Metastatic Hormone-sensitive Prostate Cancer
Conditions
Keywords
metastatic hormone-sensitive prostate cancer, docetaxel
Brief summary
RATIONALE: Androgens can cause the growth of prostate cancer cells. Androgen ablation therapy may stop the adrenal glands from making androgens. Drugs used in chemotherapy, such as docetaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. It is not yet known whether androgen-ablation therapy is more effective with or without docetaxel in treating metastatic prostate cancer. PURPOSE: This randomized phase III trial is studying androgen-ablation therapy and chemotherapy to see how well they work compared to androgen-ablation therapy alone in treating patients with metastatic prostate cancer.
Detailed description
OBJECTIVES: Primary * Evaluate the ability of early chemotherapy to improve overall survival of patients commencing androgen deprivation for metastatic prostate cancer. Secondary * Determine whether early chemotherapy can increase the time to clinical progression (radiographic or symptomatic deterioration due to disease) over hormonal therapy alone. * Determine whether early chemotherapy can increase the time to development of hormone-refractory disease over hormonal therapy alone. * Determine whether early chemotherapy can increase the time to serological progression over hormonal therapy alone. * Determine rates of biochemical response at 6 months and 12 months in the chemohormonal arm versus the hormonal therapy alone arm. * Determine the frequency of adverse events and the tolerability of chemotherapy combined with hormonal therapy versus hormonal therapy alone. * Determine whether the postulated clinically meaningful increase in disease control is associated with an alteration in overall quality of life using the Functional Assessment of Cancer Therapy-Prostate questionnaire. * Determine the ability of prostate-specific antigen (PSA) changes to be a surrogate for clinical benefit from therapy and overall survival. Tertiary * Determine whether there are proteins differentially translated from the genome in hormone-sensitive prostate cancer, prostate cancer that has responded to hormonal therapy, and hormone-refractory prostate cancer. * Determine the frequency of constitutive polymorphisms of enzymes involved in steroid metabolism and other carcinogenic processes. * Determine whether the amount and frequency of certain carcinogenic proteins in prostate cancer tissue such as C-X-C chemokine receptor type 4 (CXCR-4) and manganese superoxide dismutase can be correlated with a poor prognosis. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to age (≥ 70 vs \< 70), ECOG performance status (0-1 vs 2), combined androgen blockade for \> 30 days (yes vs no), duration of prior adjuvant hormonal therapy (\> 12 months vs ≤ 12 months), concurrent bisphosphonate use (yes vs no), and volume of disease (low vs high). Patients are randomized to 1 of 2 treatment arms. * Arm A (Androgen-Deprivation Therapy and Docetaxel): Patients receive androgen-deprivation therapy (including luteinizing hormone-releasing hormone \[LHRH\] agonist therapy, LHRH antagonist therapy, or surgical castration). Patients also receive docetaxel intravenously (IV) over 1 hour on day 1. Treatment with docetaxel repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. * Arm B (Androgen-Deprivation Therapy alone): Patients receive androgen-deprivation therapy (as in arm A) alone. Quality of life is assessed at baseline and at months 3, 6, 9 and 12. After completion of study treatment, patients are followed up periodically for up to 10 years.
Interventions
DRUGandrogen-deprivation therapy
LHRH analogs are administered with a variety of techniques such as subcutaneously, intramuscularly, or insertion, while antiandrogens (flutamide and bicalutamide) were given orally.
