General principles of endocrine therapy

Antonella Brunello, MD, PhD

Medical Oncology 1 UnitDepartment of Clinical and Experimental Oncology

Veneto Instituto of Oncology IRCCS Padova

Disclosure

Nothing to disclose

Class of drug Individual drug Dose Route Frequency

SERMs Tamoxifen 20 mg oral Once daily

AIs Anastrozole Letrozole

Exemestane

1 mg

2.5 mg 25

mg

oral Once daily

ER dowregulator Fulvestrant 500 mg i.m. Once montly

GnRH agonist Goserelin Leuprorelin

Triptorelin

7.5 mg

3.75 mg

3.75 mg

i.m.

i.m.

i.m.

Once monthly

GnRH antagonist Degarelix 240 mg

loading dose

s.c. 80 mg monthly

maintainance

Antiandrogen Flutamide

Bicalutamide

250 mg

50 mg

oral TID

Once daily

CYP450 17α inhibitors Abiraterone 1,000 mg oral Once daily

AR “super antagonists” Enzalutamide 160–240 mg oral Once daily

Somatostatin analog Octreotide Variable s.c. or i.v. Up to three times daily

Progestational agents Megestrol

Medroxyprogesterone

Variable oral

oral or i.m.

Once daily

Varies 3

Major hormonal agents used in cancer

Breast cancer

4

BC Endocrine Rx Time Line

1870

1st description of

surgical

oophorectomy

1980’s

ER/PR

detection and

resurgence in

interest in

endocrine Rx

1990’s

Demonstration

of the

therapeutic

efficacy of

Tamoxifen

1970’s

Development of

Tamoxifen

Early 2000’s

Third

generation AIs

Late 2000’s

Fulvestrant

Biological characteristics of BC

Estrogen Receptor

(ER) + 75% of

Breast Cancer

HER-2 +

20-25% of Breast

Cancer

Anti- HER-2 Rx

Endocrine Rx

Endocrine therapies

• Selective Estrogen Receptor Modulators:

– Tamoxifen

– Torimefene

• Androgens

– Fluoxymesterone

• Progestins

– Megestrol acetate

– Medroxyprogesterone acetate

• High dose Estrogens

• Aromatase inhibitors:

– Letrozole

– Anastrazole

– Exemestane

• Steroidal Antiestrogens:

– Fulvestrant

• LHRH agonists

– Leuprolide

– Goserelin

• Gland ablation

– Ovary

– Pituitary

– Adrenals

Estrogen Estrogen

Receptor

SERMS (tamoxifen),

SERDS

Cell

Growth

and

Division

Endocrine therapy in BC

Aromatase Inhibitors

Ovarian suppression

Estrogen & Progesterone receptors

• Several authors demonstrated the relationship of the cytosolic form ER to the efficacy of endocrine therapy.

• The nuclear translocation and subsequent transcription are dependent on several co-repressors and activators.

• The SRC co-activator action is particularly important in this regard.

• Role also of ER-β

Rationale for receptor based Rx

• Response rates to endocrine manipulation in ER +ve patients was as high as 53% ( only 6% in ER –ve)

• Receptors correlate with other prognostic markers:

– Cellular turnover rates,

– Nuclear grade, and

– Degree of histologic differentiation

• Receptor positivity also correlates with:

– Disease-free interval

– Decreasing tumor size

• Prolongation of DFS is independent of menopausal status, tumor size, and nodal status.

Wittliff JL. Semin Oncol 1974; Wittliff JL et al Cancer 1984

Mechanism of action

• All endocrine therapies target the estrogen receptor at one level or other.

• While the PR receptor doesn't act as a target directly it does indicate a functional ER pathway as it is a ER induced gene.

SERM

• The SERMs are chemically diverse compounds that lack the steroid structure of estrogens but possess a tertiary structure that allows them to bind to the estrogen receptor.

