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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