10 - CaP - metastatic disease Flashcards
Patient presents with PSA of 400, how would you proceed?
I would see the patient in my fast track clinic
A. First, comprehensive Hx:
1) HPI:
- why was PSA taken, any confounding factors
- local Sx including LUTS, haematuria, dysuria
- metastatic Sx including bone pain, neurological Sx
2) PMH esp:
- CVS, dLRT, seizure, fall, steroid use, DM
- bone health
- co-morbidities to estimate life expectancy
- ECOG status
3) Social history
B. Physical Examination
1) BP and BMI
2) Abdominal exam, ballotable kidneys or palpable bladder, consider BSUSG
3) DRE: hardness, anal tone
4) Spinal tenderness, neurological examination for LL power and sensation
C. Investigations
1) Bloods for baseline
2) metabolic workup
3) M staging to delineate metastatic burden
- Bone scan and contrast CT A+P
- consider PSMA PET-CT
D. Discussion on treatment
- can consider upfront ADT after counselling esp needed if symptomatic
- with early combination systemic therapy
Would you perform prostate biopsy for a patient with PSA > 400?
In view of the sky high PSA, esp if together with abnormal DRE and radiological evidence of bone metastasis, then PPV for mHNPC is almost 100%.
Can consider skipping biopsy to avoid unnecessary invasive procedure and its associated complication. This is in line with the NICE recommendation.
I would consider biopsy if there is:
- equivocal diagnosis
- consideration of upfront chemotherapy
- consideration in study setting
Patient with sky high PSA presents with symptoms of cord compression, how would you manage it?
This patient likely has mHNPC complicated with cord compression. I would regard this as a urological emergency and attend patient immediately
Assess the vital signs
Obtain history from patient esp on symptoms
P/E:
- palpable bladder or ballot kidneys
- DRE, tone
- LL power and sensation level
- spinal tenderness and alignment
Blood taking
Mx:
- Foley insertion
- SC Degarelix 240mg loading or emergency BSO
- IV Dexamethasone 16mg then 4mg Q6H
- Analgesics
- “u” MRI whole spine
- “u” consult O&T for decompressive surgery
- “u” consult oncology for RT
Natural history of mHSPC
5-year survival ~25%
Median survival:
- CHAARTED control arm with ADT ~44m
- SWOG 9346: prognosis by PSA 7m after ADT (cut off at 0.2 to 4): 13m, 44m, 75m
Median time to mCRPC: 14m (Cochrane review)
70-80% response to ADT
What prognosis factor do you know for mHSPC?
(EAU 2023)
1) Disease volume (CHAARTED)
- ≥4 bone mets with 1 outside axial skeletal OR visceral met
2) Disease risk (LATITUDE)
- 2 or more high risk features, including
- 3 or more bone mets
- ISUP grade 4 or above
- visceral met
3) PSA after 7 months of ADT
- based on SWOG 9346
- <0.2 = 75m
- 0.2-4 = 44m
- >4 = 13m
Tell me about the principles of ADT
Androgen deprivation therapy is based on the Nobel prize winning works of Prof Huggins and Hodges in 1940s
They noted castration or oestrogen will reduce acid phosphatase, whereas androgen will increase phosphatase in metastatic CA prostate
- This is because growth of prostate cancer is supported by androgen
- Loss of androgen stimulation of prostate cells ➔ Apoptosis
- Testosterone: 95% from testes, 5% from adrenals, therefore ADT targets these sites
Indication for ADT in prostate cancer
1) Symptomatic metastatic CA prostate
2) Asymptomatic metastatic CA prostate
- MRC trial by Kirk: no OS benefit, but improves CSS by 10% and reduces complications (cord com, pathological #, ureteric obstruction, AROU)
3) Locally advanced CA prostate not fit for local therapy
- EORTC 30891 by Studer: improves OS
Should immediate or delayed ADT be offered for metastatic CaP?
