How Low Should Serum Testosterone Level Be in the Treatment of Metastatic Prostate Cancer Wayne Yen-Hwa Chang, MD, PhD. Department of Urology Taipei Veterans

男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02

How Low Should Serum Testosterone Level Be in the Treatment of Metastatic Prostate

Cancer

Wayne Yen-Hwa Chang, MD, PhD.

Department of Urology

Taipei Veterans General Hospital and

National Yang-Ming University School of Medicine

Taipei, Taiwan, R.O.C


Therapy-induced HeterogeneityThe Androgen-receptor (AR)

Pathway

1. Heinlein CA & Chang C. Endocr Rev, 2004; 25: 276-308;2. Hu R et al. Expert Rev Endocrinol Metab, 2010; 5: 753-64

PI3K/AKT/ERK/mTOR

NUCLEUS

AR

T/DHT

Androgen production by adrenal glands

and prostate tumor2

AR overexpression2

AR splice variants2

AR mutants2

Signalling cross-talk1,2

Upregulation of AR cofactors1,2

1. Heinlein CA & Chang C. Endocr Rev 25:276-308, 20042. Hu R et al. Expert Rev Endocrinol Metab 5:753-64, 2010

DHT: dihydrotestosterone; ERK: extracellular signal-regulated kinase; mTOR: mammalian target of rapamycin; PI3K: phosphatidylinositol-3 kinase; T: testosterone


Castration-Resistant Prostate Cancer (CRPC): Definition

Biochemical Progression: 3 consecutive increases in PSA, one week apart, resulting in two 50% increases over the nadir, with PSA >2 ng/mL

Radiological Progression: The appearance of ≥2 bone lesions on a bone scan or enlargement of a soft tissue lesion using RECIST criteria

+ either

Castrate Serum Testosterone <50 ng/dL or 1.7nmole/L

OR

PSA: prostate-specific antigenEAU guidelines on prostate cancer (2014 update)


Testosterone Characteristics

A principal male androgen, sex hormone and anabolic steroid

Synthesis: Leydig cells in testicles, theca cells in ovaries, small amount by zona reticularis of adrenal cortex and placenta

Metabolism: 10% is converted by 5-a reductase to DHT (dihydrotestosterone), < 0.5% by aromatase to estradiol. Most of testosterone is deactivated and excreted as glucoronides

C19H28O2


Methods for Serum Testosterone MeasurementType Characteristics

Chemiluminescet uses antibodies, direct, most laboratory platforms (Abbott, Siemens, Roche) have their own antibodies, which all cross react to some extent to other substances and give consistent, but different results, typically higher than reference methods in/near castrate range

Rradioimmuoassay(RIA)

uses antibodies, typically good results if indirect RIA’s- detection after chromatography step, for direct RIA's, same as for chemiluminescence – problems with antibody selectivity

LC-MS/MS: liquidchromatography –tandem massspectrometry

uses molecular mass based identification, indirect, uses different liquid chromatography methods to extract testosterone from sample (for example “high turbulent flow”) and tandem mass spectrometry to confirm and quantify sample, gold standard

GC-MS: gaschromatography – mass spectrometry

uses molecular mass based identification, indirect, research mainly, useful for profiling different steroids in the sample, reference method, issues with “in-house” development, sample preparation, most labor and resource intensive


Typical Serum Testosterone Values arePresented in Different Units

Clinical Setting Serum Testosterone Value

Normal morning value for males, above 12 nmol/l (= 346 ng/dl = 3.46 ng/ml)

Advised supplementation for healthy males, regardless of symptoms, below

8 nmol/l (= 231 ng/dl = 2.31 ng/ml)

“Medical” castration value 1.73 nmol/l (= 50 ng/dl = 0.5 ng/ml)

Median value for premenopausal females 1.39 nmol/l (= 40 ng/dl = 0.4 ng/ml)

“Morote's” value 1.11 nmol/l (= 32 ng/dl = 0.32 ng/ml)

“Surgical” castration value 0.69 nmol/l (= 20 ng/dl = 0.2 ng/ml)

Conversion Factors: The molecular mass of testosterone (C19H28O2) is 288.42 g/mol. Therefore, if value in ng/dl is available, multiply it with 0.0347 nmol/l / ng/dl to get value in nmol/l. If value in nmol/l is available, multiplied by 28.8 ng/dl / nmol/l to get ng/dl. 1 ng/ml (or microg/l) = 100 ng/dl

Oefelein et al. Urology 56(6):1021, 2000; Djaavan et al. BJU Int 110(3):344, 2012

A recent review found that up to12.5%of patients do not reach the 1.7 nmol/L (50 ng/dL) serum testosterone target, and up to 37.5% do not attain levels <0.7 nmol/L (20 ng/dL).


