1. Campbell’s Urology Chapter 104 Hormone Therapy for Prostate Cancer Presented by Adam W Ylitalo, DO August 25, 2010

2. 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

3. 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

4. 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)

5. 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

6. 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

8. 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

9. SourceAndrogen Amount Produced per Day (mg)Relative Potency Relative Potency/Amount Produced TestesTestosterone6.610015.2 Testes and peripheral tissues Dihydrotestosterone0.3160-190533-633 AdrenalAndrostenedione1.43927.9 AdrenalDehydroepiandrosterone29150.5 Major Circulating Androgens

10. Mechanisms of Androgen Axis Blockade 1.Ablation of Androgen Sources – Orchiectomy 2.Inhibition of Androgen Synthesis – Aminoglutethimide, ketoconazole 3.Antiandrogens – Cyproterone acetate, Flutamide, Bicalutamide, Nilutamide 4.Inhibition of LHRH or LH Release – DES, Leuprolide, Goserelin, Triptorelin, Histrelin, Cetrorelix, Abarelix, Degarelix

11. 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

12. 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

13. 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

14. 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

15. Nonsteroidal Antiandrogens Flutamide- 1 st 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

16. Inhibition of LHRH or LH Release LHRH Antagonists: Leuprolide (Leupron) – IM – 7.5mg, 22.5mg, 30mg lasting 28, 84, and 112 days Goserelin (Zoladex) SC implant – 3.6mg, 10.8mg lasting 28 and 84 days Triptorelin (Trelstar) IM 3.75mg, 11.25mg lasting 28 and 84 days Leuprolide suspension (Eligard) SC Same dose and schedule as Leupron Leuprolide Implant (Viadur) 65mg SC lasts 365 days Histrelin Implant (Vantas) 50 mg SC lasts 365 days

17. 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

18. 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)

19. 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

20. 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

21. 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

22. 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

23. 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

24. META-ANALYSIS

25. 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)

26. 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

27. LN+ dz early vs. late

28. 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

29. 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

30. 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

31. Questions?