Immediate ADT is recommended. There is limited high quality evidence in this specific setting, but based on evidence:
1) MRC trial by Kirk:
- early vs delayed ADT
- for locally advanced or asymptomatic mHSPC
- no OS benefit
- improves CSS by 10%
- reduces complications (cord com, pathological #, ureteric obstruction, AROU)
2) Cochrane review 2019
- improves OS and CSS
- reduces skeletal events
- increases risk of heart failure and fatigue
- limitation: included small number of M1 disease and also not analysed separately
When may delayed ADT be considered in mHSPC? What are the pros and cons of delayed ADT
(Immediate ADT is recommended in most scenarios)
Delayed ADT may only considered in mHSPC if asymptomatic patients with strong desire to avoid ADT related side effects
Pros:
- avoid complication of ADT (increases risk of heart failure and fatigue in Cochrane review 2019)
- reduce cost
Cons:
- poorer CSS, and even maybe OS (based on Cochrane review 2019)
- more rapid disease progression with more complications (cord com, pathological #, ureteric obstruction, AROU in Kirk’s MRC trial)
Patient has locally advanced CaP, but is not suitable for curative treatment, would you offer immediate or delayed ADT?
Immediate ADT is better, based on:
EORTC 30891 by Studer
- immediate vs delayed ADT
- improved OS (HR 1.21)
- no difference in CSS
- subgroup analysis showed greatest benefit if age<70, PSA>50, PSADT<12m
What is the castration level
Testosterone level at:
- <50 ng/dL or <1.7 nmol/L
What treatments for mHNPC?
A) ADT as backbone
B) Combination with Androgen receptor pathway inhibitor:
1. ADT + Abiraterone (LATITUDE, STAMPEDE arm G)
2. ADT + Enzalutamide (ARCHES, ENZAMET)
3. ADT + Apalutamide (TITAN)
C) Triplet therapy if also fit for chemo
1. ADT + Abiraterone + docetaxel (PEACE-1)
2. ADT + Darolutamide + docetaxel (ARASENS)
D) Combination with RT if low volume disease by CHAARTED
1. ADT + RT (STAMPEDE RT arm, STOPCAP systematic review)
X) No longer ADT + chemo alone
x. ADT + Docetaxel (CHAARTED, GETUG-15, STAMPEDE)
What are the types of ADT?
1) Surgical castration by bilateral simple orchidectomy
2) LHRH antagonist
- Degarelix SC (Firmagon) 240mg induction then 80mg Q4 weeks
- Relugolix PO 120mg daily
3) LHRH agonist
- Leuproreline (Eligard, Enantone)
- Gosereline (Zoladex)
- Triptoreline (Diphereline)
What is the time to castration for different ADT?
1) Surgical castration: <12 hours
2) LHRH antagonist (degarelix, relugolix): day 3
3) LHRH agonist (leuproreline, gosereline, triptoreline): 2 to 4 weeks
How to choose between the different types of ADT?
1) If rapid castration is needed
- e.g. impending cord compression, complications
- BSO or LHRH antagonist
2) LFT
- if dLFT then contra-indicated for anti-androgen, thus not suitable for LHRH agonist
3) CVS risk
- lower CVS risk with LHRH antagonist
4) Route of administration
- oral: Relugolix
- SC: LHRH antagonist and agonists
- IM: LHRH agonist
5) QoL and cost considerations
- more painful injection with Degarelix
- less frequent injection with Leuprorelin
- BSO no need injection
Principle of surgical castration
Bilateral simple orchidectomy
=> removes all Leydig cells, thus no more testicular testosterone production (95%)
=> achieves castration level in <12 hours
Principle of LHRH agonist
First injection
- analogues of LHRH, activates the LHRH receptor at pituitary
- increases LH and FSH secretion from day 2-3 for 1/52 i.e. “flare up”
Chronic exposure:
- loss of circadian rhythm
- down regulation of LHRH receptor
- reduce testosterone production at 2-4 weeks
Therefore need anti-androgen to suppress flare-up phenomenon (start on same day or 1/52 before, for 2-4/52)
Pros and cons of:
1) LHRH agonist
2) LHRH antagonist
LHRH agonist:
+) Less subcutaneous skin reaction
+) 6-monthly injection available thus more convenient
+) Same efficacy as surgical castration
+) Reversible
+) Lower cost
-) Flare-up phenomenon
-) Need anti-androgen cover initially, which is contra-indicated if dLFT
-) Longer time to castration ~2-4 weeks
-) Higher risk of CVS event and metabolic syndrome
========
LHRH antagonist:
+) No flare-up
+) No need anti-androgen, therefore also suitable if contraindicated e.g. dLFT
+) Shorter time to castration ~3 days
+) Lower risk of CVS event and metabolic syndrome
+) Same efficacy as surgical castration
+) Reversible
+) Oral Relugolix available
-) More painful subcutaneous skin reaction with Degarelix
-) Monthly injection if Degarelix
-) More expensive
Explain “flare” phenomenon of LHRH agonist
When first started LHRH agonist, LHRH receptor is activated, with increased pituitary release of FSH and LH, and therefore testosterone
Start at day 2-3, and last for 1/52
Symptoms:
- bone pain
- cord compression
- pathological fracture
- LUTS, AROU
- ureteric obstruction
- polycythemia, thrombotic risk
Principle of LHRH antagonist
Directly blocks LHRH receptor at pituitary
➔ decrease LH production
➔ decrease testosterone
Any evidence on comparison between LHRH agonist and antagonist?