• Examples:– Tamoxifen– Raloxifen– Toremifene

• Selective modulation explained by:– Differential estrogen-receptor expression in a given target tissue

– Differential estrogen-receptor conformation on ligand binding

– Differential expression and binding to the estrogen receptor of coregulator proteins

Tamoxifen

• Chemically a triphenylethylene.

• The trans isomer is used as a citrate salt.

• MOA: Competitive binding to the estrogen receptor resulting in reduction of transcription of estrogen regulated genes.

• Dimethylaminoethoxy side chain and the trans configuration are crucial for the antiestrogenic activity of tamoxifen

• The net result is a block in the G1 phaseof the cell cycle and a slowing of cell proliferation.

• Tamoxifen is thus, a cytostatic drug.

EBCTCG, Lancet 2011

Tamoxifen is effective in ER+ BC both

pre- and postmenopausal women

5 Years of Tam vs No Tam

Recurrence BC-mortality

EBCTCG, Lancet, 2011

Current guidelines for adjuvant

endocrine therapy in BC

St Gallen2013

ASCO 2014 ASCO 2016

PREMENOPAUSAL Tam X 5 yr Tam X 5-10 yr

POSTMENOPAUSAL

Tam X ≥ 5 yr

or

AI X 5 y

or

Switch AI to Tam

or

Switch Tam to AI

AI X 5 yr

or

Tam X 5-10 yr

or

Tam X 5 yr to

AI X 5 yr

AI X 5-10 yr

or

Tam X 5-10 yr

or

Tam X 5 yr to

AI X 5 yr

RCT of 10 vs 5 yrs of Adjuvant Tam

ATLAS, Lancet, 2013 aTTom, ASCO, 2013

ATLAS: all subset benefit

Combined outcomes in ATLAS and aTTom

Breast Cancer

Mortality

Overall Survival

Years 5-9 0.97 (0.84-1.15) 0.99 (0.89-1.10)

Years 10+ 0.75 (0.65-0.86)* 0.84 (0.77-0.93)*

All years 0.85 (0.77-0.94)* 0.91 (0.84-0.97)*

* P < 0.05 favoring 10 years

Gray et al, ASCO 2013

Aromatase Inhibitors

• Prevent peripheral conversion of androgens to estrogen.

• Also cause selective impairment of gonadal steroidogenesis.

• Selective estrogen deprivation without impairment of adrenal androgen synthesis.

• Two types:– Steroidal: Enzyme inactivators (Exemestane)– Non steroidal: Competitive antagonists (Anastrozole, Letrozole)

• 3 generations:– 1st generation: Aminoglutethemide– 2nd generation: Formestane (Type I) , Fadrazole– 3rd generation: Exemestane (Type I) , Anastrazole , Letrozole

AIs: mechanism of action

3rd generation AI

• Inhibit the Aromatase enzyme selectively by blocking the heme moiety of the enzyme.

• Active sites of other steroidogenic enzymes remain free.

• 3rd generation AIs are 3 timesmore potent than aminoglutethemide.

• Dose:

– Letrozole (Femara) – 2.5 mg OD

– Anastrazole (Arimidex) – 1 mg OD

– Exemestane (Aromasin) – 25 mg OD Letrozole

Anastrazole

AIs vs TAM

EBCTCG Lancet 2015

• Best suited for a hormone receptor positive, postmenopausal woman

• Presence of HR+ve strongly influences response to preoperative endocrine therapy

• Complete and partial response rates of the order of 40 - 70%

• Majority of patients will have evidence of tumor shrinkage by 3-6 months.

• Progression of disease is uncommon in hormone-sensitive patients receiving preoperative therapy (<5%)

BC neoadjuvant setting

• Endocrine therapy should be started in all hormone receptor positive pts with metastatic breast cancer.

• AI are standard 1st line agents after tamoxifen therapy.

