`
`Published OnlineFirst June 1, 2011; DOI: 10.1158/1078-0432.CCR-11-0815 Published OnlineFirst June 1, 2011; DOI: 10.1158/1078-0432.CCR-11-0815
`
`Phase II Study of Abiraterone Acetate in Chemotherapy-Naive
`Metastatic Castration-Resistant Prostate Cancer Displaying Bone
`Flare Discordant with Serologic Response
` 
`Charles J. Ryan, Shreya Shah, Eleni Efstathiou, et al.
`Clin Cancer Res  
`
`2011;17:4854-4861. Published OnlineFirst June 1, 2011.
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`Published OnlineFirst June 1, 2011; DOI: 10.1158/1078-0432.CCR-11-0815
`
`Clinical
`Cancer
`Research
`
`Cancer Therapy: Clinical
`
`Phase II Study of Abiraterone Acetate in Chemotherapy-Naive
`Metastatic Castration-Resistant Prostate Cancer Displaying Bone
`Flare Discordant with Serologic Response
`
`Charles J. Ryan1, Shreya Shah1, Eleni Efstathiou2, Matthew R. Smith3, Mary-Ellen Taplin4,
`Glenn J. Bubley5, Christopher J. Logothetis2, Thian Kheoh6, Christine Kilian1, Christopher M. Haqq6,
`Arturo Molina6, and Eric J. Small1
`
`Abstract
`
`Purpose: Abiraterone is an oral inhibitor of CYP17, which is essential for androgen biosynthesis. This
`multicenter study assessed its efficacy in patients with castration-resistant prostate cancer (CRPC), without
`prior chemotherapy or CYP17-targeted therapy, and frequency of bone scans discordant with prostate-
`specific antigen (PSA) and clinical response.
`Experimental Design: Thirty-three patients received abiraterone acetate 1,000 mg daily with predni-
`sone 5 mg twice daily in continuous 28-day cycles. Patients were evaluated monthly for efficacy and safety.
`Bone scan flare was defined as the combination, after 3 months of therapy, of an interpreting radiologist’s
`report indicating "disease progression" in context of a 50% or more decline in PSA level, with scan
`improvement or stability 3 months later.
`Results: A 50% or more decline in PSA level at week 12 was confirmed in 22 of 33 (67%) patients.
`Declines in PSA level of 50% or more were seen in 26 of 33 (79%) patients. Undetectable PSA levels (0.1
`ng/mL) occurred in 2 patients. Median time on therapy and time to PSA progression were 63 weeks and
`16.3 months, respectively. Twenty-three patients were evaluable for bone scan flare. Progression was
`indicated in radiologist’s report in 12 of 23 (52%), and 11 of 12 subsequently showed improvement or
`stability. As prospectively defined, bone scan flare was observed in 11 of 23 (48%) evaluable patients or 11
`of 33 (33%) enrolled patients. Adverse events were typically grade 1/2 and consistent with prior published
`abiraterone reports.
`Conclusion: Clinical responses to abiraterone plus prednisone were frequent and durable in men with
`metastatic CRPC. Further investigation is needed to clarify the confounding effect of bone scan flare on
`patient management and interpretation of results. Clin Cancer Res; 17(14); 4854–61. Ó2011 AACR.
`
`Introduction
`
`As data emerge suggesting that the progression of pros-
`tate cancer in an androgen-deprived milieu is, in part,
`mediated through the selective growth of tumor cells with
`
`Authors' Affiliations: 1Genitourinary Medical Oncology Program, UCSF
`Helen Diller Family Comprehensive Cancer Center, University of Califor-
`nia-San Francisco, San Francisco, California; 2MD Anderson Cancer
`Center, Houston, Texas; 3Division of Hematology-Oncology, Massachu-
`setts General Hospital; 4Dana-Farber Cancer
`Institute; 5Beth Israel
`Deaconess Medical Center, Boston, Massachusetts; and 6Ortho Biotech
`Oncology Research and Development, a Unit of Cougar Biotechnology,
`Los Angeles, California
`
`Note: Presented in part at the 2009 American Society of Clinical Oncology
`Annual Meeting, Orlando, Florida, and the 2009 American Society of
`Clinical Oncology Genitourinary Cancers Symposium, Orlando, Florida.
