Abiraterone Accelerates Physical and Functional Impairment in Older Men with Chemotherapy-naïve Metastatic Castrate Resistant Prostate Cancer

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1 Abiraterone Accelerates Physical and Functional Impairment in Older Men with Chemotherapy-naïve Metastatic Castrate Resistant Prostate Cancer Background: -Prostate cancer (PCa) is the most common non-skin cancer diagnosed in North America, and it affects 1 in 6 men. Patients with recurrent or metastatic PCa will inevitably develop castrationresistant disease after an initial period of hormone responsiveness. CRPC is a lethal disease and depends on androgen production and androgen receptor signaling for growth. Abiraterone acetate, a selective androgen biosynthesis inhibitor of CYP17, has been shown to inhibit persistent androgen synthesis from adrenal and intratumoral sources, thereby suppressing an important stimulus of CRPC growth. It has demonstrated improvement in overall survival (median, 14.8 months vs 10.9 months; HR, 0.65; 95% CI, ; P <.001), and patient-reported quality-oflife scores compared with placebo in patients previously exposed to docetaxel chemotherapy. The adverse event profile of abiraterone acetate is also very favorable, with the predominant adverse events being the mechanism-based effects of mineralocorticoid excess (hypokalemia, hypertension, fluid retention, and edema), which are manageable and infrequently severe. Abiraterone monotherapy is now being studied at an earlier stage in PCa (high-volume asymptomatic metastatic CRPC men with progressive disease, with ECOG PS 0-1) and several Phase I and one Phase II study have shown activity in CRPC chemotherapy-naïve men as well. Phase II study demonstrates a 50% or more decline in PSA level at week 12 in 22 of 33 (67%) men, an effect that persisted for more than 1 year in more than half of patients. Median time on therapy and time to PSA progression were 63 weeks and 16.3 months, respectively. However, these studies were conducted in men (age 56-85) with ECOG performance 0 or 1 with adequate renal hepatic, and cardiac function. The effect of Abiraterone on physical and functional impairment and quality of life in a majority of older men, with lower ECOG PS, is unknown. A landmark study showed 67% of men between ages of had ECOG PS<2; (Repetto L.2002, JCO) There is growing concern among oncologists who treat older cancer patients about the affects of Abiraterone on physical and functional performance by rendering men castrate by blocking androgen biosynthesis similar to ADT. ADT renders men castrate by targeting intragonadal androgen biosynthesis and negatively affects the physical performance and functional abilities of older men with PCa. It has been shown that over 50% older cancer patients (age >=70) on ADT exhibited impaired scores on SPPB (a measure of frailty), and 24% and 42% had functional impairment as measured by ADLs and IADLs respectively. SPPB is an objective and validated test of physical performance. Lower scores on SPPB predict ADT and IADL disability, and mortality in community dwelling older adults. ADL and IADL impairment have also been independently linked with increase hospitalizations, nursing home placement and mortality. With the recent push for Abiraterone in the pre-chemotherapy phase of men with CRPC to delay initiation of chemotherapy with docetaxel, our concern is that abiraterone, just like ADT, may accelerate physical and functional impairment, resulting in worsening of overall quality of life. This can potentially limit its use in the pre-chemotherapy phase of PCa, where Phase III trials are ongoing. My primary objective is to test the hypothesis that abiraterone use in older men with asymptomatic metastatic CRPC men with progressive disease, and ECOG PS 1-2, accelerates physical and functional impairment in men, reducing overall quality of life, and falls at 3 months. My secondary objective is to test the hypothesis that longer duration of abiraterone is associated with more physical and functional decline and worse quality of life in these men. Results from this study will allow physicians to target therapy only to robust men (ECOG 0 or 1) and minimize treatment duration to prevent treatment related impairments. 1