• Selection of the appropriate initial management depends on:

– Type of disease (Slower progress, fewer symptoms)

– Vital organ involvement

– General condition of the patient

BC metastastic setting

Systemic Treatment

for Metastatic Breast Cancer

Metastatic Breast Cancer

• Limited metastases (bone & soft tissue)

• Positive hormone receptors

• Hormone responsive

• Disease-free interval ≥2 years

Hormonal Therapy

Response No response

If disease progresses,

second-line hormonal therapy

• Extensive disease or visceral crisis

• Negative hormone receptors

• No response to hormones

Chemotherapy

No progression Progression of disease

Second-line chemotherapy

Safety profile

Tamoxifen Aromatase inhibitors

Endometrial cancer

Thromboembolic events

Musculoskeletal events

Decreased bone mineral

densitometry and bone

fractures

Cardiovascular events

Comorbidities

Tamoxifen Toxicity

• Menopausal symptoms:– 50% - 60% ( N.B. 40% -

50% in placebo)– MC in premenopausal– Vaginal dryness and discharge

may occur in excess.

• Depression:– Maybe seen in as high as

10% of patients.– But no randomized

comparisons available.

• Ocular toxicity:– Keratopathy, maculopathy &

cataract– Reported with high doses– However NSABP studies have

found no increase in vision threatening ocular toxicity.

• Thromboembolism:– Severe thromboembolism

seen in ~ 1% patients in the preventive setting.

– Risk up to 10 times that experienced by healthy women

– Complication more common in elderly patients with metastatic breast cancer and who are receiving CCT

• Carcinogenesis:– Increased risk of endometrial

cancers (hazard rate of 1.7 per 1000 – NSABP B 14 data)

– Mostly low grade & stage I tumors.

• Other tumors:– Hepatomas– Clear cell sarcomas of ovary

The benefit of adjuvant tamoxifen is

independent from patient’’’’s age

EBCTCG. Lancet 2005

6

Tamoxifen in Elderly patients• ECOG evaluated 2yr tam vs placebo in 180 women > 65yrs

�Drug was well tolerated

� Significant reduction in recurrences

�Borderline significant reduction in risk of death

� Tamoxifen also reduced the incidence of contralateral breast cancers

• Problems with adjuvant tamoxifen in elderly population:�High risk of death for unrelated cancer (22% in ECOG trial)

�Poor adherence to prescribed treatment

�Risk of thromboembolism increases with age.

• Tamoxifen side effects are correlated with age:

- little uterine cancer risk or excess risk of fatal pulmonary

embolus tam-related for pts < 54 years;

- older women with intact uterus have ≈1% excess risk of

death from endometrial cancer or pulmonary embolus.

Cummings FJ, et al J Clin Oncol 1993; Fisher B et al. J Natl Cancer Inst 2005; EBCTCG. Lancet 2011

J Clin Oncol 2010

“We recommend that potent CYP2D6 inhibitors be avoided in women receiving Tam"

7 trials; 30.023 patients

Limitations:

• Literature rather than individual patient data meta-analysis

• Reports of trials with different durations of follow-up

• Information on the potentially confounding baseline host factors (eg, obesity,

hypertension, diabetes, and family history of events of interest) or the use of

concurrent medications was not reported

= � �� �

10

Bone health• Adjuvant AI vs TAM: statistically significant increase in bone

loss and fractures with AI, regardless of which AI or strategy

(upfront or sequential) was used

Amir et al.

Difference in absolute risk =2.2%

Is the negative effect of AI on bone more

evident in elderly patients?