`Corresponding Author: Charles J. Ryan, Helen Diller Family Compre-
`hensive Cancer Center, University of California, San Francisco, 1600
`Divisadero Street, San Francisco, CA 94115. Phone 415-353-9279;
`Fax: 415-353-7779; E-mail: ryanc@medicine.ucsf.edu
`
`doi: 10.1158/1078-0432.CCR-11-0815
`Ó2011 American Association for Cancer Research.
`
`a heightened sensitivity to androgens (1–4), progress and
`interest in the development of therapies that target extra-
`gonadal androgen synthesis have accelerated (5, 6). Abir-
`aterone acetate is an orally available selective androgen
`biosynthesis inhibitor that specifically inhibits CYP17.
`Abiraterone has shown activity as a monotherapy in castra-
`tion-resistant prostate cancer (CRPC) in both chemother-
`apy-naive and chemotherapy-exposed patients receiving a
`luteinizing hormone–releasing hormone (LHRH) analo-
`gue (7–12).
`On the basis of the phase I experience with abiraterone
`acetate monotherapy, it was determined that the safety
`profile of this therapy could be improved through conco-
`mitant corticosteroid administration, an approach that
`reduces the compensatory elevations in adrenocorticotropic
`hormone (ACTH) and mineralocorticoid excess induced by
`CYP17 blockade. Because corticosteroids have shown mod-
`est antitumor efficacy when given as monotherapy, the
`current phase II study was designed to determine the efficacy
`and safety of the combination of abiraterone acetate and
`prednisone in patients with metastatic CRPC. In particular,
`
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`Published OnlineFirst June 1, 2011; DOI: 10.1158/1078-0432.CCR-11-0815
`
`Translational Relevance
`
`Castration-resistant prostate cancer (CRPC) is a lethal
`disease and depends on androgen production and
`androgen receptor signaling for growth, affecting bone
`more than other distant sites. Abiraterone acetate, a
`selective androgen biosynthesis inhibitor of CYP17,
`has been shown to inhibit persistent androgen synthesis
`from adrenal and intratumoral sources, thereby sup-
`pressing an important stimulus of CRPC growth. This
`phase II study is the first assessment of abiraterone
`acetate in CRPC not previously treated with docetaxel
`or androgen synthesis inhibitors such as ketoconazole.
`Serial changes in objective imaging (i.e., bone scans)
`were utilized to assess patient outcomes. Discordant
`findings between serologic (prostate-specific antigen)
`response and increases in bone scan lesion intensity,
`although previously described in treatment-naive pros-
`tate cancer, are reported here for the first time in CRPC.
`In addition to reporting prolonged antitumor activity of
`abiraterone acetate, this study highlights the potential
`detriment for patients if increased bone scan intensity is
`erroneously interpreted as disease progression.
`
`the present trial is the first trial with abiraterone to focus on
`patients who had not been treated with either docetaxel or
`an androgen synthesis inhibitor, such as ketoconazole.
`A well-recognized barrier to therapy development in
`CRPC is the lack of reliable surrogate markers of response
`to treatment coupled with a potentially exaggerated reli-
`ance on changes in serum prostate-specific antigen (PSA) as
`an indicator of treatment efficacy. This is particularly true
`with agents that have the potential for PSA modulation
`such as abiraterone acetate or ketoconazole. Consequently,
`changes in bone scan images have been advocated as
`important markers of disease response and progression.
`However, the utility of bone scans has been called into
`question because of a transient "flare" of bone lesion
`intensity in the context of treatment response resulting
`in a false determination of disease progression (13, 14).
`Although the bone scan flare has been described in breast
`cancer and in hormone-sensitive prostate cancer, no sys-
`temic evaluation of the flare phenomenon has been under-
`taken in CRPC (15, 16). Therefore, changes in objective
`imaging, particularly bone scans, were incorporated into
`this study in addition to PSA decline and time to PSA
`progression. As noted, these imaging changes are particu-
`larly important in the context of a novel agent that can
`potentially modulate PSA, potentially rendering it a less
`useful biomarker.
