Campbell’s Urology Chapter 104Hormone Therapy for Prostate

Cancer

Presented by Adam W Ylitalo, DOAugust 25, 2010

History• Benign and malignant prostate tissue are

biochemically analogous in response to androgens

• 1930’s (Huggins)– Large amounts of acid phosphatase found in man and monkey prostates and higher in PCa and more so in met PCa which were stimulated by androgens

• 1941 – 18/21 Advanced PCa patients achieved significant improvement with castration

• Those with small testes had poorer prognosis

History Continued• 17-OH ketosteroid increased in urine after

castration leading to adrenal theory of progression of PCa

• B adrenalectomy in 1945 for ARPC did not work and high mortality

• Hypophysectomy and pituitary irradiation• 1966 Huggins awarded Nobel Prize for work• 1973 Swerdloff and Walsh – E2 1000x more

potent than Testosterone at suppressing LH and FSH

• DES most widely studied and used – equivalent to castration, but SE prevent widespread use

More History• 1971 LHRH isolated by Schally requiring 165,000

pigs’ hypothalami to obtain 0.8mg• Nobel Prize 1977 led to LHRH analogs• LHRH agonist cause initial surge in testosterone

and LH, then plummets to castrate levels after loss of phasic pituitary secretion

• Initially – short half life requiring daily injections – now depot

• Recently LHRH antagonist developed reducing flare (abarelix originally in 1990 then Degarelix or Firmagon 2009)

And Even More History• Antiandrogens – bind competitively to AR– Steroidal – Cyproterone Acetate – 17-OH

progesterone derivative centrally suppresses LH (and testosterone) through progestational inhibitory effects at cellular level – leads to hypogonadism

– Nonsteroidal – (flutamide, bicalutamide) no antigonadotropin effect, just AR blockers including in hypothalamic-pituitary axis leading to elevated LH and testosterone which is converted peripherally to Estrogen can lead to painful gynecomastia

Molecular Biology of Androgen Axis• All current ADT works by reducing ability of

androgen to activate the receptor by decreasing androgens or by blocking androgen-AR binding (actual receptor not affected)

• Is ARPC due to reactivation of pathway?• AR transcriptional activity can increase in face of

other growth-like factors even if androgen not present; mutations can increase AR activity or lead to gene amplification in AR; and IL-6 and PKA, PKC can reactivate receptors

• ARPC still needs ADT, as exogenous T can still cause flares thus androgen refractory rather than androgen independent

Sources of Androgen– Testosterone – 90% produced by testes

• >50% bound to SHBG• 40% bound to albumin• 3% circulating, unbound, functionally active

– Diffuses through cell membrane into cytoplasm where converted to DHT by 5-AR

– Similar potencies (prostrate regrowth model), but 13x T required to have same effect

– Adrenal Androgens stimulated by ACTH with cortisol being the negative feedback mechanism

– Adrenal androgens are relatively weak compared to T and DHT and are almost entirely bound to albumin

– Adrenal androgens remain normal after orchiectomy and are insufficient to maintain prostatic epithelium

Source AndrogenAmount Produced per Day (mg) Relative Potency

Relative Potency/Amount Produced

Testes Testosterone 6.6 100 15.2

Testes and peripheral tissues

Dihydrotestosterone 0.3 160-190 533-633

Adrenal Androstenedione 1.4 39 27.9

Adrenal Dehydroepiandrosterone 29 15 0.5

Major Circulating Androgens

Mechanisms of Androgen Axis Blockade

1. Ablation of Androgen Sources – Orchiectomy2. Inhibition of Androgen Synthesis –

Aminoglutethimide, ketoconazole3. Antiandrogens – Cyproterone acetate,

Flutamide, Bicalutamide, Nilutamide4. Inhibition of LHRH or LH Release – DES,

Leuprolide, Goserelin, Triptorelin, Histrelin, Cetrorelix, Abarelix, Degarelix

Ablation of Androgen Sources

• B Orchiectomy reduces T to <50ng/dl (castrate)– >90% reduction in 24 hours– Can be done under local

