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Treatment Options for Docetaxel refractory patients. Winston W Tan MD FACP Senior Consultant Hematology/Oncology Genitourinary Oncology Mayo Clinic College of Medicine. Learning Objectives.

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treatment options for docetaxel refractory patients
Treatment Options for Docetaxel refractory patients

Winston W Tan MD FACP

Senior Consultant Hematology/Oncology

Genitourinary Oncology

Mayo Clinic College of Medicine

learning objectives
Learning Objectives
  • Describe the mechanisms by which androgen receptor signaling affects prostate cancer growth despite castrate levels of testosterone
  • Summarize therapeutic options for castration-resistant prostate cancer (CRPC), including the role of chemotherapy, and emerging therapies
  • Apply clinical evidence for best treatment strategies in CRPC to improve patient care
slide3
S9364: Nadir PSA Level Predicts Survival in Patients With Metastatic Disease Treated With Primary ADT

Hussain M, et al. J Clin Oncol. 2006;24:3984-3990; with permission.

crpc evolving paradigm
CRPC: Evolving Paradigm
  • Androgen receptor (AR) signaling is a key factor in prostate cancer growth despite castrate serum levels of testosterone
    • Caused by a number of different factors:
      • Receptor overexpression/amplification
      • AR mutations
      • Increased AR ligand expression
      • AR coactivators
      • Ligand-independent AR activation
  • AR signaling leads to tumor growth and proliferation despite castrate androgen levels

Gelmann EP. J Clin Oncol. 2002;20:3001-3015.

crpc evolving paradigm5
CRPC: Evolving Paradigm
  • CRPC: A working definition
    • Evidence of PSA and/or radiographic disease progression in the setting of castrate levels of testosterone (≤50 ng/dL)
chemotherapy for aipc
Chemotherapy for AIPC
  • Mitoxantrone combined with prednisone is palliative with a median survival of 10-12 months
  • Phase I/II studies show a trend towards improved median survival with the combination of Estramustine/Docetaxel

>Time to progression 5-6 months

>Median survival 20-23 months

Petrylak et al. Semin Onc. 1999; 26(Suppl 17):28-33. Savarese et al. JCO. 2001;19:2509-2516. Petrylak et al. Eur Urol Suppl. 2002;1:15-23.

management of metastatic crpc chemotherapy
Management of Metastatic CRPC: Chemotherapy
  • The standard of care for CRPC changed from mitoxantrone/prednisone to docetaxel/prednisone based on SWOG 99-16 and TAX-327 studies1,2

- Prednisone 10 mg QD

- Mitoxantrone 12 mg/m2 every 3 wks;

every 21 days up to 10 cycles

TAX-3272

  • Prednisone 10 mg QD
  • Docetaxel 30 mg/m2 weekly;
  • 5 wks on, 1 wk off × 6 cycles

Randomized

N=1006

  • Prednisone 10 mg QD
  • Docetaxel 75 mg/m2 every 3 wks

SWOG 99-161

- Mitoxantrone 12 mg/m2; Day 1

- Prednisone 5 mg BID; 21-day cycles

Randomized

N=770

- Docetaxel 60 mg/m2 ; Day 2 + dexamethasone 20 mg TID; Days 1–2

- Estramustine 280 mg TID;Days 1–5 of 21-day cycles

1. Petrylak DP, et al. N Engl J Med. 2004;351:1513-1520.

2. Tannock TF, et al. N Engl J Med. 2004;351:1502-1512.

management of metastatic crpc chemotherapy8
Management of Metastatic CRPC: Chemotherapy
  • SWOG 99-16
    • Docetaxel/estramustine improved median survival by 2 months compared with mitoxantrone/prednisone

HR: 0.80

Petrylak DP, et al. N Engl J Med. 2004;351:1513-1520; with permission.

management of metastatic crpc chemotherapy tax 327
Management of Metastatic CRPC: Chemotherapy (TAX-327)
  • Docetaxel therapy led to improved survival and rates of response in terms of pain, PSA level, and quality of life compared with mitoxantrone/prednisone

HR: 0.83, P=0.03

Tannock TF, et al. N Engl J Med. 2004;351:1502-1512; with permission.

management of metastatic crpc chemotherapy10
Management of Metastatic CRPC: Chemotherapy
  • Long-term follow-up of TAX-327:
    • 310 additional deaths at 5 years

D3P=docetaxel every 3 weeks; D1P=weekly docetaxel; M+P=mitoxantrone/prednisone therapy.