`
`Patients and Methods
`
`Abiraterone Acetate Phase II Study in CRPC
`
`therapy (either an LHRH agonist or orchiectomy, and
`following antiandrogen withdrawal, as appropriate). PSA
`progression was defined according to Prostate-Specific
`Antigen Working Group (PSAWG) criteria (17), and all
`patients had to have baseline lesions identified by bone
`scan, computed tomography (CT), or MRI. Prior ketoco-
`nazole therapy or chemotherapy was not permitted, with
`the exception of neoadjuvant or adjuvant chemotherapy
`completed at least 1 year before study entry. Additional
`eligibility criteria included an Eastern Cooperative Oncol-
`ogy Group (ECOG) performance status of 0 or 1, adequate
`renal [serum creatinine 1.5  upper limit of normal
`(ULN)], hepatic [bilirubin 1.5  ULN, aspartate amino-
`transferase and alanine aminotransferase 2.5  ULN],
`and bone marrow (hemoglobin >9 gm/dL, absolute neu-
`trophil count >1.5  109/L, platelets >100  109/L) func-
`tion, serum potassium level 3.5 mmol/L or more, and a
`castrate level of testosterone (<50 ng/dL). Patients with
`clinically significant electrocardiogram (ECG) abnormal-
`ities were ineligible, as were patients with uncontrolled
`hypertension, New York Heart Association Class III or IV
`congestive heart failure, those with active autoimmune
`disease requiring corticosteroid therapy, or any other ser-
`ious medical or psychiatric illness. Radiation therapy or
`initiation of bisphosphonate therapy within 4 weeks of
`study entry was not permitted, although maintenance of a
`stable bisphosphonate dose was allowed. Use of hormonal
`therapies, systemic corticosteroids, or any other agent
`known to decrease PSA levels within 4 weeks prior to study
`initiation was not permitted. Written informed consent was
`obtained from all patients.
`
`Treatment and evaluations
`Treatment consisted of abiraterone acetate 1,000 mg
`daily with prednisone 5 mg twice daily. Abiraterone was
`administered without food in 28-day cycles. Treatment was
`given continuously until there was evidence of disease
`progression in patients not experiencing unacceptable toxi-
`city.
`Screening evaluations included a history and physical
`examination, performance status evaluation, and a 12-lead
`ECG. Laboratory assessments included complete blood cell
`count, serum chemistries and electrolytes, blood clotting
`evaluation (prothrombin time, partial
`thromboplastin
`time,
`international normalized ratio), and serum PSA
`and testosterone levels. Baseline tumor imaging was done
`by bone scan, CT, MRI, or other imaging procedure.
`Selected physical and laboratory assessments were repeated
`on days 1 and 8 of cycle 1, on day 1 of each subsequent
`cycle, and at the end of study. PSA values were obtained
`monthly. Adverse events were graded using the National
`Cancer
`Institute Common Terminology Criteria for
`Adverse Events (CTCAE), version 3. Bone scans and tumor
`imaging studies were repeated every 3 cycles.
`
`Patients
`Eligibility required histologically confirmed adenocarci-
`noma of the prostate progressing on androgen deprivation
`
`Study design and statistical considerations
`This was a single-arm, open-label, multicenter phase II
`study conducted under the auspices of the Department of
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`Published OnlineFirst June 1, 2011; DOI: 10.1158/1078-0432.CCR-11-0815
`
`Ryan et al.
`
`Defense Prostate Cancer Clinical Trials consortium and
`sponsored by Cougar Biotechnology. The primary study
`endpoint was the proportion of patients achieving a 50%
`or more decline in PSA levels by week 12 of therapy.
`Secondary endpoints included durability of response as
`determined by time to PSA progression, objective radio-
`graphic response rate according to RECIST guidelines (18),
`radiographic progression-free survival time, overall survival
`time, clinical benefit as determined by disease stabilization,
`change in ECOG performance status, and overall treatment
`safety.
`Bone scan flare was prospectively defined as discordant
`results after 3 months of therapy based on the combination
`of an interpreting radiologist’s report indicating "disease
`progression," typically based on increased lesion intensity
`or number that occurred in the context of a 50% or more
`decline in PSA levels, which on subsequent reevaluation
`3 months later showed improvement or stability in the
`scan. Thus, patients evaluable for bone scan flare included
`all patients who had bone scans available at baseline, after
`3 months of therapy, and after 6 months of therapy. An
`initial flare at 3 months followed by continued declines in
`PSA levels and stable scans was also considered to be of
`interest and is reported separately from true flare.
`A sample size of 32 evaluable patients was determined as
`necessary to detect a response rate of 50% or more, with
`response defined as 50% or more decline in PSA levels at
`12 weeks from baseline measurement, at a significance
`level of 0.04 for a directional test and 81% power. Dis-
`tributions of time-to-event variables were estimated using
`the Kaplan–Meier product limit method. All patients who
`received a minimum of 3 cycles of therapy were considered
`evaluable for response. All patients who received at least 1
`dose of abiraterone acetate were evaluable for safety.
