Download hormone sensitive/ hormone refractory prostate cancer

HORMONE SENSITIVE/
HORMONE RESISTANT
PROSTATE CANCER
Daniel H Shevrin, MD
Hematology/Oncology
Northshore University HealthSystem
DISCLOSURES
• Consultant: Astella, Novartis, Astra Zeneca,
Orion
• Speakers Bureau: Novartis, Sanofi-Aventis
• Grant/Research Support: Genentech, GSK,
NIH, DOD, ECOG
ADVANCED/RECURRENT PROSTATE
CANCER - 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
• Immune therapy (Provenge) has a role
• Taxotere plays major role in symptomatic disease
• New therapies becoming available after Taxotere
progression
ABI
Chemo
MDV-3100
Death
34,000
CRPC
Hormonal
Management
Fail
Local
Treatment
(30%)
Local Therapy
Incidence
240,000
10,000,000 men at risk
Androgen Ablation
Endocrine Axis in Prostate Cancer
GnRH agonist
Adrenal Blockade
Antiandrogens
Orchiectomy
Tumor Androgens
ANDROGEN ABLATION – FIRST LINE TREATMENT
• Surgical orchiectomy
• LHRH agonist
– Lupron
– Zoladex
– Casodex used first month to prevent flare
– Casodex can be used as combined therapy
• LHRH antagonist - Degaralix (Firmagon)
– No flare
ANDROGEN ABLATION – SECOND LINE
TREATMENT
• Anti-androgens
– Casodex®
– Flutamide®
– Nilutamide®
• Anti-androgen withdrawal
• Ketoconazole
• 17,20-lyase inhibitors (Zytiga, TAK-700)
Ketoconazole
• Inhibits cytochrome P-450 enzymes
– Blocks testicular and adrenal androgenesis
• 200 - 400 mg TID
– Acid environment improves absorption
– Replacement hydrocortisone required
• PSA response rate  40%
• Nausea, LFT abnormalities, rash (rare)
• Drug interactions – statins, coumadin, BP meds
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
SIDE-EFFECTS OF AAT
•
•
•
•
•
•
•
•
Hot flashes – effexor, megace
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
Intermittent vs. Continuous
– Fixed on-phase (6-8 months) of ADT
– Variable off-phase depends on recovery of testosterone
and biologic behavior of cancer
– Must monitor T and PSA levels and clinical status
– Data for less bone density loss
– Suggestion of improved sexual function and QOL
– Intermittent therapy better tolerated and not associated
with worse outcome
– Intermittent therapy is a reasonable option for patients
requiring androgen deprivation
HORMONE-RESISTANT PC
• The androgen receptor remains critical even in
the hormone-resistant state
– Some cells can grow even with exceedingly low
levels of Testosterone
– Various mechanisms to achieve this (see diagram)
• Treatment goal is to further target AR by
depriving it of as much T as possible
.
Scher H I et al. JCO 2008;26:1148-1159
©2008 by American Society of Clinical Oncology
CASTRATE-SENSITIVE, NONMETASTATIC
• 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
CASTRATE-SENSITIVE, METASTATIC
• 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-RESISTANT, NONMETASTATIC
• 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/Zytiga
Castrate Resistant, Metastatic
(Pre-Taxotere)
• Good prognosis (asymptomatic, “low
volume”)
– Standard Taxotere® chemotherapy
– Antiandrogens, ketoconazole/Zytiga
– Immunotherapy (Provenge, sipuleucel-T)
– Investigational therapies
• Poor prognosis (symptomatic, aggressive)
– Standard Taxotere® chemotherapy
– Investigational chemotherapy combinations
CASTRATE-RESISTANT, METASTATIC
(Post-Taxotere)
•
•
•
•
Jevtana (Cabazitaxel) – FDA approved
Zytiga (Abiraterone) – FDA approved
MDV3100
Other emerging drugs
APPENDICULAR AND AXIAL METASTASIS
Bone Metastases Can Have Serious Consequences
The Cycle of Bone Destruction:
Osteoblastic Effects
SKELETAL RELATED EVENTS
• SRE
– Fracture, need for XRT, cord compression, pain, hypercalcemia
• Zometa (Zoledronic acid)
–
–
–
–
Potent bisphosphonate given IV every 3-4 weeks
Inhibits osteoclasts
35% reduction in SREs, postponement to time to first SRE
Side-effects (nephrotoxicity, ONJ, flu-like symptoms)
• Xgeva (Denosumab)
– Rank ligand inhibitor (osteoclast inhibitor) given SQ every 3-4 weeks
– Slightly better reduction in SREs and time to first SRE than zometa
– Side-effects (hypocalcemia, ONJ)
• Both FDA-approved for castrate-resistant, bone mets
• ASCO – no superiority of either drug
THANK YOU!
PATIENT CASE
• A 68 yo man had T3, PSA 15, grade 8 cancer and underwent
XRT and 2 years ADT with PSA going to undetectable. One
year after completing ADT, his PSA begins to rise and reaches
2.5 ng/dL in 12 months. He is anxious but asymptomatic.
• What term is used to describe his prostate cancer?
– What assessment should be done?
a)
b)
C)
d)
e)
Serum testosterone level
Calculate PSA doubling time
Bone scan
CT ab/pelvis/CXR
All the above (correct answer)
• Testosterone level is normal at 190. PSADT is ~6
months. Bone scan and CT scans do not show
obvious mets.
– What are the correct treatment options?
a)
b)
c)
d)
e)
Continued monitoring with PSA q 3 months
Repeat XRT to prostate
LHRH agonist given continuously or intermittently
Taxotere chemotherapy
Casodex alone
• Lupron is started every 3 months. PSA falls to 0.4 after 6 months
but then rises to 5.5 over next 9 months. Repeat bone scan shows 4
new osseous lesions in the pelvis and spine c/w mets. CT shows
enlarged pelvic nodes. He remains asymptomatic other than hot
flashes.
• What term is used to describe his prostate cancer?
– What are the correct treatment options?
a) Taxotere chemotherapy
b) Add casodex 50 mg/d
c)Zytiga
d)Provenge
e) Start zometa or xgeva
f) b and e (correct)
• Casodex is added to Lupron. Zometa is started monthly.
PSA continues to rise. He reports mild low back pain
relieved with advil.
– What are the correct treatment options?
a) Another antiandrogen
b) Ketoconazole
c) Provenge
d) Taxotere chemotherapy
e)Zytiga
f) b or c (correct)
• The pt undergoes treatment with Provenge which is welltolerated. His PSA continues to rise rapidly. His back pain
worsens and is requiring hydrocodone for relief. Scans
show 4 new osseous lesions and larger nodes. CT shows
new left hydronephrosis.
– What are the correct treatment options?
a) Referral to Urologist for management of hydro
b) XRT to L-spine
c)Taxotere
d)All the above (correct)
• Urologist stents left ureter. He receives XRT to L-spine
with good palliation of pain. He is then treated with
Taxotere for 8 cycles with a 50% drop in his PSA.
Treatment stopped due to worsening fatigue. His PSA
begins to increase within the next 6-7 months. Repeat
scans show 3 new bone lesions.
– What are the correct treatment options?
a) Repeat Taxotere
b) Jevtana (Cabazitaxel)
c)Zytiga (Abiraterone)
d)Investigational drug
e)All the above (correct answer)
DISCLOSURES
• Consultant: Astella, Novartis, Astra Zeneca,
Orion
• Speakers Bureau: Novartis, Sanofi-Aventis
• Grant/Research Support: Genentech, GSK,
NIH, DOD, ECOG