1) Sciarra systematic review
- reduced risk in LHRH antagonist in terms of CVS risk, metabolic syndrome, and LUTS
2) HERO Study
- phase 3 RCT
- Relugolix vs Leuproreline
- 48 week castration level better maintained (97% vs 88%)
- Lower incidence of MACE (3% vs 6%)
Why higher cardiovascular risk with LHRH agonist?
1) LHRH receptor on T cells are activated
- pro-inflammatory state, more likely clot dislodgement
2) FSH receptor stimulated
- decrease lipid metabolism and increase fat accumulation
What general advice before starting ADT?
1) Counselling of pros and cons
2) Optimisation of CVS risk factors
- check BP, BMI, FG, Lipid, Hb, calcium
- lifestyle modification
- optimise metabolic syndrome / DM / HTN / dyslipidemia / IHD including
- referral to medical or cardiology esp if existing CVS disease
3) Optimise bone health
i) Assessment
- check RFT, Calcium, Vitamin D level
- DEXA scan to see BMD ➔ repeat every 1-2 years
- FRAX assessment tool to assess fracture risk
ii) General advice
- regular weight bearing exercise
- quit smoking and alcohol
iii) Start calcium 1.2g daily and vitamin D3 1000 IU daily supplements
What are the side effects of ADT?
A. Common side effects
1) Hot flashes (60%)
2) Fatigue
3) Loss of libido
4) ED
B. Cardiovascular and metabolic
5) Anaemia (NCNC)
6) Hyperlipidemia, DM, metabolic syndrome
7) CVS disease, MACE
C. MSK
8) Osteoporosis and osteopenia, fracture risk
9) Sarcopenia
10) Obesity
D. Other less common
11) Cognitive impairment
12) Gynaecomastia
Pathophysiology and Tx for hot flashes with ADT?
Campbell:
- poorly understood
- due to dysregulation over hypothalamus thermo-regulatory centre
- e.g. proposed due to increased adrenergic concentration in hypothalamus, or alteration in beta-endorphins and calcitonin gene related peptides acting on hypothalamus
Treatment:
1) Megestrol
2) Cyproterone acetate due to progesterone effect
3) Gabapentin
4) Antidepressant e.g. Venlafaxine
Follow-up plan for patients started on ADT
1) I will see patients 3 monthly after initiation of hormonal therapy
- median progression to mCRPC is ~14m (Cochrane)
2) Check testosterone level
- 1 month after to assess nadir testosterone level
- 6 month to ensure maintained castration level
3) Monitor oncology outcome
- symptoms
- PSA trend
4) Side effects of ADT
- common: hot flash, fatigue, no libido, ED
- CVS and metabolic syndrome including BMI BP, bloods
- Bone health: DEXA to check BMD
5) Lifestyle advice to minimise ADT side effects including exercise, healthy diet, quit smoking etc.
Why is estrogen not used for ADT?
Not considered as standard of treatment due to complication profile:
- cardiotoxicity
- thrombotic risks
What anti-androgen do you know of? What are their mechanisms?