• Bone mineral density loss in AI-treated patients does not

appear to be independently associated with age:

� In the ATAC study the rate of bone loss was greatest in those

women who were within 4 years of menopause compared to

women who were more than 4 years from menopause1

Effect of age on uNTx z score in breast cancer patients treated with

anastrozole for more than 6 months. Dotted line indicates the age-

matched mean (z score = 0) of healthy control subjects. The uNTx z

score was negatively correlated with age in these subjects (r = -0.473, P \ 0.001)

1 Eastell R et al. JCO 2008;26:1051-10572 Powel DE et al. Calcif Tissue Int 2011; 88:223-230

� Anastrozole treatment increased

bone turnover (urinary cross-

linked N-telopeptide of type I

collagen [uNTx]) more in younger

postmenopausal breast cancer

women than in older women

compared to healthycontrols2

Subpopulation Treatment Effect Pattern Plot of incidence of any bone fracture for

L vs T for overlapping subpopulations defined according to age at study entry

The incidence of bone fractures was generally consistent with regard to age

beyond the youngest subpopulations

Risk factors for fractures

• Increased age, prior fractures, diagnosis of osteoporosis at baseline, previous hormone therapy;

• AI therapy, T-score <-1.5, age >65 years, low body mass index (< 20 kg/m2), family history of hip fracture, personal history of fragility fracture after age 50 years, oral corticosteroid use >6 months, and smoking.

Rabaglio et al. Ann Oncol 2009; Hadji et al. Ann Oncol 2008

Bisphosphonates

Hadji et al. Ann Oncol 2008

• Unfortunately these studies are not powered to detect differences in fracture rate

• Whether the increase in bone mineral density translates into reduced

fracture risk is under debate

• Almost no data are available on fracture rate in patients on AIs with baseline

osteoporosis

(bone loss)

Preventive effect of risedronate on bone loss and frailty

fractures in elderly women treated with anastrozole for

early breast cancer.

Sergi G et al, J Bone Miner Metab. 2012

Group A

24 pts

Group A

27 pts

T-scores ≥ -2

no fractures

T-scores < -2

or T-scores ≥ -2 and

fractures

Treatment:

- Anastrozole

- Calcium (1000 mg qd)

- Vit D (800 mg qd)

Treatment:Treatment:

- Anastrozole

- Calcium (1000 mg qd)

- Vit D (800 mg qd)

- Risedronate 35 mg qw

- Differences in BMD and frailty fractures were evaluated after 1 and 2 years

- In group A, significant decreases in BMD but only one incident fracture

- In group B, no incident fracture

Cardiovascular events

Longer duration of AI use is associated with statistically significant increase

in the odds of developing cardiovascular disease compared with TAM alone

or shorter duration of AI use (OR 1.26; 95% CI 1.10-1.43, P<.001)

Amir et al. J Natl Cancer Inst 2011

4.2% of patients in the AI group and 3.4% of patients in the TAM group

suffered a cardiovascular event (difference in absolute risk=0.8%)

11

Cognition

• The association of estrogens with cognition is complex and is

not completely understood.

• While reduced estrogen effect (through decreased amounts

or antagonism) in the brain logically suggests decreased

mentation, a meta-analysis of 16 trials did not support that 5

years of hormone-replacement therapy or estrogen

replacement prevents any mental decline in older

postmenopausal women

• The Women's Health Initiative Memory Study (WHIMS)

showed that women aged > 65 years had worse cognition

while on hormone-replacement therapy

Lethaby et al. Cochrane Database Syst. Rev. 2008; Espeland et al JAMA 2004

AI vs

Controls

No significant difference in cognitive tasks between placebo (n = 74)

and ANA groups (n = 77) at 24 months

AI vs TAMLETRO users (n = 65) had higher cognitive test composite score when

compared with TAM users (n = 55)

AINo significant effect on cognition with AI therapy: ANA (n = 9) and

LETRO (n = 4)

AI vs TAMANA users (n = 15) had poorer learning and memory performance

than TAM users (n = 16)

AI & TAM vs

Controls

TAM (n = 31) and ANA users (n = 14) had a greater decline in

processing speed and memory compared with controls (n = 28)

AI & TAM vs

Controls

TAM (n = 30) and EXE users (n = 50) had poorer verbal fluency and

information processing speed than controls (n = 48)

AI & TAM vs

Controls

No significant difference in cognitive tasks between control (n = 120)

and EXE (n = 99) groups

Adapted from Batalo et al. Expert Rev Anticancer Ther. 2011

Cognitive dysfunction in postmenopausal

BC patients on AIs

Baseline and at 1-year

80 tamoxifen users , 99 exemestane users and 120 healthy controls

Effects of tamoxifen and exemestane on cognitive functioning of

postmenopausal patients with breast cancer: results from the

neuropsychological side study of the tamoxifen and exemestane

adjuvant multinational trial.

