EVIDENCE SUPPORTING TESTOSTERONE THERAPY IN MEN WITH PROSTATE CANCER

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1 EVIDENCE SUPPORTING TESTOSTERONE THERAPY IN MEN WITH PROSTATE CANCER Abraham Morgentaler, MD Director and Founder Men s Health Boston Associate Clinical Professor Harvard Medical School

2 And the Urology Lord Said

3 Thou Shalt Not Give Testosterone Charles Huggins 1967 Nobel Prize winner

4 Original Prohibition Based on Flimsy Evidence Huggins and Hodges 1941 (Cancer Res) Cancer of the prostate is activated by testosterone injections Concept unchallenged for 60y Based on serum acid phosphatase levels x 14d in 1 hormonally intact man Huggins and Hodges, Cancer Research 1941 Morgentaler A, Eur Urol 2006

5 T therapy in men with metastatic PCa Prout and Brewer /10 castrated men progressed or died 20 without ADT no adverse events Fowler and Whitmore /52 had rapid unfavorable response Only 4 without ADT- 3 of these had no adverse events up to 355d Lesson: T administration in men on ADT- bad outcomes T administration in men without ADT- benign outcomes Prout G and Brewer, Cancer 1967 Fowler and Whitmore, J Urol 1981

6 Paradox resolved: Saturation model Increasing T causes androgenic stimulation at low T concentrations, reaches a maximum at ~250 ng/dl (8.7 nmol/l) RCT and TriUS registry: PSA rises with TTh if baseline T<250 ng/dl No PSA rise if baseline T>250ng/dl Morgentaler, Urol Clin NA 2007; 34, 555, Rastrelli et al, JSM 2013; 10:2518, Morgentaler et al JSM 2014; 11:2818, Khera et al, J Urol 2011; 186:1005

7 Saturation Model in Action PCa diagnosedstopped T T 64 ng/dl T injections resumed

8 TESTOSTERONE THERAPY AFTER RP 103 men received TTh after RP 26 high risk (Gleason 8-10, +margins, + nodes) Comparison group: 49 men with normal T 15 high risk Median f/u 27 mo Biochemical recurrence: T therapy: 4 recurrences (4%) No T therapy: 8 recurrences (16%) Pastuszak et al, J Urol 2013

9 T THERAPY AFTER BRACHYTHERAPY Balbontin et al BJUI 2014; 114: men received T therapy after brachytherapy Gleason 5-8 T therapy for symptoms Median follow-up 31 mo SHIM improved 16 to 22 (p=.002) No cases of progression PSA Months after brachytherapy

10 98 hypogonadal men with low, intermediate, and high risk PCa treated with radiation therapy Started on TTh T and PSA monitored Q 3 months median 41 months Low Risk CaP no significant PSA increase High Risk CaP PSA increase from ng/ml (p=0.018) BCR 6.1% Pastuszak AW et al. J Urol. 2015; 194:1271.

11 Progression Rates Unchanged With T therapy During Active Surveillance T therapy in 28 men on active surveillance Gleason 6 in 22, Gleason (3+4) in 6 Comparison with 96 men with low T on active surveillance No difference in progression rates between groups (10.3% vs 9.4%, p= NS) PSA did not increase with T therapy Kacker et al, Asian J Androl 18:16, 2016

12 T Rx in Men with Treated and Untreated PCa 82 men received T therapy 50 XRT, 22 RP, 8 surveillance, 1 cryo, 1 HIFU Median age 75, f/u 41 mo No Gleason upgrading on surveillance No BCR in men after RP 3 (6%) with BCR after XRT our study supports the hypothesis that testosterone therapy may be oncologically safe in hypogonadal men after definitive treatment or in those on active surveillance for prostate cancer Ory et al, J Urology 2016

13 Survival in Men with PCa Treated with Testosterone SEER data ,354 men with dx PCa 1181 received TTh (0.79%) after PCa diagnosis TTh not associated with overall or cancer-specific mortality Not associated with use of salvage hormone therapy Kaplan AL, J Sex Med 2014

14 T Flare Not Associated with PSA Rise LHRH agonist alone N=39 Metastatic PCa Mean PSA 678 ng/ml No PSA flare Kuhn et al, NEJM 1989

15 T Therapy in Metastatic PCa 94 yo scientist Gleason 9, bone mets Bilateral nephrostomy tubes PSA >500 6 mo ADT- too weak to walk- he d/c d Requests T therapy

16 After 7 months T therapy 95 y Brain clearer Exercising regularly Appetite improved No bone pain Died at 10 months after sepsis episode

17 Why do we still fear T? a belief constantly inculcated during the early years of life, while the brain is impressible, appears to acquire almost the nature of an instinct; and the very essence of an instinct is that it is followed independently of reason. Charles Darwin, in The Descent of Man (1871)

18 Let Us Embrace Reason Benefits are obvious, immediate Risks are theoretical, possibly non-existent Cautions: Recurrences/progression does occur as natural hx of PCa PSA likely to rise in men with baseline T below saturation point (approx 250ng/dl) Beware of men on ADT- ample potential for androgenic stimulation

19 Are we fueling a fire?

20 We are stronger for having walked through the fire Daenerys in Game of Thrones