2 Specific Aims: 1. To assess physical and functional performance using validated measures, at baseline, three and six months, in asymptomatic chemotherapy naïve older men with progressive CRPC randomized to treatment (abiraterone acetate) versus observation. Eligibility requires histologically confirmed adenocarcinoma of prostate, progressing on androgen deprivation therapy (either an LHRH agonist or orchiectomy, and following antiandrogen withdrawal). PCa progression is defined later. 2. To simultaneously measure and compare patient reported quality of life on the protocol. A validated questionnaire will be instituted at time of enrollment, 3 and 6 months post-treatment. 3. To initiate abiraterone in men in the observation arm at three months, and follow and compare physical and functional performance and quality of life scores, at three and six months in all men. This will provide a comparison of the affect of duration of abiraterone in the pre-chemotherapy stage, on physical and functional impairment and worsening quality of life. 4. To complete biological assessment predictive of inflammation (IL-6, CRP, D- dimer), and p16 expression, in order to determine if there is a predictable correlation between changes in biomarkers and physical and functional impairment, and worsening quality of life scores. APPROACH: Overall research design: We will conduct a randomized controlled trial of men 60 and older with asymptomatic metastatic CRPC chemotherapy naïve men with progressive disease, and ECOG PS 1-2, to determine: 1) progression of physical and functional impairment and worsening in quality of life (at baseline and 3 months), using validated measures, in men who receive abiraterone versus men who do not; 2) physical and functional impairment and worsening quality of life (at 3 and 6 months) resulting from starting abiraterone earlier compared with starting later. The results from this trial will elucidate the impact of abiraterone in a pre-chemotherapy setting where patients are currently observed for PCa progression prior to initiating docetaxcel, on physical and functional performance and quality of life. SPECIFIC AIMS 1, 2 and 4: 1. To assess physical and functional performance using validated measures, at baseline, three and six months, in asymptomatic chemotherapy naïve older men with progressive CRPC randomized to treatment (abiraterone acetate) versus observation. Eligibility requires histologically confirmed adenocarcinoma of prostate, progressing on androgen deprivation therapy (either an LHRH agonist or orchiectomy, and following antiandrogen withdrawal) or ketoconazole therapy. PCa progression is defined later. 2

3 2. To simultaneously measure and compare patient reported quality of life on the protocol. A validated questionnaire will be instituted at time of enrollment, 3 and 6 months post-treatment. 3. #4: To complete biological assessment predictive of inflammation (IL-6, CRP, D-dimer), and p16 expression, in order to determine if there is a predictable correlation between changes in biomarkers and physical and functional impairment, and worsening quality of life scores. The first two specific aims are brought together under the clinical assessment section of the study. Once the qualifying patients are identified, recruited and enrolled-i.e. men over 60 with asymptomatic progressive CRPC who are chemotherapy naïve-these patients will be followed and data collected at baseline, 3 and 6 months. Specific aim 3 allows all men to be treated with abiraterone, while clinical assessments are being followed at specific timelines. Also described below under specific aims 4, a biological assessment will be completed at each of these time points, in both arms. These assessments will allow a comparison of clinical and biological profile of disability of men started earlier versus later on abiraterone (3 months vs 6 months), in the pre-chemotherapy phase. DATA COLLECTION: PATIENT SELECTION: Eligibility Criteria: The eligibility criteria are aimed at identifying older PCa patients, who demonstrate disease progression despite ADT (either a LHRH agonist or orchietomy) or ketoconazole therapy. Patients with significant impairment (i.e. unable to walk 4 meters as part of SPPB measured walk) will be excluded because their impairments place them at high-risk for treatment intolerance. Study patients must: Have a primary diagnosis of prostate cancer. Have asymptomatic metastatic castrate resistant prostate cancer progressing despite ADT (either a LHRH agonist or orchiectomy) or despite antiandrogen withdrawal or despite ketoconazole Have metastatic disease or PSA-only progression by the PSA Working Group Criteria (PSAonly Pogressive disease is a 25% increase over the baseline and an increase in the absolutevalue PSA level by at least 5 ng/ml, which is confirmed by a second value; Metastatic disease is a worsening bone scan, regardless of changes in PSA.) Be 60 years of age or older Have a life expectancy of >6 months. Be able to walk 4 meters without assist device. Give written informed consent. Those with a diagnosis of dementia or who score as impaired on the cognitive screen will be excluded (>5 errors on the Short Portable Mental Status Questionnaire). Have documented ability to procure Abiraterone acetate commercially Have an ECOG performance status between 1 and 2 3

