Prostate CA Flashcards
How is testosterone produced?
1) Hypothalamus secrete GnRH to pituitary.
- Pituitary then secrete ACTH to stimulate adrenal to produce adrenal androgens to prostate
- Pituitary also secrete LH to testes to secrete Testosterone
2) Adrenal gland secrete adrenal androgens to stimulate prostate
3) Testes secrete testosterone to stimulate prostate
What is androgen Deprivation Therapy?
Shuts off the production of testosterone
Surgical castration - bilateral orchidectomy Medical castration - GnRH agonist - GnRH antagonist - Estrogen
How effective is ADT?
Very effective
>90% PSA response
>80% tumor response
Not curative
Benefits of surgical castration
Immediate lowering of testosterone level
Cheaper
Adherence assured
Tell me more about medical castration
1) GnRH agonist
- Initial testosterone surge with “flare” response, wary of cord compression and AR
- Examples: Zoladex (Goserelin), Lucrin (Leurpolide), Buserelin, Triptorelin
2) GnRH antagonist
- does not have testosterone surge
3) Estrogen (DES)
- Shuts down Hypothalamic-pituitary-gonadal axis
- avoids some negative side effects of LHRH agonists
0 risk of thromboembolic events
What is the definition of Castration-resistant prostate cancer?
1) Progressive prostate cancer
- rising PSA
- radiographic progression
2) Serum testosterone at castrate levels (
What are the options after failure of CAB?
1) Switching to an alternative anti-androgen
2) Anti-androgen withdrawal
3) Secondary hormones
- Ketoconazole
- DES
- Corticosteroids
4) Chemotherapy
- Mitoxantrone
- Docetaxel
What are the classic secondary hormonal therapies?
They produce modest response rates with unknown impact on survival.
These are:
1) 2nd-line AR inhibitors
- block androgen receptor
- examples include: Flutamide, bicalutamide, nilutamide
2) Adrenal androgen biosynthesis inhibitors
- inhibit non-testicular androgen production
- eg. Ketoconazole
3) Oestrogens
- Reduce testosterone through inhibited LH and LHRH secretion
- peripheral activity
4) Steroids
Tell me about CALGB 9583 by Small in 2004 JCO
Aim: To compare Antiandrogen withdrawal alone vs AAWD+Ketoconazole
2 arms:
1) Anti-androgen withdrawal alone
- on PD, able to have Ketoconazole
2) Anti-androgen withdrawal + Ketoconazole 400mg TDS + Hydrocortisone 30/10
N=260
Results
- No difference in survival
- PSA and Objective responses in 32% vs 7%
- PSA response: 10% in AAWD alone vs 30% in AAWD/K
- Time to PSA progression: 9m in AAWD/K vs 6m
What are the new therapies in met CRPC that improve OS?
1) Chemotherapy
2) 2nd line hormonal agent
3) immunotherapy
4) Bone-seeking targeted agents
What are the contraindications to Abiraterone therapy?
Severe Liver dysfunction
Hypo kalmia
Heart failure
What is the median OS benefit with Abiraterone and enzalutamide?
Abiraterone:
- post Docetaxel = 4.6m
- chemo-naive = 5.2m
Enzalutamide: 4.8m
What are the contraindications to Enzalutamide treatment?
Seizures
What are the contraindications to Sipuleucel-T?
Steroids, narcotics for cancer-related pain, GCSF, Liver mets
What are the contraindications for Radium 223?
Visceral mets
What is the median OS achieved with Radium-223?
3.6m
What is the median OS achieved with Cabazitaxel?
2.4m
Tell me about TAX-327 trial in met CRPC?
Ian Tannock published in NEJM 2004, updated JCO 2008
1000men, CRPC 3 arms: 1) Mitoxantrone + Pred (MP) 2) Docetaxel q3w + Pred (D3P) 3) Docetaxel weekly + Pred (D1P)
Results (updated):
- median survival 16m (MP) vs 18m (D1P) vs 19m (D3P)
- survival rate 13.5% vs 16.6% vs 18.6%
Consistent results across all subgroups
2004 results also reported improved response in terms of:
- pain
- serum PSA level
- QoL
Tell me about the TROPIC study
De Bono Lancet 2010
RCT phase 3 CRPC, PD after Docetaxel-containing regimen
N=750
2 arms:
A) IV Mitoxantrone 12mg/m2 + PO Prednisolone 10 mg
B) IV Cabazitaxel 25mg/m2 + PO Prednisolone 10mg
Q3weekly
Results:
- median survival 13m vs 15m
- median PFS 1.4m vs 2.8m
What are the novel hormonal therapies? And what strategies are they based on?
