HORMONE SENSITIVE/HORMONE RESISTANT

PROSTATE CANCER

Daniel H Shevrin, MDHematology/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

10,000,000 men at risk

Death34,000

CRPC

FailLocal

Treatment(30%)

ABIChemo

MDV-3100

HormonalManagement

Local Therapy

Incidence240,000

Loca

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3-5

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5-10 years

Androgen Ablation

Endocrine Axis in Prostate Cancer

Orchiectomy

GnRH agonist

Adrenal Blockade

Tumor AndrogensAntiandrogens

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, NON-METASTATIC

• 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, NON-METASTATIC

• 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) Serum testosterone levelb) Calculate PSA doubling timeC) Bone scand) CT ab/pelvis/CXRe) 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) Continued monitoring with PSA q 3 monthsb) Repeat XRT to prostatec) LHRH agonist given continuously or intermittentlyd) Taxotere chemotherapye) 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 chemotherapyb) Add casodex 50 mg/dc)Zytigad)Provengee) Start zometa or xgevaf) 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 antiandrogenb) Ketoconazolec) Provenged) Taxotere chemotherapye)Zytigaf) b or c (correct)

• The pt undergoes treatment with Provenge which is well-tolerated. 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 hydrob) XRT to L-spinec)Taxotered)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 Taxotereb) Jevtana (Cabazitaxel)c)Zytiga (Abiraterone)d)Investigational druge)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