DRUGdocetaxel
Given IV
Sponsors
National Cancer Institute (NCI)
ECOG-ACRIN Cancer Research Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically confirmed prostate cancer * Metastatic disease * On androgen-deprivation therapy for \< 120 days * Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2 * PS 2 eligible only if decline in PS is due to metastatic prostate cancer * Absolute neutrophil count ≥ 1,500/mm\^3 * Platelet count ≥ 100,000/mm\^3 * Bilirubin ≤ upper limit of normal (ULN) * Alanine aminotransferase (ALT) ≤ 2.5 times ULN * Creatinine clearance ≥ 30 mL/min * Prothrombin time (PT) and international normalized ratio (INR) ≤ 1.5 times ULN (unless on therapeutic anticoagulation) * Partial thromboplastin time (PTT) ≤ 1.5 times ULN (unless on therapeutic anticoagulation) * Fertile patients must use effective contraception * At least 4 weeks since prior major surgery and recovered from all toxicity prior to randomization * Prior adjuvant or neoadjuvant hormonal therapy allowed provided the following are true: * Therapy was discontinued ≥ 12 months ago AND there is no evidence of disease, as defined by 1 of the following: * PSA \< 0.1 ng/dL after prostatectomy plus hormonal therapy * PSA \< 0.5 ng/dL and has not doubled above nadir after radiotherapy plus hormonal therapy * Therapy lasted no more than 24 months * Last depot injection must have expired by the 24-month mark * Prior palliative radiotherapy allowed if commenced within 30 days before starting androgen deprivation * Anti-androgen therapy allowed as single-agent therapy ≤ 7 days before medial castration to prevent flare * More than 30 days (or 6 half-lives) (whichever is longer) since prior participation in another clinical trial * Concurrent participation in nontherapeutic trials allowed * Concurrent antiandrogen therapy (e.g., bicalutamide or flutamide) allowed, but not as sole hormonal therapy
Exclusion criteria
* Prostate-specific antigen (PSA) level has risen and met criteria for progression from its lowest point between the start of androgen-deprivation therapy and randomization * Prior malignancy in the past 5 years except for basal cell or squamous cell carcinoma of the skin * Other malignancies that are considered to have low potential to progress (e.g., grade 2, T1a transitional cell carcinoma) may be allowed if approved by study chair * Peripheral neuropathy \> grade 1 * History of severe hypersensitivity reaction to docetaxel or other drugs formulated with polysorbate 80 * Active cardiac disease, including the following: * Active angina * Symptomatic congestive heart failure * Myocardial infarction within the past 6 months * Prior chemotherapy in adjuvant or neoadjuvant setting * Prior hormone therapy in the metastatic setting * Concurrent 5-alpha reductase inhibitors * Simultaneous enrollment on Cancer and Leukemia Group B (CALGB) 90202
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Assessed every 3 months if patient is < 2 years from study entry; every 6 months if patient is 2 - 5 years from study entry; then annually if patient is 5 - 10 years from study entry | Overall survival is defined as the time from randomization to death or date last known alive. Survival data reflects the database as of December 23, 2013. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Clinical Progression | Assessed every 3 months if patient is < 2 years from study entry; every 6 months if patient is 2 - 5 years from study entry; then annually if patient is 5 - 10 years from study entry | Time to clinical progression is defined as the time from randomization to clinical progression. Clinical progression is defined as increasing symptomatic bone metastases, progression per Response Evaluation Criteria In Solid Tumors (RECIST) criteria or clinical deterioration due to cancer per investigator's opinion. Patients without documented clinical progression were censored at the date of last disease assessment. Secondary endpoint data reflect the database as of December 23, 2014. |
| Time to Castration Resistant Prostate Cancer (Hormone Refractory Disease) | Assessed every 3 months if patient is < 2 years from study entry; every 6 months if patient is 2 - 5 years from study entry; then annually if patient is 5 - 10 years from study entry | Time to castration resistant prostate cancer is defined as the time from randomization to PSA progression or clinical progression, whichever occurred first. Patients without documented progression were censored at the date of last disease assessment. Secondary endpoint data reflect the database as of December 23, 2014. |