Schilder CM et al J Clin Oncol 2011

After 1 year of adjuvant therapy, tamoxifen use is associated with

statistically significant lower functioning in verbal memory and executive

functioning (vs healthy controls ), whereas exemestane use is not

associated with statistically significant lower cognitive functioning in

postmenopausal patients with BC.

The patient group, as a whole, had a significantly worse overall cognitive functioning compared to

healthy controls (P .03). Considering the eight cognitive domains separately, the only significant lower

performance in the patient group was in the verbal fluency domain (P.01)

AI: 1st line therapy• 3 major pahse III trials have directly compared tamoxifen against AI.

• All have shown an improvement in time to progression (TTP)

• The study by the International Letrozole Breast Cancer Group is the largest in the series.

Trial Drug N RR TTP (mo) Comment

Nabholtz et al1

Ana 353 21% 11.1* Retrospective analysis revealed longer TTP with Anastrazole after combining these two trials3,4

Tmx 17.7% 5.6

TARGET trail2 Ana 668 32.9% 8.2

Tmx 32.6% 8.3

Mouridsen et al5

Let 907 30% 9.4

Tmx 20% 6.0

Fulvestrant

• ER antagonist

• No known agonist activity

� causes ER downregulation

• Like tamoxifen, competitively binds to the ER but with a higher affinity—approximately 100 times greater than that of tamoxifen thus preventing endogenous estrogen from exerting effect in target cells.

HO

OH

S+ CF�CF�O–

���� ����� �� ��� � �� �� �� ��Wo

Howell A, et al. Cancer 2000;89:817–825

Fulvestrant

• Poorly soluble, low and unpredictable oral bioavailability

• i.m. formulation � prolonged release over several weeks.

• Long time needed to reach a steady state � 500-mg loading

dose regimen superior to 250 mg

Howell A, et al. Cancer 2000;89:817–825

• Two phase III RCT using the 250 mg per month dose

demonstrated fulvestrant to be as effective as anastrozole in

the treatment of postmenopausal women with advanced HR–

positive BC previously treated with antiestrogen therapy..

• In the setting of first-line HR-positive metastatic BC, RCT

comparing tamoxifen to fulvestrant (250 mg per month)

demonstrated no differences in response or time to

progression.

Adapted from Robertson JFR et al. Cancer 2003; 98: 229–238

Hazard ratio (95% CI): 0.95 (0.82–1.10); p=0.48

Median TTP: Faslodex 250 mg 5.5 months

Anastrozole 1 mg 4.1 months

Time to progression (months)

Pro

po

rtio

n n

ot

pro

gre

sse

d

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 6 12 18 24 30 36

Faslodex 250 mg vs anastrozole 1 mg:

Combined analysis of Trials 0020 and 0021

Combined analysis of Trials 0020 and 0021

Recommended dose of Faslodex is 500 mg at intervals of one month, with additional 500 mg given two weeks after

initial dose

Faslodex 250 mg

Anastrozole 1 mg

Fulvestrant 500 mg vs 250 mg

0.1

0

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80

362 333 288 254 227 202 178 163 141 123 114 98 81 64 47 30 26 15 8 1 0500 mg

374 338 299 261 223 191 164 137 112 96 87 74 64 48 37 22 14 8 3 2 0250 mg

Time (months)

Proportion of

patients alive

Patients at risk:

HR (95% CI) 0.81 (0.69, 0.96)

p-value 0.02a

aNominal value, cannot be claimed as significant as no

adjustments were made for multiplicity

Median TTD (months)

Faslodex 500 mg 26.4

Faslodex 250 mg 22.3

Adapted from DI Leo A et al. J Natl Cancer Inst 2014;106:1–7

Fulvestrant 500 mg

Fulvestrant 250 mg

Fulvestrant: safety profile

Howell A, et al. Cancer 2000;89:817–825

• Fulvestrant is well tolerated.