Eg. Abiraterone and Enzalutamide
Abiraterone: Better suppression of non-testicular testosterone (and related hormones) production)
Enzalutamide: Better inhibition of androgen receptor
What is Abiraterone?
Potent, irreversible inhibitor of CYP17
10x more potent than ketoconazole
Initially used as post-Docetaxel
What is the evidence behind Abiraterone After prior chemo?
De Bono NEJM 2011; COU-AA-301 trial
N=1200, 2:1 ratio. S/p Docetaxel
2 arms:
A) PO Prednisone 5 mg BD + PO Abiraterone Acetate 1000mg or
B) PO Prednisone 5 mg BD + Placebo
Results: (–> updated)
OS: 15m vs11m HR 0.65 –> 16m vs11m
PFS 5.6m vs 3.6m
Time to PSA progression 10m vs 7m –> 8.5m vs 6.6m
PSA Response rate 30% v 6% –> 30% vs 20%
What is the evidence behind Abiraterone before prior chemo?
COU-AA-302
Ryan Charles, fist published NEJM, updated Lancet Oncol 2015
N=1100, No prior chemo
2 arms:
A) PO Abiraterone 1000 mg OM + PO Prednisone 5mg BD
B) PO Placebo + PO Prednisone
Updated results at 4 years (50m)
- Med OS: 45m vs 30m HR 0.8
- Most common G3/4 AE: Cardiac disorders 8% with Abi and 4% with placebo)
Interim results:
- med Radiographic PFS: 16.5m vs 8m HR 0.5
- better time to initiation of chemo, opiate use for cancer-related pain, PSA progression, Decline in PS
How does Enzalutamide work?
1) Binds to the Androgen binding site in the androgen receptor (AR)
2) Inhibition of nuclear translocation of AR
3) Inhibition of the association of the AR with nuclear DNA
Tell me about the AFFIRM study
Aim: To evaluate if Enzalutamide prolongs survival in men with CRPC After chemotherapy
N=1200
After chemotherapy
2:1
2 arms:
A) PO Enzalutamide 160 mg OM
B) PO Placebo
Results:
- Med OS 18m s 13m
- Superiority of Enzalutamide shown in all secondary end points:
» Reduction of PSA by 50% or more: 50% vs 2%
» Soft tissue response rate 30% vs 4%
» QoL RR 40% vs 20%
» Time to PSA progression 8m vs 3m
» Radiographic PFS 8m vs 3m
» Time to 1st skeletal-related event 17m vs 13m HR 0.7
** Seizures reported in 0.6%
What about the PREVAIL study?
Aim: To investigate the survival benefit if Enzalutamide was given before chemo.
N=1700
2 arms:
A) Enzalutamide 160 mg OM
B) Placebo
Results: - rPFS 65% vs 14% - Improved OS 70% vs 60% at cutoff date >> 32m vs 30m - benefitted all secondary end points: >> Time until chemo HR 0.35 >> time until 1st SRE HR 0.7 >> Time until PSA PD HR 0.2 >> Rate of decline of at least 50% of PSA 80% vs 5%
What is the different OSs like between Enzalutamide and Abiraterone?
ENZALUTAMIDE:
- AFFIRM (after chemo): 18m vs 13m
- PREVAIL (before chemo): 32m vs 30m
ABIRATERONE:
- COU-AA-01 (after chemo): 16m vs 11m
- COU-AA-02 (before chemo): 35m vs 30m
Name the side effects of Enzalutamide
Hypertension Seizure risk (0.6%) Fatigue/Asthenia Back pain Hot flush Falls
Why are steroids needed when Abiraterone is given?
To ameliorate symptoms of mineralocorticoid excess:
- fluid overload
- hypo kalmia
- hypertension
What is Sipuleucel-T?
An autologous dendritic Cell therapeutic vaccine designed to enhance the immune T Cell response to PAP
Tell me about the trial that is associated with Sipuleucel-T
IMPACT study by Kantoff NEJM 2010
Stipulecel-T = Active cellular immunotherapy
- a type of therapeutic cancer vaccine
- consists of autologous peripheral-blood mononuclear cells (PBMCs) including antigen-presenting cells, that have been activated ex-Vivo with a recombinant fusion protein.
- Fusion protein is fused to GM-CSF, an immune-cell activator
N=500 2:1
2 arms:
A) IV Sipuleucel-T
B) Placebo
Results:
- 22% reduction in risk of death HR 0.78
= 4 month improvement in median survival (26m vs 22m)
- 3-year survival rate 30% vs 20%
- time to objective PD similar
What is the evidence of Radium-223?