| Proportion of Patients With PSA Complete Response (CR) at 6 Months | Assessed at 6 months | PSA CR is defined as a PSA level less than 0.2 ng/ml measured for 2 consecutive measurements at least 4 weeks apart. Patients who met the criterion of PSA CR and had PSA level less than 0.2 ng/ml before and after the 6-month time point are considered as having a PSA CR at 6 months. |
| Proportion of Patients With PSA Complete Response (CR) at 12 Months | Assessed at 12 months | PSA CR is defined as a PSA level less than 0.2 ng/ml measured for 2 consecutive measurements at least 4 weeks apart. Patients who met the criterion of PSA CR and had PSA level less than 0.2 ng/ml before and after the 12-month time point are considered as having a PSA CR at 12 months. |
| QOL Change From Baseline to 3 Months | Assessed at baseline and 3 months | The primary QOL change was evaluated by the Functional Assessment of Cancer Therapy - Prostate (FACT-P) instrument. FACT-P is a self-report measure of both general and disease-specific QOL. Higher scores represent better QOL. The FACT-P (version 4) contains 39 likert items distributed over 5 subscales: physical (7 items), social/family (7 items), emotional (6 items), and functional (7 items) well-being, and the additional concerns related to prostate cancer scale (12 items). The FACT-P total score is calculated by summing all these 5 subscales and ranges from 0 to 156. |
Countries
United States
Participant flow
Recruitment details
This study was activated on July 28, 2006, accrued its first patient on September 26, 2006, and closed to accrual on November 21, 2012, after accrual of 790 patients.
Participants by arm
| Arm | Count |
|---|---|
| Androgen-Deprivation Therapy and Docetaxel Patients receive androgen-deprivation therapy (including luteinizing hormone-releasing hormone \[LHRH\] agonist therapy, LHRH antagonist therapy, or surgical castration). Patients also receive docetaxel IV over 1 hour on day 1. Treatment with docetaxel repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. | 397 |
| Androgen-Deprivation Therapy Alone Patients receive androgen-deprivation therapy (including luteinizing hormone-releasing hormone \[LHRH\] agonist therapy, LHRH antagonist therapy, or surgical castration). | 393 |
| Total | 790 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 30 | 0 |
| Overall Study | Chemotherapy discontinued only | 1 | 0 |
| Overall Study | Complicating disease | 1 | 0 |
| Overall Study | Death | 2 | 0 |
| Overall Study | Disease progression | 12 | 0 |
| Overall Study | Never started treatment | 7 | 0 |
| Overall Study | Non-compliance | 1 | 0 |
| Overall Study | Physician Decision | 3 | 0 |
| Overall Study | Withdrawal by Subject | 5 | 1 |
Baseline characteristics
| Characteristic | Androgen-Deprivation Therapy Alone | Total | Androgen-Deprivation Therapy and Docetaxel |
|---|---|---|---|
| Age, Continuous | 63 years | 63 years | 64 years |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 393 Participants | 790 Participants | 397 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 38 / 390 | 1 / 392 |
| serious Total, serious adverse events | 116 / 390 | 12 / 392 |
Outcome results
Primary
Overall Survival
Overall survival is defined as the time from randomization to death or date last known alive. Survival data reflects the database as of December 23, 2013.
Time frame: Assessed every 3 months if patient is < 2 years from study entry; every 6 months if patient is 2 - 5 years from study entry; then annually if patient is 5 - 10 years from study entry
Population: All randomized patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Androgen-Deprivation Therapy and Docetaxel | Overall Survival | 57.6 months |
| Androgen-Deprivation Therapy Alone | Overall Survival | 44.0 months |
Comparison: The study was designed to detect a 33.3% improvement in median survival time across treatments with one-sided type I error of 0.025 and 80% power.p-value: 0.0003Log Rank
Secondary
Proportion of Patients With PSA Complete Response (CR) at 12 Months
PSA CR is defined as a PSA level less than 0.2 ng/ml measured for 2 consecutive measurements at least 4 weeks apart. Patients who met the criterion of PSA CR and had PSA level less than 0.2 ng/ml before and after the 12-month time point are considered as having a PSA CR at 12 months.
