Chemotherapy in Hormone Refractory Prostate Cancer

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Chemotherapy in Hormone Refractory Prostate Cancer
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Adenocarcinoma of the Prostate

• Most common cancer in men (excluding skin cancer)
• 220,900 men diagnosed in 2003 with 28,900 deaths
• Second leading cause of cancer mortality in men
• Median age at diagnosis 65 years
• Heterogeneous tumor, clinical course can vary
  from aggressive to indolent

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Metastatic Prostate Cancer

• Major sites of metastatic disease are bone and
  pelvic lymph nodes
• Primary treatment is androgen ablation
• Orchiectomy
• LHRH agonists
• 80-90 response rate
• Response duration 12-18 months

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Hormone Refractory Prostate Cancer

• Median survival approximately 1 year
• Treatment options
• Secondary hormonal manipulation
• Anti-androgen withdrawal
• Chemotherapy

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Secondary Hormonal Manipulation

• Addition of steroidal or non-steroidal
  anti-androgens to primary androgen blockade
• Change anti-androgen
• Ketoconazole
• Corticosteroids
• Response rates average 20 with response
  durations of 2-3 months

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Anti-Androgen Withdrawal

• Response rates 20
• Response duration 4-6 months

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Eligibility/Response Assessment in Hormone
Refractory Prostate Cancer Trials

• Difficult to assess response in prostate cancer
• 70-80 of patients with metastatic disease have
  disease limited to bone
• Bone scans difficult to assess response
• Serum PSA, clinical benefit (improvement in pain
  or decreased analgesic use) often used to measure
  response

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• PSA 34 kD glycoprotein found in normal and
  neoplastic prostate tissue and seminal fluid
• Elevated in 95 of patients with advanced
  prostate cancer
• Changes in PSA often precede changes in bone scan
  or measurable disease
• Some studies have shown a correlation in gt50
  decrease in PSA with prolonged survival

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Recommendations Prostate-Specific Antigen
Working Group for Hormone Refractory Prostate
Cancer Clinical Trials

• Eligibility Criteria
• Progressive measurable disease
• Bone scan progression
• PSA progression
• 2 consecutive increases in PSA
• PSA gt 5ng/ml
• Continued elevation of PSA 4-6 weeks after
  cessation of anti-androgen treatment
• Continued androgen suppression

Bubley, G.J, et al, JCO, 17(11), 1999, 3461
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• Response Criteria
• Objective response
• PSA response decrease in PSA of gt50 which is
  confirmed by a second PSA 4 weeks later and no
  evidence of measurable disease progression
• Progressive Disease
• Measurable disease
• Bone scan progression
• PSA progression
• 25 increase over baseline (if no response)
• 50 increase over nadir (if response)

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Phase 2 Trials
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Phase 3 Trials

• Mitoxantrone Steroid vs. Steroid (3 trials)
• Vinblastine Estramustine vs. Vinblastine
• Suramin Hydrocortisone vs. Hydrocortisone
• Docetaxel Estramustine vs. Mitoxantrone
  Prednisone
• Docetaxel Prednisone vs. Mitoxantrone
  Prednisone

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Mitoxantrone Hydrocortisone (CALGB 9182)

• 242 patients with metastatic disease
• Treatment
• A Mitoxantrone (14mg/m2 q 3weeks)
  Hydrocortisone (30mg am, 10mg pm)
• B Hydrocortisone (30mg am, 10mg pm)
• Primary end-point survival duration
• No cross-over permitted

Kantoff, P.W., JCO, 17(8) 1999, 2506.
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Median survival M H 12.3 months H 12.6
months
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Median time to progression M H 3.7
months H 2.3 months
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PSA Response
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Survival by PSA Reduction
Median Survival gt50 decrease in PSA 20.5
months lt50 decrease in PSA 10.2
months
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Mitoxantrone Prednisone(Canadian)

• 161 patients with symptomatic metastatic disease
• Treatment
• A Mitoxantrone (12mg/m2 q 3 weeks) Prednisone
  (5mg BID)
• B Prednisone 5mg BID
• Primary end-point reduction in pain intensity
  scale
• Secondary end-point 50 reduction in analgesic
  score
• Cross over permitted

Tannock, I.F., JCO 14(6), 1996, 1756.
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Results
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No significant difference in overall survival
PSA Response (P0.11)
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Vinblastine Estramustine vs. Vinblastine

• 193 patients with metastatic disease
• Treatment
• A Vinblastine (4mg/m2 weekly for 6 of 8 weeks)
  Estramustine (600mg/m2 PO days 1-42 of 8 week
  cycle)
• B Vinblastine (4mg/m2 weekly for 6 of 8 weeks)
• Primary end-point overall survival

Hudes, G., et al., JCO 17(10), 1999, 3160.
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Survival Update (ASCO 2003) Median Survival V
9.4 months V EM 12.5
months (P0.051)
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Disease Progression
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PSA Response
(P0.0001)
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Toxicity

• Neutropenia (grade 3/4)
• V 27
• V EM 8
• Nausea
• V 7
• V EM 27
• Edema
• V 3
• V EM 11
• DVT 3 patients (V EM)
• Neuropathy (gt grade 2) 11-12 both arms
• CHF
• V 1 patient
• V EM 3 patients

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Docetaxel/Estramustine vs. Mitoxantrone/Prednisone
(SWOG99-16)

• 770 patients with progressive hormone refractory
  prostate cancer
• Treatment
• A Docetaxel 60mg/m2 D2 Estramustine 280mg D1-5
  q 3weeks (decadron 20mg TID x 3 doses)
• Protocol amended coumadin 2mg qday ASA 325mg
  qday
• B Mitoxantrone 12mg/m2 D1 q 3weeks Prednisone
  5mg BID
• Primary end-point overall survival

Petrylak, D.P., et al, ASCO abst. 3, 2004
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Results

• Median survival
• D E 18 months
• M P 16 months (P0.01)
• Median time to disease progression
• D E 6 months
• M P 3 months (Plt0.0001)
• PSA response
• D E 50
• M P 27 (Plt0.0001)
• Objective response
• D E 17
• M P 11 (P0.15)

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Toxicity
No significant difference in toxic deaths D E
patients Decrease in cardiac ischemic events
with anticoagulation No difference in rates of
DVT with anitcoagulation Increased bleeding
events in patients not receiving anticoagulation
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Docetaxel Prednisone vs. Mitoxantrone
Prednisone

• 1006 patients with metastatic hormone refractory
  prostate cancer
• Treatment
• A Docetaxel 75mg/m2 q 3weeks x 10 cycles
  Prednisone 5mg BID
• B Docetaxel 30 mg/m2/week for 5 of 6 weeks x 5
  cycles Prednisone 5mg BID
• C Mitoxantrone 12 mg/m2 q 3weeks x 10 cycles
  Prednisone 5mg BID
• Primary end-point survival

Eisenberger, M.A., et al, ASCO abst. 4, 2004
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Results
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Toxicity

• Neutropenia (grade 3/4)
• A 32
• B 1.5
• C 21.7
• Similar results for other toxicities reported

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Conclusions

• Goal of chemotherapy for hormone refractory
  prostate cancer mainly to relieve symptoms
• Modest survival advantages have now been shown
  with some regiments