`Adverse events were summarized by worst grade of
`severity per patient. The study protocol was approved
`by the institutional review boards at all participating sites
`and was conducted in accordance with the ethical prin-
`ciples of the World Medical Association Declaration of
`Helsinki.
`
`Results
`
`Patient characteristics and treatment
`Between October 2007 and May 2008, a total of 33 men
`with metastatic prostate cancer progressing despite a
`castrate level of testosterone were enrolled across 5 study
`centers within the United States. Baseline patient demo-
`graphics and clinical characteristics are shown in Table 1.
`The median baseline PSA level was 23 ng/mL and ranged
`from 5.9 to 1,110 ng/mL. All patients had radiographic
`evidence of metastatic disease and 26 of 33 (79%) had
`bony metastases. All patients had received androgen
`deprivation therapy with an LHRH antagonist (N ¼
`31) or orchiectomy (N ¼ 2), and 32 (97%) had also
`received an antiandrogen and undergone antiandrogen
`withdrawal. All patients had castrate serum testosterone
`levels (median 8.5 ng/dL; range, 0.9–24.1 ng/dL). The
`
`Table 1. Baseline demographic and clinical
`characteristics of 33 patients enrolled in a
`phase II trial of abiraterone acetate plus predni-
`sone
`
`PSA, median (range), ng/mL
`Metastases, n (%)
`Visceral only
`Viscera plus bone/soft tissue
`Bone only
`Soft tissue only
`Bone and soft tissue only
`Gleason score, median (range)
`Hemoglobin, median
`(range), g/dL
`Testosterone, median
`(range), ng/dL
`Alkaline phosphatase, median
`(range), units/L
`Number of hormonal therapies,
`median (range)
`
`Baseline value
`
`23.0 (5.9–1,110.0)
`
`1 (3)
`2 (6)
`10 (30.3)
`6 (18.2)
`14 (42.4)
`8 (5–9)
`12.8 (10.6–15.3)
`
`25.5 (4.0–49.0)
`
`82.0 (39.0–1,078.0)
`
`2 (2–4)
`
`majority of patients (88%) had received 2 prior hormonal
`therapies, with 3 patients (9%) having received up to 4
`hormonal therapies including estrogens or glucocorti-
`coids. No patient had undergone prior treatment with
`abiraterone, ketoconazole, or chemotherapy. At the time
`of analysis (January 2010), the study population had
`received a median of 63 weeks (range, 8–104 weeks) of
`treatment with abiraterone acetate plus prednisone, with
`15 patients (46%) continuing to receive therapy. Treat-
`ment had been discontinued secondary to disease pro-
`gression in 14 patients (42%) and adverse events in 3
`patients (9%); 2 patients discontinued treatment as a
`result of grade 3 adverse events (1 each for back pain
`and pathologic fracture). Twenty-three patients were eva-
`luable for the bone flare phenomenon. All 33 patients
`were evaluable for response and safety.
`
`PSA response and durability
`Changes in PSA levels, both after 3 months of therapy
`and maximal, for each patient are depicted in Figure 1. A
`decline in PSA level of 50% or more after 3 months, the
`primary study endpoint, was confirmed in 22 (67%) of 33
`patients. Confirmed maximal declines in PSA levels of 50%
`or more and 90% or more were seen in 26 (79%) and 15
`(46%) patients, respectively. In 2 patients, PSA levels
`became undetectable (0.1 ng/mL), declining from base-
`line values of 204 ng/mL and 9 ng/mL, respectively. These
`patients continued to receive study therapy after 20 and 21
`months, both with continued stable bone scans and reso-
`lution of adenopathy in 1 patient.
`Median follow-up time for
`this analysis was 19.3
`months. The median time to PSA progression was 16.3
`
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`Published OnlineFirst June 1, 2011; DOI: 10.1158/1078-0432.CCR-11-0815
`
`Abiraterone Acetate Phase II Study in CRPC
`
`Figure 1. Changes in PSA levels in
`CRPC patients treated with
`abiraterone acetate plus
`prednisone. Waterfall plots of
`maximal PSA change (top) and
`PSA change at week 12 (bottom).