Berthold DR, et al. J Clin Oncol. 2008;26:242-245.

ar targeting therapies abiraterone acetate
AR-Targeting Therapies: Abiraterone Acetate

ECOG PS, Eastern Cooperative Oncology Group Performance Status

  • Ryan C, et al. J Clin Oncol. 2009;27(suppl):245s (abstract 5046).
  • Reid AH, et al. J Clin Oncol. 2009;27(suppl):246s (abstract 5047).
  • 3. Danila DC, et al. J Clin Oncol. 2009;27(suppl):246s (abstract 5048).

Inhibits the CYP 17 (17α-hydroxylase and C17,20-lyase) dual enzyme complex, which is principally responsible for androgen synthesis

Results in PSA decline, tumor response, and improvements in ECOG performance scores

ar targeting therapies mdv3100
AR-Targeting Therapies: MDV3100
  • Novel small-molecule AR antagonist
  • Binds the AR with greater relative affinity than the clinically used antiandrogen bicalutamide
  • Reduces the efficiency of its nuclear translocation and impairs both DNA binding to androgen response elements and recruitment of coactivators
  • Results of recent phase I/II study:
    • PSA declines of >50% observed in 43% of CRPC patients
  • Phase III trial in the post-docetaxel setting ongoing

Scher HI, et al. Lancet Oncology. 2010;375:1437-1446.

ar targeting therapies bms 641988
AR-Targeting Therapies: BMS-641988

1. Attar RM, et al. Proc Amer Assoc Cancer Res. 2006;47:Abstract 5345.2. Clinical Trials.gov. www.clinicaltrials.gov/ct2/show/NCT00326586.3. Clinical Trials.gov. www.clinicaltrials.gov/ct2/show/NCT00644488.

  • Hypothesized to slow growth of prostate cancer by blocking action of androgens
  • Found to have superior potency and efficacy compared with bicalutamide1
  • Found to promote an expressionprofile more similar to castration than bicalutamide1
  • Awaiting data from 2 completed Phase I trials for CRPC
    • Randomized multicenter dose-escalation study (United States)2
    • Nonrandomized multicenter, open-label study (Japan)3
management of metastatic crpc docetaxel refractory patients
Management of Metastatic CRPC: Docetaxel-Refractory Patients
  • No standard of care
  • Salvage chemotherapeutic regimens include:
    • Mitoxantrone and/or ixabepilone plus prednisone1-3
    • Carboplatin plus docetaxel4,5

1. Thomas C, et al. Urologe A. 2009;48:1070-1074.

2. Rosenberg JE, et al. Cancer. 2007;110:566-563.

3. Rosenberg JE, et al. J Clin Oncol. 2009;27:2772-2778.

4. Reuter CW, et al. World J Urol. 2010;Mar 14 [Epub ahead of print]

5. Ross RW, et al. Cancer. 2008;112:521-526.

management of metastatic crpc docetaxel refractory patients15
Management of Metastatic CRPC: Docetaxel-Refractory Patients
  • Mitoxantrone or ixabepilone plus prednisone

MP=mitoxantrone/prednisone.

Rosenberg JE, et al. Cancer. 2007;110:566-563; with permission.

management of metastatic crpc docetaxel refractory patients16
Management of Metastatic CRPC: Docetaxel-Refractory Patients
  • Carboplatin/docetaxel therapy
    • Recent data suggest that platinum salts may be effective when combined with taxanes (docetaxel)

Progression-free survival

Overall survival

Ross RW, et al. Cancer. 2008;112:521-526; with permission.

management of metastatic crpc docetaxel refractory patients17
Management of Metastatic CRPC: Docetaxel-Refractory Patients
  • Cabazitaxel
    • Novel taxane that appears to be active in docetaxel-resistant tumor cell lines
    • Evaluated in the phase III TROPIC study
      • Median survival cabazitaxel treatment group vs mitoxantrone treatment group
      • Improved progression-free survival and tumor response rates

Sartor AO, et al. [Abstract No. 9]. 2010 Genitourinary Cancers Symposium; San Francisco, CA.

tropic phase iii registration study
TROPIC: Phase III Registration Study

mCRPC patients who progressed during and after treatment with a docetaxel-based regimen

(N=755)

Stratification factors

ECOG PS (0, 1 vs. 2) • Measurable vs non-measurable disease

cabazitaxel 25 mg/m² q 3 wk + prednisone* for 10 cycles

(n=378)

mitoxantrone 12 mg/m² q 3 wk+ prednisone* for 10 cycles

(n=377)

*Oral prednisone/prednisolone: 10 mg daily.