• The most common drug-related events (greater than 10%

incidence) from the randomized phase III studies were

injection-site reactions and hot flashes.

• Common events (1% to 10% incidence) included asthenia,

headache, and gastrointestinal disturbances such as nausea,

vomiting, and diarrhea, with minor gastrointestinal

disturbances being the most commonly described adverse

event

Overcoming endocrine-resistance

• Anti-mTOR

• PIK3CA inhibitors

• CDK 4/6 inhibitors

• …..

Prostate cancer

52

PC Endocrine Therapy

General Concepts

• Natural history is variable and can be very long

• PSA kinetics helpful

• Androgen ablation therapy (AAT) remains mainstay of therapy

• Androgen receptor remains relevant throughout tumor progression, ie further androgen ablative therapies useful even after initial progression

• Abiraterone/Enzalutamide play major role in symptomatic disease

• Chemotherapy (docetaxel) plays a major role in castration-resistant disease

Role of AR (and androgens) in disease

• Orchiectomy (1941)

• Estrogens (1967)

• LHRH analogues(1971)

Endocrine Rx for PC: facts

• PC is highly hormone-sensitive

- castration is 1° line therapy for metastasticPC

- response rates ≈ 85%

• Castration failure is inevitable :

- median time to progression ≈ 12 months

- median survival 24-36 months;

• PC becomes castrate resistant:

- still possible hormonal manipulation

- … lower results

Serum testosterone

tumor burden

(PSA levels)

50

100

150

time

20

Castrationthreshold

Testosterone

serum levels

(ng/dl)

0

Disease progression

ADT resistance

Prostate carcinoma

• Basal cells suppression

• Proliferation of luminal cells

• Ability to metastasize

AR becomes an «oncogene»

Modified from N Engl J Med 2004;351:1488-90

Castration-resistant phase

• AR-dependent pathway

• AR-independentpathway

Permanent activation of androgenic signal

modificata da N Engl J Med

2004;351:1488-90

1

2

3

4

Prostate carcinoma

1) Suppression of testicular androgen secretion:

• Bilateral orchiectomy (1941)

• LHRH agonists (1985)

• LHRH antagonists (degarelix 2009)

2) Negative feed-back on hypothalamic-pituitary axis:

• Estrogens (1941)

• Steroidal antiandrogens (ciproterone acetate 1970)

How to obtain androgen ablation?

3) Antagonism of testosterone at receptorial level:

• Steroidal antiandrogen steroidei (ciproteroneacetate 1970)

• Non-steroidal antiandrogens - I gen. (flutamide1980)

• Non-steroidal antiandrogens - II gen. (enzalutamide, 2012)

4) Inhibition of steroidogenesis:

• prednisone

• Abiraterone (2011)

How to obtain androgen ablation?

Hormone-sensitive PC

• The androgen receptor (AR) is the most important target in prostate cancer

– Initial lowering of testosterone (T) targets AR and is effective > 90% time

– Cells that are “sensitive”, ie require normal levels of testosterone will die

– PSA always declines (often to undetectable)

– Clinical response is seen (tumor shrinkage, pain improves)

– Side-effects develop from lowering of T

– Treatment is not curative – some cells do not die and grow in spite of low T levels

First line treatment: androgen ablation

• Surgical orchiectomy

• LHRH agonist

– plus antiandrogen bicalutamide first month to

prevent flare

– Bicalutamide can be used as combined therapy

• LHRH antagonist - Degarelix

– No flare

Second line treatment: androgen ablation

• Anti-androgens

– Bicalutamide

– Flutamide

– Nilutamide

• Anti-androgen withdrawal

• Ketoconazole

• 17,20-lyase inhibitors (Abiraterone, orteronel)

Side effects of AAT

• Hot flashes – venlafaxine?