`Reference lines: black, 90%;
`orange, 50%; green, 30%.
`
`months [95% CI 9.2 months, not estimable; Fig. 2]. Nine-
`teen (58%) patients received study treatment for at least 12
`months.
`
`Objective tumor response
`Of 13 patients with measurable disease consisting of
`lymphadenopathy, 9 (69%) had a partial response and 3
`(23%) had stable disease.
`
`Bone scan results and bone scan flare
`At baseline, 26 patients had positive bone scans. One
`had a solitary bone metastasis, 7 patients had between 2
`and 4 metastases, and 18 patients had more than 4 discrete
`metastases. Twenty-three patients had the combination of a
`positive baseline bone scan, a 50% or more decline in PSA
`after 3 months, and bone scans at 3 and 6 months and thus
`were available for evaluation of bone scan flare. Reports
`were available on 92 total bone scans from 41 unique
`
`Figure 2. Time to PSA progression in CRPC patients treated with
`abiraterone acetate and prednisone (N ¼ 33). NE, not estimable.
`
`radiologists dispersed geographically among the study
`sites. Of the 23 eligible patients, bone scan progression
`was indicated in the radiologists’ reports in 12 (52%) of the
`scans taken after 3 months of therapy. Four of the 12
`patients had a report worded specifically as "progression
`of disease" without new lesions (e.g., based solely on
`increased intensity of existing lesions), whereas for 8 of
`12 patients, progression of disease due to new lesions was
`noted. For imaging following 6 months of therapy, the
`radiologists’ reports indicated subsequent improvement in
`4 of 12 and stability in 7 of 12 patients. One patient had a
`worsened scan at 6 months despite continued PSA decline,
`showing a new lesion. Thus, overall, bone scan flare, as
`defined by the combination of PSA decline, initial flare,
`and subsequent improvement or stability in bone scans at 6
`months, was observed in 4 of 23 (17%) and 7 of 23 (30%)
`evaluable patients and 4 of 33 (12%) and 7 of 33 (21%)
`enrolled patients, respectively.
`Two responding patients were not evaluable for bone
`scan flare: 1 had persistent declines in PSA levels (from
`baseline to the end of month 3 and from month 3 through
`month 6 of therapy), with a negative bone scan at baseline
`that was not repeated; the second discontinued study
`therapy after 4 months on therapy because of a pathologic
`femoral neck fracture despite a decline in PSA level of
`91.7%.
`In the 11 patients with bone flare at 3 months and
`stable or improved scans at 6 months, median age was
`72 years (range, 54–85), median PSA level at baseline was
`21.9 ng/dL (range, 6.8–204.3), and median alkaline
`phosphatase level at baseline was 88.5 units/L (range,
`49.0–372.0), not significantly different from the study
`population as a whole. Alkaline phosphatase levels did
`not change in patients experiencing flare: median base-
`line value was 88.5 units/L. After 3 months of therapy, the
`median remained at 88.5 units/L and after 6 months, it
`was 83.5 units/L. Four patients had less than 4 metastases,
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`
`Ryan et al.
`
`Figure 3. Disposition of patients who did and did not experience a bone scan flare. *, of the 2 patients, 1 patient had a negative bone scan at baseline
`that was not repeated given the decline in PSA level; 1 patient came off study at month 4 due to a pathologic femoral neck fracture. †, patient came
`off study after month 9 (and thus never underwent another bone scan).
`
`and 7 patients had multifocal disease. Patient disposition
`is summarized in Figure 3.
`Radiologist interpretation of bone scans in these 11
`patients was as follows: 4 patients had month 4 bone
`scans being read as having increased intensity of existing
`lesions; the other 7 patients had bone scans that were
`read as having new lesions (Fig. 4). Of these 11 patients
`with flare, 10 maintained a decline in PSA levels of 50%
`or more from baseline and 1 developed an increase in
`PSA level from month 4 to month 7 of 4.9 ng/dL (73%
`increase above nadir and 21% decline from baseline)
`after 6 months. The remaining patient with discordant
`results following 3 months of therapy continued to have
`decline in PSA levels past 3 months but had a bone scan
`after 6 months of therapy that was interpreted as pro-
`gressive disease. This patient came off
`study after
`8 months of therapy (and thus never underwent another
`bone scan).
