Prostate Cancer Flashcards
MOA:
Leuprolide
Goserelin
GnRH agonist
Increase LH release
MOA:
Degarelix
Abarelix
GnRH Antagonist
MOA:
Abiraterone
Ketoconazole
Androgen Synthesis Inhibitors (Adrenal)
Ketoconazole: CYP 17, 11B hydroxylase
Abiraterone: CYP 17
MOA:
Bicalutamide
Flutamide
Nilutamide
1st Gen Anti-Androgen
decreases binding at AR
MOA:
Enzalutamide
Apalutamide
Darolutamide
2nd Gen Anti-Androgen
decreases binding at AR, decreases nuclear translocation and transcription
MOA:
Docetaxel
Cabazitaxel
Chemotherapy
microtubule disruption
MOA:
Mitoxantrone
Chemotherapy
Topoisomerase II inhibition
MOA:
Olaparib
Rucaparib
PARP inhibitor
BRCA 1/2 mutations, other HRR mutations
MOA:
Sipuleucel-T
Immunotherapy
Target cells displaying PAP-GMCSF
MOA:
Pembrolizumab
Immunotherapy
Anti-PD1
PLCO Trial
- RCT - Screening trial
- Prostate, lung, colorectal, ovarian screening = PLCO
- No difference in prostate cancer specific mortality with yearly PSA screening vs. no screening
- Criticism = contamination (there was a LOT of screening and even previous biopsy in the control arm as well)
MOA:
Denosumab
Zoledronic acid
Bone Protecting Agents
Decrease osteoclast activity
MOA:
Radium-223
Alpha particle creating double strand breaks in DNA
Treatment options:
Low Risk Prostate Cancer
AS Cryo (HIFU) RP (no LND) XRT (prostate +/- SV) Brachy monotherapy
Treatment options:
Favorable Intermediate Risk Prostate Cancer
AS Cryo (HIFU) RP (no LND) XRT (prostate +/- SV +/- LN) +/- 4-6 months ADT Brachy +/- XRT
Treatment options:
Unfavorable Intermediate Risk Prostate Cancer
(AS)
RP + LND
XRT (prostate + SV + LN) + 4-6m ADT
Brachy + XRT +/- 4-6m ADT
Treatment options:
High Risk Prostate Cancer
RP + LND
XRT (prostate + SV + LN) + 2-3y ADT
Brachy + XRT + 1-3y ADT
Treatment Options:
N1M0 Prostate Cancer
WW ADT immediately (alone; intermittent or continuous) RP + LND + XRT + long term ADT XRT (prostate + SV+ LN) + long term ADT
Definition:
Low Volume Metastatic Burden in Prostate Cancer
No visceral mets
Any # nodal mets
Bone mets confined to vertebral bodies/pelvis
Definition:
High Volume Metastatic Burden in Prostate Cancer
At least 1 visceral (non-nodal) met
>= 4 bone mets with at least one bone met outside of vertebral column/pelvis
ERSPC Trial
ERSPC = European Randomized Study for the Screening of Prostate Cancer
- RCT, 162k men age 55-69, PSA checked every 4 years
- Primary outcome = prostate cancer specific mortality (1 death fewer per every 1,000 men screened)
Urine Biomarkers
PCA3
Select MDx
MiPS
Tissue Biomarkers
OncotypeDx
ConfirmMDx
Prolaris
Decipher
Serum Biomarkers
PHI
4K score
CAP/ProtecT trial
- 415k men randomized to one single PSA vs no PSA at 50-69 years
- 10 years follow up
1. More cancer in intervention arm
2. No difference in cancer mortality
3. No difference in survival - -> Single PSA test not recommended for population screening
Important AEs
Abiraterone
Glucocorticoid deficiency, increased mineralocorticoid production
Give with steroids
Important AEs:
Enzalutamide
Seizures, falls, HTN, hallucination, CV, mental
AUA Guideline Statement for screening in men >70 in excellent health
- Higher threshold for biopsy (>10 ng/mL)
- Stop screening if PSA <3ng/mL
Important AEs:
Apalutamide
rash, hypothryoidism, falls/fractures, seizures, CV
Important AEs:
Ketoconazole
Decreased androgen, glucocorticoid and mineralocorticoid synthesis
Hepatotoxicity, N/V
Important AEs:
Docetaxel, Cabazitaxel
BM suppression, neutropenia
How do tumor look on multiparametric MRI?