Management of CRPC: Maintenance of Castrate Testosterone

Levels

- ECOG retrospective analysis of 341 patients treated in 4 clinical trials for HRPC- Correcting for weight loss, age, and performance status, continued androgen suppression was a predictor of survival

Androgen deprivation should be continued even in CRPC

If the patient cannot continue LH-RH treatment , the option would then be bilateral orchiectomy

In the absence of further treatment to block androgen production, his testosterone levels should be tested on a regular basis

No orchiectomy, hormone therapy discontinued prior to study entry

Orchiectomy plus continued hormonal therapy

Mos

Pro

bability

0 6 12

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

Taylor CD, et al. J Clin Oncol. 11:2167-2172, 1993.


Testosterone levels during ADT may Serve as anEarly Predictor of Prostate Cancer Progression

Freedom from CRPC based on 9 month testosterone levels

1.0

0.8

0.6

0.4

0.2

0

Fre

edo

m f

rom

CR

PC

0 1 2 3 4

Time since commencing ADT (years)

Median PFS12.5 months

Median PFS33.1 months

9-month absoluteT ≥32 ng/dL

9-month absolute T <32 ng/dL

Log rank p=0.001

Patients with mean testosterone <32 ng/dL at 9 months had a significantly longer time to CRPC compared to those with mean testosterone 32-50 ng/dL

First-year mean testosterone also associated with time to CRPC

Median PFS: 33.1 months for <32 ng/dL versus 12.5 months for 32–50 ng/dL (p=0.05)

*Patients with recurrence after local therapy, locally advanced disease, metastatic disease and for concurrent treatment with primary external beam radiotherapy for D’Amico intermediate- or high-risk disease.ADT=androgen-deprivation therapy; CRPC=castration-resistant prostate cancer; LHRH=luteinising hormone-releasing hormone; PFS=progression-free survival.

Dason S, et al. Can Urol Assoc J 7:E263-7, 2013

This study supports a lower testosterone threshold to define optimal medical castration (T <32 ng/dL) than the previously accepted standard of 50 ng/dL.

Testosterone levels during ADT serve as an early predictor of disease progression and thus should be measured in conjunction with PSA


Testosterone Levels during ADT may Predict Risk of Disease Progression

1.0

Cum

ulati

ve s

urvi

val f

ree

of A

IP (%

)

0

Follow up (months)

0.2

0.4

0.6

0.8

0 50 100 150 200 250

p=0.0258

Survival free of CRPC analysis according toserum testosterone behavior Patients with breakthrough

increases in serum testosterone >32 ng/dL (1.1 nmole/L) had a significantly shorter mean survival free of CRPC (88 months) than patients with all three determinations of serum testosterone <32 ng/dL (137 months; p<0.03)

CRPC was defined as three consecutive PSA increases after the nadir

Patients with all serum testosterone determinations less than 32 ng/dL (n=33)

Patients with breakthrough increases greater than 32 ng/dL (n=40)

Morote et al. J Urol 178: 1290-95, 2007


0 24 48 72 96 120 144 168

Months under ADT

192 216 240

0,0

0,2

0,4

0,6

0,8

1,0C

um

su

rviv

al

fre

e o

f P

SA

p

rog

res

sio

n

Group 3

Group 2

p = 0.0207

Group 1Group 1 (43.6%): all 3 serum testosterone 20 ng/dL

Group 2 ( 31.5%): with breakthrough

increases between 20 and 50 ng/dL

Group 3 (24.7%): with breakthrough

≥50 ng/dL

106 months

90 months

72months

AIP, Androgen independent

progression

20 ng/dL = 0.7 nmol/L50 ng/dL = 1.7 nmol/L

Survival Free of AIP According to Serum Testosterone Level

Morote et al. J Urol 178: 1290-95, 2007


Sustained Profound Suppression of Testosterone May Affect Prognosis and Survival

Hazard ratio* (95% CI) for cancer-specific survival

0.8 0.9 1.2 1.6 1.81.0 1.1 1.3 1.4 1.5 1.7

Gleason score

6-month PSA

HR 1.31, p<0.01

HR 1.39, p<0.01

Increased risk of death

6-month testosteroneHR 1.33, p<0.05

AgeHR 1.04, p=0.08

Retrospective analysis in 129 prostate cancer patients with bone metastases suggests a direct correlation between testosterone levels at 6-months after ADT and risk of cancer-specific death

Treated with Goserelin

Monitor every 3 month

Mean follow up: 47.5 months

Mean testosterone:

Baseline: 440 ng/dL

6 months: 40 ng/dL

Nadir: 21 ng/dL

*Cox’s proportional hazard model.