`
`Safety
`Adverse events were most often grade 1 or 2 (see Table 2)
`and clinically manageable. The most common treatment-
`related adverse events were fatigue, hot flush, bone pain,
`peripheral edema, arthralgia, dizziness, and hypokalemia.
`In addition to those listed in Table 2, there was a single
`occurrence each of grade 3 supraventricular arrhythmia and
`
`atrial flutter. One incident each of grade 3 hypokalemia
`and hypertension was observed.
`
`Discussion
`
`In the current study, a large proportion of patients (67%)
`with CRPC experienced a 50% or more decline in serum
`PSA levels while on abiraterone acetate, an effect that
`persisted for more than 1 year in more than half of patients.
`An important and surprising observation in this study was
`that discordant bone scan findings after 3 months of
`therapy were observed in a large proportion of patients
`(36% of the total and 48% of those who experienced a
`50% decline in PSA levels).
`In this study, the potential clinical utility of abiraterone
`acetate in CRPC used determinants of efficacy that included
`decline in PSA levels, time to PSA progression, and changes
`in objective imaging with bone scan and CT scans. Evalua-
`tion of bone scans resulted in an observation of a high
`incidence of bone flare during the first 6 months of the
`study.
`Potential confounding variables that may lead to erro-
`neous determination that a flare has occurred were con-
`sidered. These included the possibility of a significant delay
`between baseline bone scan and initiation of therapy (and
`therefore disease progression before starting therapy) and
`
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`Published OnlineFirst June 1, 2011; DOI: 10.1158/1078-0432.CCR-11-0815
`
`Abiraterone Acetate Phase II Study in CRPC
`
`Figure 4. Examples of bone scan
`flare in patients receiving
`abiraterone acetate. A, example of
`a patient with a declining PSA level
`but a month 4 bone scan being
`read as having a new metastasis in
`the right pubic ramus, as indicated
`by the arrow (although in
`retrospect, one can see the lesion
`in the baseline bone scan). By
`month 7, this lesion shows
`improvement, indicating that this
`lesion seen at month 4 was
`present at baseline and thus was
`secondary to bone flare. B,
`example of a patient with a
`declining PSA level but a month 4
`bone scan being read as
`progression in existing lesions. By
`month 7, this progression
`improved, indicating that the
`progression seen at month 4 was
`due to bone flare.
`
`bisphosphonate initiation. All patients initiated treatment
`within 28 days of the baseline bone scan, and initiation of
`bisphosphonate therapy was not permitted within 28 days
`before starting or at any time while on the study, thus
`decreasing the possibility that these factors falsely elevated
`the incidence of diagnosed flare.
`
`The high incidence of the discordant interpretation of
`bone scans by radiologists in the presence of a 50% or
`more decline in PSA levels highlights several important
`issues related to study design and management of CRPC.
`First, this phenomenon is not systematically assessed in
`the setting of highly active, hormonal therapies that
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`Published OnlineFirst June 1, 2011; DOI: 10.1158/1078-0432.CCR-11-0815
`
`Ryan et al.
`
`Table 2. Incidence of most frequent (10%) treatment-related adverse eventsa (N ¼ 33)
`n (%) of patients
`
`Toxicity by preferred term
`
`Total grade 1–4
`
`Grade 1
`
`Grade 2
`
`Grade 3
`
`Grade 4
`
`Fatigue
`Hot flush
`Bone pain
`Peripheral edema
`Arthralgia
`Dizziness
`Hypokalemia
`Back pain
`Hypertension
`Muscle spasms
`Constipation
`Ecchymosis
`Hyperbilirubinemia
`Hyperglycemia
`Contusion
`Nausea
`Musculoskeletal pain
`Pain in extremity
`Upper respiratory tract infection
`Vomiting
`
`15 (46)
`10 (30)
`8 (24)
`8 (24)
`7 (21)
`7 (21)
`7 (21)
`6 (18)
`6 (18)
`6 (18)
`5 (15)
`5 (15)
`5 (15)
`5 (15)
`4 (12)
`4 (12)
`4 (12)
`4 (12)
`4 (12)
`4 (12)
`
`aMost frequent according to the total percentage observed.