A. Non-steroidal anti-androgen (NSAA)
- mechanism: Androgen receptor antagonist, compete with testosterone and DHT for binding with AR in prostate gland, also accelerates degradation of AR
- Flutamide
- Bicalutamide
- Nilutamide
B. Steroidal anti-androgen
- mechanism: synthetic hydroxyprogesterone, can cross BBB and centrally down regulate LHRH secretion, thus decreases testosterone production, also androgen receptor antagonist
- Cyproterone acetate (Androcur)
Can we use NSAA instead of ADT for mHSPC? How is NSAA compared to ADT
No, because non-steroidal anti-androgen (NSAA) is inferior to ADT
Based on Cochrane review 2014 NSAA compared to ADT:
- poorer OS
- poorer clinical progression
- higher treatment failure
- higher treatment discontinuation
But leads to 1.5x increase in testosterone and LH level, therefore:
- libido and erectile function preserved
- BMD not affected
- cognitive dysfunction not seen
What are the side effects of anti-androgen
Flutamide:
- hepatotoxicity
- gynaecomastia
- diarrhoea
Bicalutamide:
- moderate liver impairment
- gynaecomastia
Nilutamide:
- Hepatotoxicity
- Alcohol intolerance
- Interstitial pneumonitis
- Visual disturbances
Cyproterone acetate
- fulminant hepatotoxicity
- gynaecomastia
- steroid side effects
- CVS complications
Tell me about maximal androgen blockage
Usually ADT (medical or surgical castration) in combination with non-steroidal anti-androgen:
- bicalutamide 50mg daily
- flutamide 250mg TDS
- nilutamide
In theory it can suppress all androgen produced by testis and adrenal glands
PCTCG (PCa Trialist Collaborative Group) Lancet systematic review:
- 3-year OS improved by 3% with NSAA combination compared to ADT monotherapy
- worse OS and higher mortality with steroidal AA
While it is statistically significant, it may not be clinically significant (months). MAB should therefore only be considered if other combination therapy is not a/v e.g. ARPA or chemo
Pros and cons of maximal androgen blockage
+) Suppression of all androgen produced by testis and adrenal gland
+) Statistically significant improvement in OS (3-year OS by 3% in PCTCG systematic review)
-) More side effects from anti-androgen, including hepatotoxicity, gynaecomastia, diarrhoea, visual disturbances
-) OS benefit is not shown in all RCTs, and even if genuine, is only 3% so may not be clinically significant
-) Increased cost
-) Inferior survival outcomes compared to combination therapy with newer agents including chemo or ARPA
Explain anti-androgen withdrawal syndrome
A subset ~30% of patients will benefit from the withdrawal of anti-androgen, leading to PSA decline of >50% after withdrawal, with clinical improvement
This is secondary to adaptive mutation in androgen receptors, which render NSAA as AR agonists
How would you choose between different combination therapy for patients with mHSPC?
Latest evidence supports ADT as backbone, followed by combination therapy with either AR pathway inhibitor, with or without docetaxel, or RT
Exact choice depends on disease factor and patient factor
1) Disease factor
- volume of disease ➔ low volume can consider ADT + RT (STAMPEDE RT arm)
- de novo mHSPC ➔ consider early intensification with triplet (PEACE-1 / ARASENS)
2) Patient factor
- medical co-morbidities ➔ determine which ARPI to use (e.g. steroid contraindication, seizure, fall)
- fitness for chemotherapy
- contraindication for RT
What’s the evidence for ADT + chemo alone for mHSPC? What is its role in this era?
ADT + chemo was previously considered a SOC, but with the latest results from PEACE-1 and ARASENS demonstrating superiority of triplet therapy, ADT + chemo should only be considered if no ARPI is available
Evidence for ADT + chemo vs ADT:
1) CHAARTED 2018 update
- OS benefit 10 month for all
- OS benefit 17 month for high volume mHSPC
- no sig for low risk disease
2) GETUG-15
- negative trial but there is less high volume disease included and underpowered, so does not refute that high volume patient may benefit from ADT + chemo
3) STAMPEDE Arm G
- multiarm trial
- included M1 and N1 patient
- OS benefit 10 month for all
- OS benefit 22 month for M1
=> HR ~0.7
What is docetaxel
It is a anti-mitotic chemotherapy belonging to the taxane group
Mechanism:
- promote micro-tubule stabilisation by inhibiting micro-tubule depolymerisation
- therefore inhibits mitosis and interphase ➔ mitotic arrest
- also induce apoptosis by binding to BCL-2 oncoprotein
Metabolism: by hepatobiliary system, therefore safe even with renal impairment
Explain the mechanism of:
- Enzalutamide
- Apalutamide
- Darolutamide
Belongs to Androgen Receptor Pathway inhibitor (ARPI), specially androgen receptor inhibitors
Inhibits AR signalling at multiple levels:
- competitive AR binding
- prevent nuclear translocation of AR
- prevent dimerisation and DNA binding
- prevent AR mediated transcription