Time frame: Assessed at 12 months
Population: All randomized patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Androgen-Deprivation Therapy and Docetaxel | Proportion of Patients With PSA Complete Response (CR) at 12 Months | 0.277 proportion of participants |
| Androgen-Deprivation Therapy Alone | Proportion of Patients With PSA Complete Response (CR) at 12 Months | 0.168 proportion of participants |
p-value: <0.0001Fisher Exact
Secondary
Proportion of Patients With PSA Complete Response (CR) at 6 Months
PSA CR is defined as a PSA level less than 0.2 ng/ml measured for 2 consecutive measurements at least 4 weeks apart. Patients who met the criterion of PSA CR and had PSA level less than 0.2 ng/ml before and after the 6-month time point are considered as having a PSA CR at 6 months.
Time frame: Assessed at 6 months
Population: All randomized patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Androgen-Deprivation Therapy and Docetaxel | Proportion of Patients With PSA Complete Response (CR) at 6 Months | 0.320 proportion of participants |
| Androgen-Deprivation Therapy Alone | Proportion of Patients With PSA Complete Response (CR) at 6 Months | 0.196 proportion of participants |
p-value: <0.0001Fisher Exact
Secondary
QOL Change From Baseline to 3 Months
The primary QOL change was evaluated by the Functional Assessment of Cancer Therapy - Prostate (FACT-P) instrument. FACT-P is a self-report measure of both general and disease-specific QOL. Higher scores represent better QOL. The FACT-P (version 4) contains 39 likert items distributed over 5 subscales: physical (7 items), social/family (7 items), emotional (6 items), and functional (7 items) well-being, and the additional concerns related to prostate cancer scale (12 items). The FACT-P total score is calculated by summing all these 5 subscales and ranges from 0 to 156.
Time frame: Assessed at baseline and 3 months
Population: Patients with both baseline and 3-month QOL assessments are included in this analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Androgen-Deprivation Therapy and Docetaxel | QOL Change From Baseline to 3 Months | -2.7 units on a scale | Standard Error 0.9 |
| Androgen-Deprivation Therapy Alone | QOL Change From Baseline to 3 Months | -1.1 units on a scale | Standard Error 1 |
p-value: 0.0009Wilcoxon signed rank test
p-value: 0.4Wilcoxon signed rank test
Secondary
Time to Castration Resistant Prostate Cancer (Hormone Refractory Disease)
Time to castration resistant prostate cancer is defined as the time from randomization to PSA progression or clinical progression, whichever occurred first. Patients without documented progression were censored at the date of last disease assessment. Secondary endpoint data reflect the database as of December 23, 2014.
Time frame: Assessed every 3 months if patient is < 2 years from study entry; every 6 months if patient is 2 - 5 years from study entry; then annually if patient is 5 - 10 years from study entry
Population: All randomized patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Androgen-Deprivation Therapy and Docetaxel | Time to Castration Resistant Prostate Cancer (Hormone Refractory Disease) | 20.2 months |
| Androgen-Deprivation Therapy Alone | Time to Castration Resistant Prostate Cancer (Hormone Refractory Disease) | 11.7 months |
p-value: <0.0001Log Rank
Secondary
Time to Clinical Progression
Time to clinical progression is defined as the time from randomization to clinical progression. Clinical progression is defined as increasing symptomatic bone metastases, progression per Response Evaluation Criteria In Solid Tumors (RECIST) criteria or clinical deterioration due to cancer per investigator's opinion. Patients without documented clinical progression were censored at the date of last disease assessment. Secondary endpoint data reflect the database as of December 23, 2014.
Time frame: Assessed every 3 months if patient is < 2 years from study entry; every 6 months if patient is 2 - 5 years from study entry; then annually if patient is 5 - 10 years from study entry
Population: All randomized patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Androgen-Deprivation Therapy and Docetaxel | Time to Clinical Progression | 33.0 months |
| Androgen-Deprivation Therapy Alone | Time to Clinical Progression | 19.8 months |
p-value: <0.0001Log Rank