• Subcapsular Orchiectomy– Hormonal and cancer responses same as

complete simple B orchiectomy– Must remove all intratesticular tissue and Leydig

cells

Inhibition of Androgen Synthesis• Aminoglutethimide – inhibits conversion of cholesterol

to pregnenolone (also blocks production of aldosterone and cortisol) ie medical adrenalectomy and – need replacement of steroids– 37% had >50% decline in PSA for median 9 months

• Ketoconazole – orally active, broad spectrum antifungal, interferes in 2 cytochrome P450 pathways – inhibits adrenal steroidogenesis – Immediately reversible (requires continuous dosing)– Castrate at 4 hours in some cases, but T rises to low/normal

within 5 months– Need concurrent steroid replacement– SE - Gynecomastia

Antiandrogens

• Steroidal – cyproterone acetate – direct androgen blocking effects and rapidly lowers T 70-80% through central progestational effect– SE – hypogonadal (loss of libido, erections, lassitude),

cardiac – 10%, gynecomastia <20%, and hepatic toxicity

• Nonsteroidal – block central feedback causing 1.5x T and LH levels (no hypogonadism but similar sexual activity, ED as surgical castration)– Peripheral aromatase activity T E2 leading to painful

gynecomastia; also GI and liver toxicity

Antiandrogen Withdrawal Syndrome

• With removal of antiandrogen (including cyproterone and DES), with concurrent GNRH administration, PSA declines of 50% or more and objective response is noted for a median of 3.5-5 months in 15-30%, but no difference in survival

Nonsteroidal Antiandrogens• Flutamide- 1st agent, 6 h T½, TID dosing, no fluid

retention or thromboembolic events like with steroidal.– Head to head met PCa, vs DES survival 28.5 vs 43.2 mos

• Bicalutamide – 6d T½, most potent and best tolerated– Inferior to castration in met PCa as monotherapy (50mg/d)– But at high doses (150mg/d), equivalent to medical or

surgical castration, and better QOL in sexual interest and physical capacity, but high rate of mastodynia (72.8%) and gynecomastia(66.2%)

– Significantly worse than watchful waiting in overall survival in low risk, localized PCa

• Nilutamide – 56 h T½, 25% have delayed darkness adaptation after bright light exposure, 1% interstitial pneumonitis pulm fibrosis

Inhibition of LHRH or LH ReleaseLHRH Antagonists:Leuprolide (Leupron) – IM – 7.5mg, 22.5mg, 30mg lasting

28, 84, and 112 daysGoserelin (Zoladex) SC implant – 3.6mg, 10.8mg lasting

28 and 84 daysTriptorelin (Trelstar) IM 3.75mg, 11.25mg lasting 28 and

84 daysLeuprolide suspension (Eligard) SC Same dose and

schedule as LeupronLeuprolide Implant (Viadur) 65mg SC lasts 365 daysHistrelin Implant (Vantas) 50 mg SC lasts 365 days

Androgen Flare

• All can cause life threatening androgen Flare• 10x LH level for 10-20 days• Co-administration of antiandrogen for 21 to

28 days• No PSA difference if antiandrogen started one

week prior to LHRH antagonist

LHRH antagonists

• Bind immediately and competitively to LHRH receptor in pituitary reducing LH by 84% in 24 hours

• No need for antiandrogen, because no flare• Severe allergic histamine response• Abarelix, Degarelix (Firmagon)

Response to Androgen Blockade• Magnitude and rapidity predict durability – (shows how

much is androgen refractory)• >80% PSA drop in first one month is best• Nadir PSA predicts survival• Rising PSA preceded bony mets by mean 7.3 months• Progression to ARPC within 24 months 15x greater if

undetectable PSA not achieved.• 70% hazard increase to ARPC per 1 Gleason score • Slow pre-ADT rise in PSA and fast decline post-ADT

better than opposite• Most stay on ADT once ARPC developed

Complications of Androgen Blockade

• Osteoporosis – More than half of men are osteopenic/osteoporotic prior to ADT (2.5 SD below BMD for age) After 5 years on ADT 19.4% vs 12.6% will have fx. Four years of ADT will place average man as osteopenic. – DEXA prior to, stop smoking, start weight bearing

exercise and vit D/Ca++– BMD increased with Bisphosphanates on ADT

• Should be used in any man with osteopenia/osteoporosis• Transdermal E2 increased BMD in men with prostate Ca• Nonsteroidal antiandrogens may maintain BMD better than