ALSYMPCA trial by Parker. NEJM 2013
Radium-223 is an alpha emitter that selectively targets bone mets with alpha particles
RCT n=900 2:1
2 arms:
A) 6 injections of IV Radium-223 (50kBq/kg) q4w
B) Placebo
Results:
- Improved OS 14m vs 11m –> updated 15m vs 11m HR 0.7
- Secondary endpoints all achieved
Denosumab vs Zoledronic acid for prostate CA
Fizazi Lancet 2011
RCT phase III, n=1900
CRPC, at least one bone met
2 arms:
A) Denosumab 120 mg q4w
B) Zometa 4mg q4w
Results:
- Time to 1st SRE 21m vs 17m in favor of Denosumab
- no difference in terms of OS nor PD
What is the CHAARTED study?
Sweeney NEJM 2015
Aim: to assess if concomitant treatment with ADT+Docetaxel would result in longer OS than with ADT alone
N=790
Met, hormone-sensitive prostate cancer
2 arms:
A) ADT + Docetaxel (75) x 6 cycles
B) ADT alone
Results:
- med OS 58 months vs 44 months
- med time to biochemical/symptomatic/Radiographic PD was 20m vs 12m HR 0.6
What is the STAMPEDE trial?
James Lancet 2016
Multi arm, multistage platform design
Recruits: high-risk/locally advanced/met or Recurrent prostate ca men who are starting 1st line long-term hormone therapy.
N=3000
60% with M+ disease, 25% with N0M0 disease
Med f/u 4 years
4arms, 2:1:1:1
A) SOC = hormone therapy for at least 2 years
B) SOC+ZA
- ZA 4mg x6q3weekly –>q4weekly until 2 years
C) SOC+ Doc
- Doc (75) q3weekly x6 + Pred 10 mg
D) SOC+ZA+DOC
Results: - Med OS > SOC = 70m, > SOC+ZA NR (HR 0.9) > SOC+Doc 80m (HR 0.8) > SOC+ZA+DOC 76m (HR 0.8)
Conclusion:
- ZA showed no evidence of survival improvement
- Docetaxel should become part of SOC in those who are fit.
What evidence is there against Docetaxel in non-castrate resistant prostate CA?
GETUG-AFU15
Gravis Lancet Onco 2013
N=200
2 arms:
A) ADT
B) ADT + Docetaxel (75) q3w x9
Results:
- med OS 60m (ADT+Doc) vs 54m
- ADT + Doc = 20% neutropenia rate, FN 3%, with 4-treatment-related deaths
Intermittent or continuous therapy and why?
Hussain et al. NEJM 2013
The hypothesis was that replacing androgens before PD will prolong androgen dependence.
N=3000, ITT 1500
Newly Dx, met hormone-sensitive prostate CA
PSA 5 or more s/p LHRH + anti androgen for 7 months
When PSA 4 ng/ml or less, then randomized to:
- Continuous ADT
- Intermittent ADT
Results:
Med f/u 10 years
Med OS 5.8 years (Continuous) vs 5.1 year
Intermittent therapy a/w better erectile function and mental health at month3, but not thereafter.
Conclusion: inconclusive. Unable to rule out 20% greater risk of death with intermittent therapy
What is the evidence FOR intermittent therapy of ADT?
NEJM 2012, Crook et al
Non-inferiority trial
PSA >3 more than 1 year after primary or salvage RT for LOCALIZED prostate CA
Intermittent treatment provided in 8-month cycles with no treatments dependent on PSA level
N=1400
Intermittent therapy provided benefit with respect to physical function, fatigue, urinary problems, hot flashes, libido, erectile function
Med OS 8.8 yrs in intermittent group and 9.1 years in continuous therapy
–> intermittent non-inferior
What hormones does Pituitary gland produce?
1) LH –> Stimulates testes to produce testosterone
- Negative feed back to Hypothalamus and pituitary gland
2) ACTH –> Stimulates adrenal glands to produce adrenal androgens
What are your GnRH agonists?
Goserelin (Zoladen)
Leuprolide (Lucrin)
Buserelin
Triptorelin
How does estrogen work in androgen deprivation therapy?
Diethylstilbestrol (DES) is an agent we can use.
Works by shutting down the hypothalamic-pituitary-gonadal axis.
Can avoid some negative side-effects of LHRH agonists.