Inclusion: Patients with measurable disease must have progressed by RECIST; otherwise must have had new lesions or PSA progression

Primary endpoint: OS

Secondary endpoints: Progression-freesurvival (PFS), response rate, and safety

Sartor AO, et al. Presented at the 2010 Genitourinary Cancers Symposium. March 5-7, 2010; San Francisco, CA.

tropic primary endpoint overall survival intent to treat analysis
TROPIC Primary Endpoint: Overall Survival (Intent-to-Treat Analysis)

Proportionof OS (%)

CBZP

MP

Median OS (months)

12.7

15.1

Hazard Ratio

0.70

95% CI

0.59–0.83

P Value

<.0001

Numberat risk

MP377 300 188 67 11 1

CBZP378 321 231 90 28 4

Approved by FDA: June 2010

Sartor AO, et al. Presented at the 2010 Genitourinary Cancers Symposium. March 5-7, 2010; San Francisco, CA.

management of crpc docetaxel refractory patients
Management of CRPC: Docetaxel-Refractory Patients
  • Conclusions from the TROPIC trial
    • Cabazitaxel demonstrated a statistically and clinically significant overall survival improvement compared with mitoxantrone
      • 30% risk reduction of death (HR = 0.70, P<.0001)
      • Median overall survival improvement in favor of cabazitaxel
        • Benefit was consistent across subgroups
    • Progression-free survival, relative risk, and time to progression were also significantly improved
    • Safety profile was predictable and manageable
      • Neutropenia, diarrhea, fatigue and asthenia were the most common adverse events

Sartor AO, et al. Presented at the 2010 Genitourinary Cancers Symposium. March 5-7, 2010; San Francisco, CA.

docetaxel in novel combination regimens for hrpc
Docetaxel in Novel Combination Regimens for HRPC
  • Docetaxel + Thalidomide
  • Docetaxel + Calcitriol (Vitamin D)
  • Docetaxel / Estramustine + Herceptin
  • Docetaxel + Exisulind
satraplatin
Satraplatin
  • Second line
  • 950 patients
  • Satraplatin/prednisone vs prednisone
  • 40% decrease in TTP
  • 9.7 vs 11 weeks TTP
  • Petrylak et al ASCO (prostate) 2007
satraplatin23
Satraplatin
  • Satraplatin is an orally active platinum compound that has significant activity in cisplatin-resistant tumor models. Activity in prostate cancer was suggested in early clinical studies .
  • Satraplatin was evaluated more extensively in a phase III trial, in which 950 men who had progressed after first-line chemotherapy for castrate-resistant prostate cancer (51 percent of whom had been treated with docetaxel) were randomly assigned to prednisone plus either satraplatin (80 mg/m2 for five days every five weeks) or placebo . Final results of this trial were presented at the American Society of Clinical Oncology (ASCO) meetings in 2008.
  • Progression-free survival (PFS) was significantly increased in patients assigned to satraplatin compared to placebo (one-year PFS rate 17 versus 7 percent, median PFS 11.1 versus 9.7 weeks, hazard ratio [HR] 0.67, 95% CI 0.57-0.77).
  • There was no difference in overall survival (61 weeks on both treatment arms, HR 0.95, 95% CI 0.84-1.15).
  • Treatment was generally well tolerated, with myelosuppression being the major cause of grade 3 or 4 adverse events (neutropenia, thrombocytopenia, and anemia in 22, 23, and 12 percent of satraplatin-treated patients, respectively).
antiangiogenic agents bevacizumab
Antiangiogenic Agents: Bevacizumab
  • CALGB 90401
    • Phase III trial comparing docetaxel/prednisone with or without bevacizumab in hormone-resistant prostate cancer1
    • Preliminary data suggest that this trial did not reach its primary endpoint of overall survival2
      • Data to be presented at the 2010 American Society of Clinical Oncology (ASCO) annual meeting, June 4 to 8, 2010.