T1/T2?
DWI?
DCE?
- T1 + T2: Water content – tumors are water poor/dark on T2
- Diffusion‐weighted images (DWI): Water diffusion – tumors are dense/dark
- Dynamic contrast enhanced images (DCE): Contrast flow – vascularity, tumors are bright
Important AEs:
Zoledronic Acid, Denosumab
Osteonecrosis of the jaw
PROMIS Trial
- 576 Men
• MRI, TRUS‐bx and Saturation transperineal bx
• Avoid 27% of the biopsies if negative MRI
• MRI guidance ‐ found 18% more cases of significant cancers
Important AEs:
Olaparib
Anemia, fatigue, anorexia, diarrhea, cough, dyspnea, thrombocytopenia, AKI
Definition:
Castration
Bilateral Orchiectomy
LHRH Agonist
GnRH Antagonist
Goal Testosterone <50 ng/dL
Definition:
Biochemical Recurrence after RP
Undetectable PSA after surgery –> 2+ increases above threshold 0.2 ng/dL
PRECISION trial
- 500 men randomized to MRI vs. standard biopsy
Clinically Significant Cancer (GS ≥ 3+4): More found in MRI targeted group
Clinically Indolent Cancer: More found in standard biopsy group
28% in MRI group could avoid a biopsy
Definition:
Biochemical Recurrence after RT
PSA increase by >= 2ng/mL above nadir
Treatment Options:
M1 CSPC
ADT + Abiraterone/prednisone Docetaxel (high volume) Apalutamide Enzalutamide EBRT (low volume)
Treatment Options:
M1 CRPC
ADT+ Abiraterone/prednisone Docetaxel Enzalutamide Radium 223 Mitoxantrone Sipuleucel T Pembrolizumab
Treatment Options:
M0 CRPC
Ensure castrate levels of testosterone
If PSADT >10m (long): may be able to monitor
If PSADT <10m (short): Enzalutamide, apalutamide, darolutamide
AUA vs. NCCN Risk Stratification Table
Prostate Cancer Staging
SPCG-4 Trial
- Swedish trial, mostly healthy younger patients with intermediate or higher risk disease, followed for 23 years
- Surgery (RP) vs. watchful waiting
- Improved overall and disease specific survival in RP group compared to observation
PIVOT Trial
- Mixed risk disease, older sicker VA patients
- Underpowered*
- Surgery (RP) vs. watchful waiting
- No survival advantage in surgery group
- BUT surgery reduced the risk of metastases (p=0.0001) among men with Gleason score ≥ 7 tumors
CHAARTED Trial
M1 CSPC
ADT + Docetaxel
- 790 men with mHSPC randomized to ADT +/‐ docetaxel
- Improved OS (57.6 mo vs 44 mo)
- Improved PFS and rate of PSA <0.2
- Significant improvement in high‐volume disease
- At long term follow up, even greater OS benefit, especially in high volume disease
STAMPEDE Trial
M1 CSPC
ADT + Docetaxel
- Long term follow up
- Improved OS (43.1 mo vs 59.1 mo)
- No difference in low vs high volume disease
ADT + Abiraterone
-37% relative improvement in survival (HR 0.63) at 40 month follow up
ADT + Prostate EBRT
- 2061 men randomized to ADT v ADT plus EBRT to primary tumor
- Median OS 48m (EBRT) vs 46m (control)
- In all pts: HR 0.92, p 0.266
- In low met burden: HR 0.68, p 0.007
PROTECT Trial
- Mostly low risk disease
- Surgery (RP) vs. Radiation (RT) vs. Active Surveillance (AS)
- No differences in overall or disease specific survival between groups
‐ RP and RT were better than AS for Clinical progression (p<0.001) and Metastatic disease (p=0.004)