Perachino M, et al. BJUI 105:648-51, 2009.


The Cumulative Side Effects ofAndrogen Deprivation Syndrome

Visible Non-visible

Most common What you see What you don’t see What you feel

Loss of libido

Erectile dysfunction

Hot flashes

Weight gain (Obesity)

Gynecomastia

Loss of muscle mass, strength

(Sarcopenia)

Decreased size of penis and testes

Hair changes

Loss of BMD (Osteoporosis

/Fraccture)

Anemia

Hypertension, Diabetes, Lipid profile changes (Metabolic syndrome)

Fatigue

Lack of energy

Lack of initiative

Depression

Emotional distress

Alterations in cognitive function

Adapted from Higano et al. Urology 61:32-8, 2003


Long-term Side Effects of ADT

Bone lossObesity and Sarcopenia


Rationale of Intermittent Androgen Deprivation (IAD)

Heterogeneity of prostate cancer cells response to testosterone in vivo (demonstrated in vitro)

Concept: Advantageous to hit cells hard in induction phase, targeting androgen sensitive and less sensitive cells

Recovery of androgen sensitive cells in off treatment interval


ADT in Advanced Prostate Cancer:Is IAD the New Standard of Care?

Klotz and Toren Current Oncol 19(3):S13-21, 2012

Partially insensitive

Stem cells, androgen insensitive

Androgen sensitive

T < 20

T >> 20

On treatment

On treatment

Off treatment

Off treatment

Less androgen dependence

Eventual adaptation/selection pressure

Greater androgen dependence


Intermittent versus Continuous Androgen Deprivation in Metastatic Hormone

Sensitive Prostate Cancer

Hussain et al. N Engl J Med 368:1314-25, 2013

HR 1.10 (0.99-1.23)

7 year Surviva

l (%)

42%

38%


Klotz et al. JCO 33(10):1151-6, 2015


Low Nadir Serum Testosterone (<20 ng/dL) within the first year of ADT Predicts Treatment

Outcomes

Klotz et al. JCO 33(10):1151-6, 2015

Prospective study N=626 Continuous ADT

Monitor every 2 month, Median follow up of 6.9 years

Time to CRPC Cancer-specific survival


Clinical Implication for Patients on Androgen Deprivation Therapy

Serum testosterone and PSA levels should be monitored regularly during the first year of ADT

Testosterone not achieving testosterone <0.7 nmol/L (0.2 ng/ml) within the first year warrants consideration of a change in hormone therapy, either to another LHRH-agonist, to an LHRH-antagonist, or to orchiectomy (if continuous therapy is intended)

However: Intracrine synthesis of androgens by prostate cancer

cells with autocrine stimulation is a primary mechanism for CRPC

Klotz et al. JCO 33(10):1151-6, 2015


Bipolar Androgen Therapy (BAT): Adaptive auto-regulation of AR and induction of DNA damage with testosterone therapy

By actively exposing cells with “adaptive changes in AR function” to supraphysiologic levels of androgen, nuclear AR loses the flexibility to be removed from origin of DNA replication sites (AR degradation) thereby interrupting mitosis and causing tumor cell death

This is then followed by a return to a castrate level of testosterone leaving surviving cells with baseline low AR or adaptive down-regulated AR again vulnerable to cell death

Isaacs JT et al. Prostate 72:1491-505, 2012 Haffner MC et al. Nat Genet 42:668-75, 2010


METHODS: 16 asymptomatic CRPC patients with low to moderate metastatic burden were treated with testosterone cypionate (400 mg IM; day 1 of 28) and etoposide (100 mg PO daily; days 1 to 14 of 28). After three cycles, those with a declining PSA continued on intermittent testosterone therapy monotherapy.

RESULTS: BAT was well tolerated & produced high rates of PSA responses (7/14 pts) and radiographic responses (5/10 pts). Eventually all men showed PSA progression, but 4 men remained on BAT for ≥1 year. All patients (10 of 10) demonstrated PSA reductions upon receiving androgen ablative therapies after BAT, suggesting that BAT may help restore sensitivity to ADTs.


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How Low Should Serum Testosterone Level Be in the Treatment of Metastatic Prostate Cancer Wayne Yen-Hwa Chang, MD, PhD. Department of Urology Taipei Veterans