Every 3 weeks:

Docetaxel: 75 mg/m2 IV on Day 1 +

Prednisone: 5 mg BID PO on Days 1-21 +

placebo IV on Day 1

  • - Hormone refractory prostate cancer
  • - Metastatic disease
  • Testosterone <50 ng/mL
  • No prior chemotherapy

N=1020

Every 3 weeks:

Docetaxel: 75 mg/m2 IV on Day 1 +

Prednisone: 5 mg BID PO on Days 1-21 +

Bevacizumab: 15 mg/kg IV on Day 1

1. Clinicaltrials.gov. www.clinicaltrials.gov/ct2/show/NCT00110214.

2. Kelly WK, et al. J Clin Oncol. 2010;28:7s (Abstract LBA4511).

antiangiogenic agents sunitinib
Antiangiogenic Agents: Sunitinib
  • Tyrosine kinase inhibitor currently approved for renal cell carcinoma and gastrointestinal tumors
  • Several trials of sunitinib in CRPC:

1. Dror Michaelson M, et al. Ann Oncol. 2009;20:913-920.

2. Sonpavde G, et al. Ann Oncol. 2010;21:319-324.

bone targeting therapies zd4054
Bone-Targeting Therapies: ZD4054

1. James ND, et al. Eur Urol. 2009;55:1112-1123.

2. Clinicaltrials.gov. www.clinicaltrials.gov/ct2/show/NCT01000948.

  • Endothelin-A receptor antagonist
  • Recent multinational phase II trial in metastatic CRPC1
    • Primary endpoint of time to progression not achieved
    • Improvement in overall survival observed in both treatment arms
  • Second phase II trial in metastatic CRPC currently underway2
bone targeting therapies denosumab
Bone-Targeting Therapies:Denosumab

Cumulative Incidence of New Vertebral Fracture

New Fracture (%)

3.9

3.3

1.9

1.5

1.0

0.3

1. Smith MR, et al. N Engl J Med. 2009;361:745-755.

2. Clinicaltrials.gov. www,clinicaltrials.gov/ct2/show/NCT00838201.

Monoclonal antibody that acts against receptor activator of nuclear factor-κB ligand to improve bone mineral density and fractures

Useful in CRPC, as ADT is associated with bone loss and increased risk for fracture

Recent study in men receiving ADT for prostate cancer1

Current phase III trial underway in non-metastatic CRPC patients undergoing ADT2

immunomodulatory therapies lenalidomide
Immunomodulatory Therapies:Lenalidomide
  • Highly potent immunomodulatory derivative of thalidomide
  • Potentiates the action of paclitaxel in vitro against prostate cancer cell lines in co-culture with mononuclear cells
  • Phase I study in metastatic CRPC patients:
    • Combined with weekly paclitaxel
    • PSA declines by >50% in 2 of 7 evaluable patients
    • Frequent dose-limiting toxicity

Mathew P, et al. Cancer Chemother Pharmacol. 2010;65:811-815.

management of metastatic crpc integrating novel therapeutics
Management of Metastatic CRPC: Integrating Novel Therapeutics
  • Current therapeutic paradigm
    • Second-line hormonal therapy
    • Docetaxel-based chemotherapy
    • Retreatment with docetaxel, mitoxantrone, investigational therapy, supportive care
custersin studies
Custersin studies
  • Phase III of docetaxel vs docetaxel plus custerin docetaxel after initial response and then on progression is randomized in patient with castrate resistant prostate cancer with metastasis with symptomatic pain
  • Phase III first line same arms
mdv phase iii studies
MDV Phase III studies
  • Phase III AFFIRM study MDV 3100 vs placebo in patients who have progressed on docetaxel
  • Phase III study on chemotherapy naïve patients also being studied
summary
Summary

Metastatic CRPC management will likely evolve over the next 12–24 months with the introduction of novel agents, including AR-targeting agents and new chemotherapies

Introduction of new agents will challenge the clinical research community to design and conduct studies that bring some clarity into optimal use/sequence of these agents