• Loss of libido/ED – sexual rehab

• Weight gain – diet, exercise!

• Muscle weakness – exercise!

• Loss of bone density – DEXA, Ca/D, bisphos

• Cardiovascular effects – PCP, cardiologist

• Glucose/Insulin effects – PCP, diet

• Cognitive effects – neuro consult

Castrate resistant PC

• The androgen receptor remains critical even in

the hormone-resistant state

– Some cells can grow even with exceedingly low

levels of Testosterone

• Treatment goal is to further target AR by

depriving it of as much T as possible

• Testosterone <50 ng/dl (cut-off in LHRH agonists registrative trials)

• Surgical castration reduced testosterone to a lower level (12-17 ng/dl)

• Cut-off 20 ng/dl seems the most appropriate

Castration: rationale

.

Scher H I et al. J Clin Oncol 2008;26:1148-1159

Castrate-sensitive, non-metastastic

• Rising PSA after primary therapy

– Biochemical recurrence

– Stage D0

• If prostatectomy, consider XRT

• PSA doubling time predictor of risk for metastasis

– PSADT < 12 months

• Androgen ablation therapy standard of care

• Data supporting intermittent therapy

• Clinical trials

• Metastasis typically bone and nodes

• Wide variation in natural history– Depends on extent of osseous mets

– Presence of visceral mets

– Grade of tumor

– PSADT

• Good risk– Time to progression 3-5+ years

• Poor risk– Time to progression 1-3 years

• Standard of care is AAT

• Evidence supporting intermittent AAT

Castrate-sensitive, metastastic

Castrate-sensitive, metastastic

Median OS may currently reach up to 69 months

Hussain NEJM 2013

Standard Adapted choices

Continuous LH-RH analogue Delay start of treatment

(+/- Bicalutamide)

Intermittent ADT

LH-RH antagonist

Bicalutamide monotherapy

Intermittent vs. Continuous

o Fixed on-phase (6-8 months) of ADT

o Variable off-phase depends on recovery of

testosterone and biologic behavior of cancer

o Must monitor T and PSA levels and clinical status

o Data for less bone density loss

o Suggestion of improved sexual function and QOL

o Intermittent therapy better tolerated and not

associated with worse outcome

o Intermittent therapy is a reasonable option for

patients requiring androgen deprivation

• Defined as rising PSA on LHRH therapy

– Castrate testosterone level

– Negative scans

– No symptoms of disease

• Variable natural history

– Time to metastasis 1-3+ years

– PSADT helpful ≤9 months predicts mets within 2 years

• Treatment is second-line AAT

– Antiandrogens

– Ketoconazole/Abiraterone

Castrate-resistant, non-metastastic

Castrate Resistant, Metastatic

First line

• Good prognosis (asymptomatic, “low volume”)– Standard Docetaxel chemotherapy

– Antiandrogens, ketoconazole/abiraterone

– Immunotherapy (Provenge, sipuleucel-T)

– Investigational therapies

• Poor prognosis (symptomatic, aggressive)– Standard Docetaxel

– Investigational chemotherapy combinations

• Cabazitaxel

• Abiraterone

• Enzalutamide

• Other emerging drugs

Castrate Resistant, Metastatic

Second line

Abiraterone Acetate

oral

irreversible inhibitor of CYP-17 in testosterone

biosynthesis

coadministrered with Prednisone 5 mg x2/die

main side effects associated with an excess of

mineralcorticoids

• hypokaliemia

• arterial hypertension

• general edema

• atrial fibrillastion

• eleveted liver function tests

Excess of mineralcorticoids

Attard JCO 2008

Testosterone level < 1 ng/mL

Abiraterone

Enzalutamide

oral

high-affinity AR antagonist

unlike Bicalutamide, it has no agonistic

properties

it shows preclinical activity in bicalutamide

resistant prostate model

side effects:

• fatigue

• diarrehea

• hot flashes

• seizures

Hoffman-Censit J1, Kelly WK. Clin Cancer Res. 2013

Enzalutamide

Scher J et al J Clin Oncol 2013

Cardiac disorders were noted in 6% of patients receiving

enzalutamide and in 8% of patients receiving placebo (grade 3 in 1%

and 2%, respectively) in the pre-docetaxel setting.

Hypertension or increased blood pressure was observed in 6.6% of

patients in the enzalutamide group and 3.3% of those in the

placebo group.

No significant modification of glycemia, cholesterol and increase of

body weight

No modification of QTc

Cardiac safety of enzalutamide

Beer N ENG J MED 2014

ABIRATERONE: metabolized by CYP3A4 and is strong inhibitor of

CYP2D6 and CYP2C8

Potential increased exposure to amiodarone, fentalyl oxycodone

and tramadole, metoprolol, haloperidol, etc

ENZALUTAMIDE: metabolized mainly by CYP2C8 (rifampicine) but is

a strong inducer of CYP3A4, and moderate inducer of CYP2C9

(reduced activity of Warfarin) and CYP2C19.

Drug interactions

Chemotherapy

Rationale: combined therapy

Cancer Res 2011;71:6019-29

PC: some issues

• Safety of long-term androgen ablation

• Intermittent therapy?

82

TESTOSTERONE

DEPLETION

(ADT)

IMPOTENCE

GYNECOMASTIA

DEPRESSION

OSTEOPOROSIS

HOT FLASHES

FATIGUE

GLUCOSE

CHOLESTEROL

TRIGLYCERIDES

CARDIOVASCULAR

EVENTS

THROMBOSIS

MUSCLE MASS

Lean body mass decreased

Blood Pressure unchanged

ADT correlates with increase in cardiovascular events

in some studies. D’’’’Amico Jama 2008; NandaJama 2009

Cardiovascular risk

Early start of ADT may reduce progression and deaths from PC but is

associated with increased risk of all-cause mortality (RR=15% in

Loblow JCO 2007)

Intermittent ADT has not been shown to be non-inferior to

continuous treatment (Hussain JCO 2013) but is a reasonable

alternative in asymptomatic men and low-volume disease, who

have achieved a good PSA response, able to understant the goal of

pause.

Anti-androgen monotherapy may be inferior to LH-RH analogues,

but may be a good choice for a large spectrum of elderly pts with

cardiac or metabolic disorders, impaired functional autonomy, etc.

Delay

Pause

De-potentiate

First line endocrine treatment

Abiraterone and enzalutamide have both demonstrated to

improve survival and delay radiological progression and

start of cytotoxic chemotherapy in untreated mCRPC.

There is currently no shared algorythm for the choice

between either agents or docetaxel

ABI or ENZA DOCETAXEL

Low-volume disease High-volume disease

Asymtomatic – low symptoms Highly symptomatic

No visceral mets (if ABI) Visceral disease

Early progr under ADTUnable to receive chemo

Which first line treatment?

Strong rationale for early

prehabilitation initiatives

but….very few resources in the

everyday practice!!

Strong rationale for early

activation of supportive care

“SIMULTANEOUS CARE”

5 randomized studies, 5 uncontrolled studies evalutated

clinical outcomes of physical exercise (usually 3 weekly

session of aerobic or resistance training).

•Improvement in muscle strenght, cardiorespiratory

fitness, functional state, lean mass and less FATIGUE

•Uncertain effect on fat distribution, cardiovascolar risk-

factors and quality of life.

Physical exercise

Gardner JR et al, J Clin Oncol 2014