However, risk of thromboembolic events
What is the difference between Orchidectomy and DES?
No difference in OS
DES 5 mg has increased cardiac toxicity and CVA.
Orchidectomy is complete, immediate lowering of testosterone.
No worries about compliance
How about if it is PSA-only disease. Does it matter whether we start ADT early or late?
No. Similar survival whether we start ADT within 3 months of relapse (“early”) or when we start it only when there’s mets/symptoms/short doubling time (=”delayed”)
Evidence comes from retrospective analysis by Garcia-Albeniz in Eur J Cancer 2015 (CaPSURE) study
Tell me about the CaPSURE study
CaPSURE = Cancer of the Prostate Strategic Urologic Research Endeavor
Garcia-Albeinz Eur J Oncology 2015 Retrospective analysis N=2000 S/p prostatectomy or RT with PSA relapse as the only evidence of recurrence All cT3aN0M0 or better
2 arms: (Emulated, as this is a retrospective analysis)
1) Immediate: Initiate ADT within 3 months of PSA relapse
2) Deferred: if ADT initiated only when they p/w mets/symptoms/short PSA doubling TME.
RESULTS:
Similar survival
Any evidence supporting continuous ADT?
Yes. (A) Hussain et al NEJM 2013. Against this : Crook et al NEJM 2012 JPR.7 trial ========== (A) Hussain et al N=1500 Newly Dx, metastatic, Hormone sensitive Prostate CA , PSA 5ng/ml or higher given LHRH analogue + anti androgen for 7/12. Then randomly assigned patients in whom the PSA level fell to 4ng/mL or lower to: 1) Continuous ADT 2) Intermittent ADT
F/u ~10 years
RESULTS:
Med OS 5.8y in continuous arm and 5.1y in intermittent arm. HR 1.10
Intermittent Tx a/w better erectile function and mental health at month3, but NOT thereafter.
Conclusions: Statistically inconclusive results.
Cannot rule out a 20% greater risk of death with intermittent therapy.
==========
Crook et al NEJM 2012
= JPR.7 trial
N=1400, PSA > 3 Ng/mL more than 1 year after primary/salvage RT for localized prostate cancer.
Intermittent therapy provided in 8-month cycles, with non-treatment periods determined according to PSA level.
RESULTS:
Adverse events between groups similar
Med OS: 8.8y (intermittent group) vs 9.1y HR 1.02
Intermittent therapy deemed non-inferior to continuous
Estimated 7y cumulative rates of disease-related death 18% vs 15%
Conclusion = intermittent androgen deprivation was non-inferior to continuous therapy with respect to OS.
What are the benefits of intermittent ADT?
1) Physical function
2) Fatigue level
3) Urinary problems
4) Hot flashes
5) libido
6) Erectile function
Tell me about the INT 0036 study:
600 men with metastatic disease randomized to:
1) Leuprolide
2) Leuprolide + Flutamide
Conclusion: combination therapy had significantly longer PFS and median survival.
PFS 16.5m vs 14m
OS 36m vs 29m
What about the INT 0105 study?
N=1400
Metastatic disease randomized to:
1) Orchiectomy + Placebo
2) Orchiectomy + Flutamide
RESULTS: NO differences in med OS and med PFS
34m vs 30m and 20m vs 19m
What are the 3 chemo-hormonal therapy trials that you know of?
1) STAMPEDE
2) CHAARTED
3) GETUG-AFU15
Tell me about he GETUG-AFU 15 trial
Gravis et al Lancet Oncol 2013
N=400
Histo-confirmed adenoCA of prostate + Radiological proven met disease.
2 arms:
1) ADT
2) ADT + 9# Docetaxel
Docetaxel (75) D1 Q21 days
ADT can be achieved by:
- Orchiectomy
- LHRH Agonist alone
- LHRH agonist + Non-steroidal anti-androgen
RESULTS:
- median OS 59m vs 54m
Tell m about the CHAARTED study
Sweeney et al. NEJM 2015
N=800
Metastatic, hormone-sensitive prostate CA
2 arms:
1) ADT + Docetaxel
2) ADT alone
Docetaxel was given at 75 mg/m2 Q3w X 6#
Median f/u 2.5 years
Defn of high-volume disease = visceral mets and/or 4 or more bone mets
RESULTS:
1) OS 58m vs 44m HR 0.6
2) median time to biochemical PD/symptomatic or radiographic PD 20m vs 12m HR 0.6
3) High-volume disease: OS 49m vs 32m R 0.6
4) Low-volume disease: need further f/u
Conclusion = 6# of Docetaxel at beginning of ADT for met prostate CA resulted in significantly longer OS than with ADT alone.