`
`modulate PSA expression in CRPC. As a result, incorpora-
`tion of these data into subsequent phase II and phase III
`designs may further clarify the clinical meaning of this
`phenomenon (e.g., whether it predicts a favorable long-
`term outcome). Second, it suggests that there may be an
`initial discordance between PSA and bone scan that will
`change with time, in many cases leading to the stable
`presence of bone lesions following an initial increase in
`tracer uptake. Of note, consensus criteria such as the
`Prostate Cancer Working Group 2 (PCWG2) formally
`addresses bone flare and includes the recommendation
`to carry out a first follow-up bone scan 12 or more weeks
`after the start of therapy; and furthermore defines pro-
`gression in bone when a minimum of 2 new lesions are
`observed and confirmed on a second scan done 6 or more
`weeks later (19). These bone flare findings further high-
`light a need for closer communication between clinicians
`and interpreting radiologists. This phase II study did not
`mandate central review of scans, nor did it require that
`scans be carried out at the main clinical site of the study.
`Indeed, there were 41 individual radiologists from 4
`different states (Massachusetts, Texas, New Mexico, and
`California) who interpreted 92 bone scans in this study,
`which suggests that these results are not the result of an
`institutional or regional bias. Therefore, it is necessary
`that this phenomenon be recognized to avoid prema-
`turely discontinuing efficacious therapy on the basis of a
`potentially erroneous bone scan interpretation. Mandat-
`
`8 (24)
`7 (21)
`6 (18)
`7 (21)
`6 (18)
`6 (18)
`6 (18)
`3 (9)
`3 (9)
`6 (18)
`5 (15)
`4 (12)
`4 (12)
`2 (6)
`4 (12)
`3 (9)
`2 (6)
`3 (6)
`2 (6)
`3 (9)
`
`6 (18)
`3 (9)
`1 (3)
`0
`1 (3)
`0
`0
`2 (6)
`2 (6)
`0
`0
`1 (3)
`1 (3)
`2 (6)
`0
`1 (3)
`2 (6)
`1 (3)
`2 (6)
`1 (3)
`
`1 (3)
`0
`1 (3)
`1 (3)
`0
`1 (3)
`1 (3)
`1 (3)
`1 (3)
`0
`0
`0
`0
`1 (3)
`0
`0
`0
`0
`0
`0
`
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`
`ing central review of scans where possible is recom-
`mended.
`Finally, bone
`flare
`can potentially be
`evaluated by the measurement of markers of bone turn-
`over, as changes in bone-specific isoenzyme of alkaline
`phosphatase and osteocalcin have been reported to be
`sensitive predictors of subsequent radiologic response
`(20). These parameters may provide useful clinical infor-
`mation to a physician after only 1 month of therapy, long
`before radiologic evidence of response can be expected
`(21). Imaging techniques, such as positron emission
`tomography, utilizing novel tracers such as radiolabeled
`dihydrotestosterone, are also in development as a poten-
`tial means to more specifically image androgen receptor
`and ligand interactions.
`The PSA response proportion of 67% in this study is
`slightly higher than that observed in previous phase II
`studies with abiraterone acetate (36%–55%; refs. 9, 12,
`22). Potential explanations for this observation are many
`and include the fact that this was a population with less
`extensive disease than in past studies (e.g., median PSA
`level was 23 in this study), no patients were previously
`treated with either chemotherapy or CYP17 inhibitors such
`as ketoconazole, and finally that prednisone may contri-
`bute to a modest increase in the likelihood of a decline in
`PSA levels.
`Grade 3 and 4 toxicities were infrequent in this study,
`and toxicities related to mineralocorticoid excess that
`were observed in earlier studies of abiraterone acetate
`
`4860
`
`Clin Cancer Res; 17(14) July 15, 2011
`
`Clinical Cancer Research
`
`
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`Downloaded from on August 8, 2014. © 2011 American Association for Cancer Research. clincancerres.aacrjournals.org
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`Published OnlineFirst June 1, 2011; DOI: 10.1158/1078-0432.CCR-11-0815
`
`without steroid replacement therapy were rare (9–12).
`Although hypokalemia remained a common event, it
`occurred with lower incidence and severity than was
`observed in patients previously treated with steroid repla-
`cement therapy. This decrease was most likely due to
`suppression of the compensatory increase in ACTH levels
`by prednisone, as well as a heightened awareness of this
`potential toxicity and early intervention with potassium
`supplementation.
`Collectively, these results, as well as the favorable long-
`term safety profile of this combination, suggest that this
`therapy is highly active in CRPC. Advancement of this dose
`and schedule of abiraterone to a pivotal phase III study in
`this patient population is warranted.
`
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