4 Serum creatinine 15 X the institutional upper limit of normal (ULN), bilirubin 1X ULN, AST and ALT 2.5 XULN, serum potassium 3.5 mmol/l, baseline ACTH stimulation peak cortisol level of more than 18 ug/dl. Study patients must not: Have prior chemotherapy for prostate cancer Have used narcotics for prostate cancer related pain Have uncontrolled HTN, NYHA III or IV CHF, autoimmune disease requiring corticosteroid therapy, or other illness interfering with study participation. Have used systemic steroids or any other product known to decrease PSA levels within 4 weeks of treatment initiation Methods. Subjects will be enrolled at the University of Chicago Medical Center. Patients will be primarily recruited from the Genitourinary Multidisciplinary Clinics where medical oncologists, radiation oncologists, and urologists care for older prostate cancer patients collaboratively. The Genitourinary Multidisciplinary Clinic at the University of Chicago is currently following 1400 prostate cancer patients. Over 250 new patients are treated per year. Ninety percent of prostate cancer patients seen are aged 60 and over. We estimate that there will be 4 eligible patients per month. 2 people will consent, leading to 6-8 patients per months enrolling, 48 by six months. There will likely be some losses to follow-up in subsequent waves of data. We have established relationships with two separate GU oncologists, Dr.Russell Szmulewitz and Dr. Walt Stadler. Both see a large number of older men with Prostate Cancer. We will further attend weekly GU Oncology Research Meetings to discuss patient recruitment. Eligible patients who express interest with their physician will meet with a member of the research team at their scheduled clinic visit to sign the consent form, if they choose to enroll. Neutral language will be used when describing the arms of the study and explaining study procedures. The questionnaires will take approximately one hour to complete at each time point. A research coordinator will be present at all times to assist the subject in completion of the questionnaires, if necessary, and to answer any questions. After providing written informed consent, patients will undergo eligibility assessment. During the eligibility assessment, the patient will complete an On-Study Data questionnaire to collect demographic and oncology history and will undergo a brief cognitive test. Cancer history, including relevant treatment information and recent laboratories, will be abstracted from the medical record. At the baseline visit, eligible patients will complete the assessments (shown in Table 1 below). At the end of the baseline assessment, subjects in both arms will be provided a pedometer and provided a booklet to record pedometer readings. Patients will be randomized after completion of the baseline assessment into one of the two arms. At 3 month follow-up, patients will complete follow-up assessments, described in Table 1 below). Patients will also complete pedometer assessment. To facilitate accrual and retention, patients randomized to both arms will receive their pedometers following the conclusion of the study. All subjects will receive $50.00 in the form of a check after each completed assessment time-point and any travel/parking will be reimbursed. There will be no costs to the subjects for the assessments, laboratory tests, or equipment. Data collection elements at baseline, 3 months and 6 months. Table 1 1: Study Measures* Aim Outcome Muscular mass Test DEXA, Bioelectrical Administration Objective Time (min) Impedance Physical Short Physical Objective Muscular strength Repetition Objective 15 Performance Performance Maximum Test, Battery (SPPB) Handgrip Test Functional abilities Composite Subjective 10 1 Aerobic Capacity 6-minute walk Objective 6 ADLs/IADLs 2 QoL FACIT-F Subjective 15 4

5 Exploratory Comorbidity OARS Comorbidity Subjective 5 Index Exploratory Physical Activity Pedometer Objective N/A Exploratory Comprehensive VES-13, Fried s Subjective 5 Geriatric Assessment Frailty Criteria, Fall History Exploratory Mood POMS Subjective 10 Exploratory Depression CES-D Subjective 10 Exploratory Cognition FACT-cog Subjective 15 Exploratory Physical measures BMI, Height, Weight Objective 5 1 Chart Extraction (Clinical Risk) 4 Exploratory Biological Assessment 1 Treatment related toxcicity Gleason score, PSA( and PSA Doubling time), Date of progression, Medications IL-6, CRP, D-dimer, p 16 hypokalemia, hypertension, fluid retention, and edema, fatigue Objective 5 Objective Objective 3 N/A Patient Assessments: Self-reported questionnaires will be completed in minutes while time to completion for objective tests is one hour. The study measures will be collected at 3 time points: baseline, 3-months follow-up and 6-months follow-up. Biological assessment predictive of inflammation (IL-6, CRP, D-dimer), and p16 expression will be completed at the time of enrollment, 3-months follow-up and 6-months follow-up. (Specific Aim #4) Instruments: i)the On-Study Data questionnaire will be used to record demographic, comorbidity, diagnostic, and treatment information including time on androgen deprivation therapy, agents used, body mass index, and relevant laboratories from the clinical record (testosterone, PSA, hemoglobin, albumin, liver and kidney function) ii) Exercise Stages of Change Short Form and the Short Portable Mental Status Questionnaire (SPMSQ) to assess stage of exercise and cognitive status, respectively. Those subjects with >5 errors on the SPMSQ, signifying significant cognitive impairment, will be excluded from the study. This tool has been well-validated for the detection of clinically significant cognitive impairment in community-dwelling older adults and has been utilized in our previous research. The study measures described in the following sections will be collected at 3 time points: at baseline, 3 month follow-up and 6 month follow-up. Physical Performance will be assessed with both objective performance-based as well as self-reported physical function measures Objective physical performance, the primary outcome variable, will be assessed with the Short Physical Performance Battery (SPPB). The SPPB produces a summary ordinal score based on three tests, which include the tandem stand, the chair rise-and-sit, and walking speed. For the chair rise-and-sit test, participants are asked to stand up from a sitting position with their arms folded across the chest five times, and the total elapsed time to perform the task is recorded. Walking speed is assessed by asking participants to walk at 5

6 their usual pace for a short distance (4 meters), and the faster of two such walks is used to estimate walking speed. Subjects who cannot complete the 4 meter walk without an assist device will be excluded from the study. Functional Abilities will be assessed with a composite score of the Activities of Daily Living and Instrumental Activities of Daily Living Scales These scales measure the ability of an elder to care for himself in basic (ADLs) needs and ability to live independently in the community (IADLs). Skeletal muscle mass and muscular strength will be assessed with objective measures. Muscle mass will be assessed using Dual Energy X-ray Absortiometry (DEXA) and Bioelectrical Impedance (BIA). DEXA is currently the most widely used method to measure bone mineral density and also can provide measures of body composition, specifically fat mass and lean mass, from which estimates of skeletal muscle mass can be derived. The Bioelectrical Impedance System is a non-invasive, easy-to-administer and safe method of assessing lean body mass. Muscular strength will be assessed objectively using the The Handgrip Dynamometer Test, which is a grip strength test used to assess the maximal voluntary contraction generated by the arm muscles. The best score of the three hand-grip trials will be used for right and left limbs to calculate static strength. Aerobic capacity will be assessed using the 6-Minute Walk Test. Participants walk for a total of 6 minutes and cover as much distance as they can during this time. Immediately upon completion of the test, the total distance walked is recorded and used to calculate an estimate of aerobic capacity (VO2max: Maximal Oxygen Consumption), and an exercise heart rate is recorded via palpation of the radial pulse. If a participant cannot walk for the entire 6 minutes, the test is presumed complete (distance and heart rate are recorded) when the patient stops the test. Quality of life will be assessed using the Functional Assessment of Chronic Illness Therapy- Fatigue (FACIT-F). The FACIT-F is a 28-item health-related quality of life (HRQoL) scale developed specifically for use in cancer clinical trials, along with 13 additional questions directly related to the impact of fatigue on daily activities. Physical activity will be assessed subjectively with the Physical Activity Scale for the Elderly (PASE) as well as objectively via a Pedometer. These activity monitors are important to determine the affect of abiraterone on physical activity. Prior validation studies have demonstrated that PASE, a 5 minute physical activity survey designed for the elderly that asks about activities over the prior 7 days, is significantly associated with 48-hour physical activity records. The Oregon Scientific Pedometer with Calorie Counter (PE316CA) device will be used to assess duration of physical activity via Daily Steps Walked. Comprehensive Geriatric Assessment (CGA) measures of frailty will include the Vulnerable Elder s Survey-13 (VES-13) and frailty criteria as described by Fried. The VES-13 is a short, functionally-based screening tool that captures self-rated health, function, and subjective physical disability. In our prior research, we have demonstrated that VES-13 scores are significantly associated with scores on the SPPB, the primary outcome of this proposal, so patients will be stratified at baseline based on score (<3 vs >3). The 5 components of the frailty criteria will be measured by the following tools: lean muscle mass loss (bioelectrical impedance), self-reported exhaustion (FACIT-F), poor grip strength (hand-grip dynamometer), slow walking speed (6-min walk test), and low physical activity (physical activity questionnaire). Fall history will also be collected. 6