Tell me about the STAMPEDE study
James et al. Lancet 2016.
N=3000 60% with metastatic disease 15% with N+ 25% with N0M0 disease High-risk, locally advanced, metastatic or recurrent prostate CA. Treatment-naive
Multi-arm, multistage platform design 4 arms: A) SOC B) SOC + ZA C) SOC + ZA + Docetaxel D) SOC + Docetaxel
SOC = Hormone therapy for at least 2 years
RT as encouraged for N0M0, subsequently mandated
ZA: 4mg Q3weekly X 6doses, then Q4weekly until 2 years
Docetaxel = 75mg/m2 Q3weekly x6 + Prednisolone 10mg OD
RESULTS: Median OS: - SOC 71m - SOC+Doc 81m - SOC+Doc+ZA 76m - SOC+ZA = not reached
Conclusion:
1) ZA did not show evidence for survival improvement and should NOT be part of SOC
2) Docetaxel given at time of long-term hormone therapy initiation showed improved OS + increased adverse events
3) Docetaxel should become SOC
What is CRPC?
Castrate-resistant Prostate Cancer
Defined as:
1) Progressive prostate cancer
- rising PSA
- Radiographic PD
2) Serum testosterone at castrate levels (0.5 ng/mL)
How is ketoconazole given?
PO 400 mg TDS + Hydrocortisone 30/10
What are the contraindications for Abiraterone?
Severe liver dysfunction
Hypokalemia
Heart failure
How do you dose Cabazitaxel?
TROPIC study by de Bono Lancet 2010
IV Cabazitaxel 25mg/m2 over 1 hour Q3w.
Will require Prednisolone 10 mg OM
What does Abiraterone inhibit?
CYP17
What is the difference in mechanism of Abiraterone and Enzalutamide?
Abiraterone = better suppression of non-testicular testosterone and related hormones production
Enzalutamide = Better inhibition of the androgen receptor
What is the dose of Abirtaerone?
1000 mg
Need to give with Prednisone 5 mg BD
What are the Mineralocorticoid-related adverse events?
Fluid retention
Hypertension
Hypokalemia
What are the results of COU-AA-301
Testing Abiraterone Vs placebo
S/p Docetaxel treatment
Updated results at close to 2 years:
Med OS = 16m vs 11 Med Time to PSA progression 8.5m vs 6.5m Median radiologic PFS: 5.6m vs 3.5m Proportion with PSA response 30% vs 6% Trend towards improved QoL
What is the dose of Enzalutamide?
PO 160mg OM
What are the side-effects of Enzalutamide?
Fatigue Diarrhea MSK pain Headaches Seizure Cardiac disorder Transaminitis
What is Sipuleucel-T?
An autologous dendritic cell therapeutic vaccine
Designed to enhance the immune T-cell response to PAP
What are the common side-effects of Sipuleucel-T?
Chills
Fever
Headache
How do you dose Radium-223?
Q4weeks for 6 cycles IV injections
Dose of 50 kBq/kg
Who should be offered adjuvant RT following radical prostatectomy?
Positive surgical margins
Extra capsular extension after radical prostatectomy
Who can be spared from a surgical staging?
PSA
Who can be offered active surveillance (according to ESMO)?
Low tumor burden
- one or two biopsy cores positive
- Gleason score
What are the possible radical local treatments?
1) Prostatectomy
- open
- laparoscopic
- robot-assisted laparoscopy
2) RT
- External beam RT
- Brachytherapy
What is localized prostate cancer?
Stages T1-3 N0M0
Tell me about the ProtecT trial
J Athene Lane Lancet Oncology 2014
Aim: Investigate the effectiveness of treatments for localized prostate cancer
N 1600 Localized prostate cancer. Randomized to: - Active monitoring - RT - Surgery
RESULTS:
230 000 invited, 100 000attended initial appointment
82% (82500) had PSA test
8500 patients with PSA 3-20, 87% of these (7400) underwent biopsies.
2900 man diagnosed with prostate cancer (4 of tested men, 40% of those who had a biopsy)
What is RTOG 96-01 about?
Phase 3 trial to compare antiandrogen therapy and Salvage RT to placebo and SRT
2 arms:
- bicalutamide 150 mg/day + SRT
- placebo + SRT
Addition of 24m of Bcalutamide during and after RT significantly improved freedom from PSA progression from 40% to 57% and also reduced incidence of mets from 12.5% o 7.5%