LHRH agonists

Complications of Androgen Blockade

• Hot Flashes – warmth in upper torso and head followed by perspiration – not life threatening – 50-80% of patients, generally decrease over time and thought to be due to hypothalamus– Treatment – Megace, cyproterone, DES or E2 (90% dec) but

can lead to mastodynia, gynecomastia, and thromboembolism, SSRI venlafaxine (50% dec), PO clonidine

• Sexual Dysfunction – ED, loss of libido – up to 20% still sexually active. 5% still have libido and 10-17% still able to get erections – may lose penile length, volume, testes size, and nocturnal tumescence.– Difficult to treat – PDE-5i, ICI – most patients do not have a

problem with it

Complications of Androgen Blockade

• Cognitive Function – Testosterone improves verbal fluency, but not memory. Most cognitive functioning studies regarding ADT are underpowered and small. ADT can increase depression, anxiety, fatigue

• Change in Body Habitus 1.8-3.8% weight gain in first year; 9.4-23.8% increase in body fat. 34% increase in PCa death in obese vs. normal weight. Men over 65 had a 70% reduction in death if more than 3 hours/week of vigorous exercise

• Gynecomastia/mastodynia – peripheral conversion of E2 from testosterone; 66.3%/72.7% on casodex treat with prophylactic radiation (10 Gy) or subq mastectomy/lipo/tamoxifen

• Anemia – 90% of men have 10% hb drop – responds to Epo - reversible

Combination Therapy• Works well with EBRT but not RRP• No difference in neoadjuvent vs RRP alone• ADT with EBRT showed increased OS, freedom from

progression, and disease specific survival• No difference in antiandrogen with castration or

GNRH analogue (meta-analysis of 27 studies)• No advantage in OS in RCT of orch vs orch &

antiandrogen in any level of met dz

META-ANALYSIS

Timing of Therapy• Early ADT delays biochemical and clinical progression but

survival benefit unclear• Always indicated in symptomatic, metastatic disease• Continuous vs. Intermittent– S/P RRP median time from recurrence to mets (8 years) and mets

to death (5 years) without ADT– Despite aggressive ADT PCa death 80% vs 20% other causes– ADT causes rapid aging

• 1973 VA - 1900 pts with met PCa or locally advanced• Death from PCa occurred in 48% early vs 47% late (met dz)• Death from PCa occurred in 14% early vs 17% late (local adv)

Timing Cont. - Early vs Late

• ADT can’t hurt right?– Localized Disease, early caused decreased OS in RCT• See, 2003 Euro Urol Placebo vs. Bicalutamide

– In LN+ Met dz after RRP, median survival 13.9 vs 11.3 years in early vs late, bad study, underpowered, and numbers rerun showed no difference when grades compared, and primary must be removed to show benefit

– In Asymptomatic Met dz, time to death from PCa longer in immediate ADT, and time to death from any cause equivalent

LN+ dz early vs. late

Economic Considerations

• LHRH agonist in 1997 US Medicare - $761 Mil• Every other GU expenditure $1.1 Bil – (64%)• 10.7x - 13.5x cost of B orchiectomy• CAB is 17.3x - 20.9 x cost of B orchiectomy • DES is cheapest of ADT - without radiation of

breast – (cardiac SE)• Break even at 4.2 months for Leupron and 5.3

months for Goserelin and no difference in survival

Economic Considerations Cont.

• B Orch vs CAB – no difference in benefit• Two studies - 70% of patients desire medical

treatment vs surgical (side effect difference is psychological – disfigurement, permanence)

• Will Medicare reimbursement follow suit

Future of Hormone Therapy

• Intermittent ADT – (1) Two preclinical animal trials (breast and prostate) showed longer time to resistance; (2) Better quality of life due to side effects?

• Neither of these are proven yet

• Androgen Receptor Pathway Targeting– Targeting Androgen Receptor Pathway

independent of activating ligands seems somewhat more promising

Questions?