7 Mood and Depression will be assessed using the Profile of Mood States (POMS) and the Center for Epidemiologic Studies (CES-D), both in shortened versions to decrease participant response burden. The POMS consists of 30 adjectives in six subscales: depression/dejection, fatigue/inertia, tension/anxiety, vigor, anger/hostility, and confusion/bewilderment. Subjects rate each adjective on a 5-point scale to describe their moods over the past week. The CES-D was developed for use in studies of the epidemiology of depressive symptoms in the general population and has been associated with impaired physical performance in older populations. Perceived cognitive abilities will be assessed using the FACT-cog. Although subjects with overt cognitive impairment will be excluded with the Short Portable Mental Status Questionnaire, subjective cognitive complaints are common in men on ADT. Objective cognitive abilities will be measured with 1) The Hopkins Verbal Learning Test Revised (HVLT-R) is a brief measure of verbal learning and memory. The HVLT-R has been normed for individuals from 18 to 80+ years. This test has adequate psychometric properties and is commonly used in cognitive screening. 2) The Trail Making Test (TMT) is a measure of attention, speed and mental flexibility. The adult version of this test is normed for individuals from 15 to 89 years of age. The TMT has adequate reliabilities. Together, these tests can be administered within minutes. Specific Aim 4: Laboratory assessments: Biomarkers including TNF-alpha, IL-6, CRP, have all been linked to frailty in studies in the general geriatrics population, and will be measured. In addition, we will collect data on body fat composition by impedance, and muscle mass by DEXA. In addition, testosterone levels will be measured to know pre-abiraterone levels and postabiraterone levels. Cytokine measurements will be done by ELISA methods. The blood sample (approximately 25 ml) for cytokines will be drawn in 2 red (serum) and 1 purple-top (EDTA heparin plasma) vacutainers by personnel in Cancer Research Lab and will be spun, and stored. For longer storage, the samples will be frozen at -20 C or below. p-16 expression: The retinoblastoma (RB) cell cycle regulatory pathway is deregulated in all known human tumors. P16, an upstream regulator of prb, are among the most commonly affected products of this pathway. In the multivariate analysis, loss of p16 was significantly associated with reduced disease-specific survival and increased risk of local failure and distant metastasis. A borderline association with reduced overall survival (P =.07) was also evident. Loss of p16 is significantly associated with adverse clinical outcome in cases of locally advanced prostate cancer. Feedback Questionnaires assessing the acceptability and perceived efficacy of the interventions will be completed at 3-month and 6-month follow-up. SPECIFIC AIM 3: 3. To initiate abiraterone in men in the observation arm at three months, and follow and compare physical and functional performance and quality of life scores, at three and six months in all men. This will provide a comparison of the affect of duration 7

8 of abiraterone in the pre-chemotherapy stage, on physical and functional impairment and worsening quality of life. Abiraterone acetate and its metabolite, abiraterone, are potent and selective inhibitors of CYP17 alpha-hydroxylase and C lyase activities, both important steps in androgen biosynthesis. Like androgen deprivation therapy, abiraterone targets testosterone synthesis depleting testosterone even further. We believe that like ADT, men on abiraterone are likely vulnerable to physical and functional impairments with subsequent reduced quality of life. Although Phase I and II trials on Abiraterone in the patient population suggest favorable long-term safety profile, with grade 1-2 toxicity, these studies were done in a healthier subset of men (ECOG PS 0-1), as is done in more cancer trials. However, 67% of men aged have ECOG PS<2 with asymptomatic CRPC and progressive disease on ADT, and are more vulnerable to functional and physical impairments while on androgen inhibition. Wave 1 (first three months) of our study provides pivotal information on these impairments among the treatment versus control group. Treatment equipoise will be achieved by initiating docetaxel in men with progressive PCa despite abiraterone in the treatment group, or development of symptomatic disease in the observation group. These men will be removed from the study. The latter half of the study (Wave 2) will enable us to measure and compare the affects of continuous abiraterone therapy on physical and functional performance and quality of life. Wave 2 and 3 will help elucidate the benefit versus risk of continuous abiraterone therapy (6 months) in asymptomatic metastatic CRPC, by studying its effect on physical and functional performance, and quality of life in men. Data collection and assessments are elaborated under Methods, Specific Aims 1 and 2 above. T0 Wave 1 Wave 2 Abiraterone Abiraterone Abiraterone Vs 8