LATITUDE Trial
M1 CSPC
- 1199 patients receive ADT +/‐ abiraterone acetate + prednisone
- 50% symptomatic at baseline
- Needed 2of 3 high risk features (Gleason >=8, >=3 bone lesions, visceral mets)
- Improved OS and radiographic PFS
ENZAMET Trial
M1 CSPC
ADT + Enzalutamide
- Compared ADT + enzalutamide with standard of care (ADT+ bicalutamide, nilutamide, flutamide, docetaxel)
- Improved OS (HR 0.67)
- More AEs in enzalutamide group
TITAN Trial
M1 CSPC
ADT + Apalutamide
-HR 0.67
Adjuvant vs. salvage XRT after RP
Adjuvant • pT3 pathology • Positive margin • No BCR • Consider genomic testing
Salvage
• PSA recurrence
• Low pretreatment PSA and long PSADT better
• Give with ADT
Trials: Salvage RT + ADT
GETUG 16 • 743 Patients with PSA failure after RP – PSA between 0.2 and 2 ng/mL • RT vs RT plus 6 months ADT • Improved progression free survival
RTOG 9601
• 760 Men with PSA failure after RP
• RT vs RT plus bicalutamide
• Improved overall survival
Biochemical Recurrence after Prostatectomy
- Undetectable PSA after surgery with a subsequent increases on
2 or more determinations above threshold of 0.2 ng/mL
Biochemical Recurrence after RT Treatment
– RTOG‐ASTRO Phoenix Consensus: PSA increase by > 2 ng/mL
above the nadir
– Consider earlier evaluation in candidates for salvage local
therapy (young, healthy)
Definition: CRPC
Testosterone <50 ng/dL AND
New radiographic or clinical mets on ADT OR
PSA greater than 2ng/mL and rising
SPARTAN Trial
M0 CRPC
PSADT <= 10m
ADT + Apalutamide (vs. ADT + placebo)
-Improved MFS (40.5 mo vs 16.2 mo)
PROSPER Trial
M0 CRPC
PSADT <= 10 mo
ADT + Enzalutamide (vs ADT + placebo)
-Improved MFS (36.6 mo vs 14.7 mo)
M1 CRPC ADT + Abiraterone Trials
• COU‐AA‐301 – ADT + Abiraterone
– Prior docetaxel
• COU‐AA‐302 – ADT + Abiraterone
– No prior docetaxel/chemotherapy naive
Addition of abiraterone: time to PSA progression and progression free survival both better in Abiraterone groups
M1 CRPC ADT + Enzalutamide Trials
AFFIRM – ADT + Enzalutamide
– Prior docetaxel
• PREVAIL – ADT + Enzalutamide
– No prior docetaxel/chemotherapy naive
Addition of enzalutamide better for overall survival
Chemotherapy Drugs for M1 CRPC
- Docetaxel (TAX 327, SWOG 9916): OS improved
- Cabazitaxel (TROPIC, FIRSTANA) - FDA approved after Docetaxel, OS improved
• Mitoxantrone (CALGB 9182)
– Currently limited role in mCRPC
ARAMIS Trial
M0 CRPC
PSADT <= 10 mo
ADT + Darolutamide (vs ADT + placebo)
-Improved MFS (40.4 mo vs 18.4 mo)
IMPACT Trial
M1 CRPC Immunotherapy with Sipuleucel-T
- Improved OS
- No difference in PFS
- No PSA decline
PROFOUND Trial
PARP Inhibitor: Olaparib
mCRPC
– Patient who progressed on enzalutamide or abiraterone
– >/= 1 homologous recomb. repair gene mutated
Improved PFS and OS
SE: anemia, fatigue, anorexia, diarrhea, cough, dyspnea, thrombocytopenia, AKI
TRITON2 Trial
PARP Inhibitor: Rucaparib
Phase 2 trial, mCRPC
>/=1 somatic or germline mutation
– Progressed on prior AR‐therapy and taxane
Most notable response rates (ORR/PSA) for BRCA1/BRCA2 mutations
• Accelerated FDA approval
