       Effective without need for surgery

 ·       Flare phenomenon

·       Castration takes > 1 week at least (?up to 30d)

·       Long dose duration -> long period of side effects

·       Expensive cf. other options

 

 

LHRH antagonist

Degarelix (Firmagon).

Competitive antagonist to LHRH receptors, preventing subsequent production of LH and testosterone.

Reasonably quick onset – majority of men castrate within 3 days.

Can be used as initial loading dose (2 x 120 mg = 240 mg) and then monthly long term (80 mg).

Pros: Cons:
·       Quicker onset cf. agonists

·       No flare phenomenon

·       Potentially less cardiac side effects

 ·       Worse local injection site symptoms

·       Only one month dosing for long term use

·       Expensive cf. other options

 

Steroidal anti-androgen

Cyproterone (Androcur) – 100 mg BD-TDS

2 mechanisms – Inhibit binding of DHT and testosterone to the nuclear androgen receptor, and also reduces testosterone levels by inhibiting the hypothalamic-pituitary axis

Can be used at lower doses 50 – 100 mg daily for hot flushes.

Side effects as per ADT but also liver toxicity, higher VTE risk, fluid retention, increased cardiac risks and worse gynaecomastia.

Compared to LHRH agonists there is a shorter time to progression when used as monotherapy.

Pros: Cons:
·       Oral option preferred by some

·       No hot flushes

 ·       Less effective cf. LHRH agonists

·       Worse side effect profile (liver, cardiac, clots)

 

 

Non steroid antiandrogen

Bicalutamide (Cosudex) 50 mg daily ; nilutamide, flutamide

Novel non steroidal anti-androgens enzalutamide, darolutamide, apalutamide – higher affinity for AR receptor cf. bicalutamide.

Inhibit binding of DHT and testosterone to the androgen receptor; without reduction in serum testosterone levels

Monotherapy with is oncologically inferior to LHRH agonists or surgical castration.

Side effects as per ADT but also frequent GI upset and occasional hepatotoxicity, and painful gynaecomastia (from aromatisation of excess testosterone)

– Fatigue common with enzalutamide. Darolutamide does not cross blood brain barrier.

Most commonly used in flare suppression or to achieve complete/maximal androgen blockade in conjunction with LHRH agonists.

Pros: Cons:
·       Oral option

·       Useful for flare/complete blockade

·       ??Potentially preserved potency if monotherapy given preserved serum T

 ·       Oncologically inferior as monotherapy

·       GI side effects + painful gynaecomastia

 

 

Inhibitors of androgen synthesis

Ketoconazole is a nonselective inhibitor of several CYP450 enzymes including CYP17 (17 α-hydroxylase), of which inhibition reduces synthesis of androgens by testes and adrenal.

  • Fast castration ~ 4 hours, and also reversible

Abiraterone is a more selective irreversible inhibitor, more potent selective for CYP17 (17 α-hydroxylase)

  • Blocks conversion of pregnenolone to 17-hydroxypregnenolone -> less androgen production, also reduction in glucocorticoid but increase in mineralocorticoids
  • Therefore needs steroids given concurrently and watch for fluid retention, hypokalaemia, hypertension.

 

Castration level

Typically and historically defined as < 1.7 nmol/L serum testosterone.

EAU suggests better results if aiming for and using definition of < 1.0 nmol/L.

 

Immediate vs delayed ADT

MRC study randomised men with M0 locally advanced or M1 disease:

No overall survival benefit, but less progression, less complications and symptomatic progression of prostate cancer, and better cancer specific survival with immediate ADT

TOAD study looked at PSA recurrence after local treatment without radiological disease:

Overall survival benefit for immediate ADT at 5 years 91 vs 86 %

 

All cases should be managed in an individualised fashion with respect to patients performance status, preference for treatment, co-morbidities and life expectancy, as well as disease characteristics (PSAdt, chance of symptomatic progression or complications).

 

Watchful waiting – EAU guidelines suggest offering ‘deferred treatment policy using ADT’ to M0 patients who are asymptomatic with PSAdt < 12 months and PSA < 50 ng/mL.

 

 

Intermittent vs continuous ADT

The interruption of ADT in hormone sensitive patients with reintroduction based on rising serum PSA.

Offers potential benefits in quality of life by reducing exposure to ADT side effects. Also may theoretically delay development of castrate resistance.

Large RCTs have failed to show superiority for survival for either continuous or intermittent ADT; with potential benefits in terms of hot flushes, sexual function and physical activity in intermittent ADT.

These trials stopped ADT when PSA < 4 ng/mL, and restarted at 10 – 20  ng/mL.

 

Good candidates for intermittent ADT:

  • Good PSA responders
  • Symptomatic from ADT
  • Longer life expectancies

Bad candidates / do not stop ADT:

  • Spinal cord or vertebral involvement
  • High PSA prior to commencement, with nadir > 4 or poor initial PSA response

 

 

Side effects of ADT

Early:

  • Hot flushes
    • Cool compresses
    • Cyproterone 50 mg daily
    • Medroxyprogesterone 20 mg daily
    • Venlafaxine 12.5 mg BD
  • Fatigue
    • Exercise programs
  • Mood changes
    • Counselling
  • Sexual dysfunction
    • Near universal loss of libido – difficult to treat
    • Sexual counselling
    • PDE5i, ICI, penile prosthesis
    • Loss of penile length, testis size is common
  • Flare phenomenon
    • Start with bicalutamide or LHRH agonist
  • Injection site reaction
    • Icepacks, anti-histamines

 

 

Late:

  • Osteoporosis
    • 20 – 40 % may have osteoporosis before even starting ADT
    • Higher risk of fracture the longer on ADT
    • DEXA scans and recognition
    • Weight-bearing exercise
    • Adequate dietary calcium and sun exposure vitamin D
    • If osteoporosis on DEXA – oral alendronate or 6 monthly denosumab
  • Cardiovascular risk
    • Screening of lipids, cholesterol, sugars, blood pressure, and treatment as appropriate
    • Increased risk of cardiovascular events
    • Exercise programs
  • Loss of muscle, increased fat
    • Exercise programs
  • Cognitive decline
    • Controversial/conflicting evidence as to true effect
  • Gynaecomastia and breast tenderness
    • Due to peripheral aromatisation of testosterone to oestrogen
      Radiation therapy and tamoxifen have been studied, most evidence in prophylaxis rather than treatment
    • Mastectomy if severe pain
  • Anaemia

 

Follow up

  • Symptomatic reviews
  • PSA and testosterone levels
  • FBC (Hb), eLFTs
  • DEXA scan at baseline, repeat every 2 years
  • Cardiovascular risk screening