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Outcomes with Abiraterone Acetate in Metastatic Castration-resistant Prostate Cancer Patients Who Have Poor Performance Status

European Urology 2015 Mar;67(3):441-7

Abstract

Background

Although abiraterone acetate (abiraterone) has proven efficacy in two randomised phase 3 trials in metastatic castration-resistant prostate cancer (mCRPC), patients who had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥2 were either excluded or under-represented in these trials.

Objective

To compare outcomes in ECOG PS 0–1 and ≥2 in mCRPC patients treated with abiraterone.

Design, setting, and participants

Cancer registries from three Canadian centres were used to retrospectively identify mCRPC patients (postdocetaxel and docetaxel-naïve) treated with abiraterone. ECOG PS, clinicopathologic characteristics, prostate-specific antigen (PSA) response, and survival data were collected.

Outcome measurements and statistical analysis

Survival outcomes were estimated using the Kaplan-Meier method and compared using the log-rank test. Cox proportional hazards modelling was used to examine the effect of clinicopathologic characteristics on overall survival (OS) and time to PSA progression.

Results and limitations

A total of 519 patients were identified; 61% (n = 318) and 39% (n = 201) were ECOG PS 0–1 and ≥2, respectively. ECOG PS 0–1 patients were significantly more likely than PS ≥2 patients to achieve a PSA decline ≥50% from baseline (45% vs 32%; p = 0.003, Fisher exact test) and had significantly longer median time to PSA progression (5.2 mo vs 4.1 mo; p = 0.023), median treatment duration (7.4 mo vs 4.5 mo; p < 0.001), and median OS (20.0 mo vs 9.1 mo; p < 0.001). On multivariate analysis, ECOG PS was a significant factor for OS (p < 0.001), time to PSA progression (p = 0.043), and PSA decline (p = 0.002). Potential limitations include the retrospective study design and subjective nature of ECOG PS classification.

Conclusions

ECOG PS ≥2 mCRPC patients treated with abiraterone have inferior outcomes compared with ECOG 0–1 patients, especially in regard to OS. These data indicate that early initiation of abiraterone prior to a decline in PS may be warranted.

Patient summary

We found that advanced prostate cancer patients who have worse performance status (PS) derive less benefit from abiraterone, indicating that earlier treatment before PS declines could improve outcomes.

Take Home Message

We show that metastatic castration-resistant prostate cancer patients who have Eastern Cooperative Oncology Group performance status (PS) ≥2 have inferior outcomes compared with PS 0–1 patients after treatment with abiraterone. Early initiation of abiraterone before a decline in PS occurs may be warranted.

Keywords: Abiraterone acetate, Prostate cancer, Castration-resistant prostate cancer, ECOG, Performance status.

1. Introduction

The therapeutic armamentarium for metastatic castration-resistant prostate cancer (mCRPC) has rapidly expanded in recent years [1] and [2]. Among the agents now available to treat mCRPC is abiraterone acetate (abiraterone), a novel, orally available inhibitor of CYP17, an enzyme centrally involved in extragonadal androgen synthesis [3]. In phase 3 randomised trials in mCRPC, abiraterone improves radiographic progression-free survival in docetaxel-naïve patients (COU-AA-302 trial) [4] and overall survival (OS) in patients previously treated with docetaxel (COU-AA-301 trial) [5]. The COU-AA-302 trial was restricted to Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0–1 patients, while in the COU-AA-301 study, only 10% of enrolled patients were ECOG PS 2. Thus, the activity of abiraterone in ECOG PS ≥2 patients is not well described, which may have important implications for the generalizability of the COU-AA-301 and COU-AA-302 trials, because in clinical practice, abiraterone is commonly used in ECOG PS ≥2 patients [6]. Using an unselected cohort from three large cancer centres in Canada, the aim of this retrospective study was to compare the efficacy of abiraterone in ECOG PS ≥2 and 0–1 patients.

2. Patients and methods

2.1. Patient population

Cancer registries at the British Columbia Cancer Agency (BCCA) Alberta Health Services–Cancer Care (AHS-CC) and Princess Margaret Cancer Centre (PM) were reviewed to identify mCRPC patients treated with abiraterone. A total of 519 eligible patients were identified—325 at BCCA, 78 at AHS-CC, and 116 at PM. ECOG PS at initiation of abiraterone was recorded as per assessment of the treating clinician. Patient demographics, prior treatments, and clinicopathologic characteristics were also documented from the medical records of each patient. Research ethics board approval was obtained at all sites. Data were transferred between centres in a deidentified manner.

2.2. Outcomes

For each patient, prostate-specific antigen (PSA) response and modes of progression on abiraterone (PSA, measurable, clinical) were recorded. PSA and measurable progression were classified as per Prostate Cancer Working Group 2 criteria [7], while clinical progression was defined as worsening disease-related symptoms (pain, fatigue, anorexia or weight loss, or urinary symptoms) necessitating a change in antineoplastic therapy (eg, use of palliative bone radiation therapy or institution of new systemic therapy) or a decrease in ECOG PS ≥2 levels. Overall survival was defined as the time from initiation of abiraterone to death of any cause or censoring on 1 November 2013.

2.3. Statistics

Baseline clinicopathologic characteristics in ECOG PS 0–1 and ≥2 patients were compared using the Fisher exact test and Student t test. Time to PSA progression, treatment duration, and OS were estimated using the Kaplan-Meier method and compared using the log-rank test. Cox proportional hazards modelling was used to examine the effect of baseline characteristics on OS and time to PSA progression. Multivariate logistic regression was used to examine the correlation between baseline characteristics and PSA decline ≥50%.

Multivariate survival analysis was performed with a prognostic index recently developed from a post hoc analysis of the COU-AA-301 trial [8]. Development of this index involved the following steps: (1) Important clinicopathologic factors were identified and dichotomised for high and low values, as needed; (2) baseline clinicopathologic factors were assessed for association with OS using a univariate Cox proportional hazards model; (3) factors that were significant on univariate analysis were incorporated in a step-wise procedure into a multivariate Cox proportional hazards regression model; (4) factors that were significant on multivariate analysis were incorporated into the final model, which was subject to validation by a bootstrapping approach; (5) the C-index was used to assess the accuracy of the model, which consisted of six factors; and (6) patients were categorised into risk groups based on the number of baseline risk factors with median OS calculated for each risk group.

3. Results

3.1. Patient population

Baseline clinicopathologic characteristics stratified by ECOG PS are presented in Table 1. The following factors significantly differed between ECOG PS 0–1 and ≥2 patients: median time from commencement of androgen depravation therapy (ADT) to starting abiraterone, serum lactate dehydrogenase (LDH), serum alkaline phosphatase (ALP), and serum albumin. There was also a strong trend towards higher rates of visceral metastases in ECOG PS ≥2 patients, although the difference did not reach statistical significance, which may be accounted for by the relatively small total number of patients who had visceral metastases (n = 81). The proportion of patients who had received prior docetaxel did not differ between the two groups.

Table 1

Baseline characteristics at initiation of abiraterone acetate stratified by Eastern Cooperative Oncology Group performance status

CharacteristicOverall cohortECOG 0–1 (n = 318)ECOG ≥2 (n = 201)p valueTest
Age, yr:
 Mean (range)73 (45–96)72.7 (48–96)73.9 (45–96)0.15t test
Gleason score, no. (%):
 6–7159 (31)105 (33)54 (27)
 8–10264 (51)157 (49)107 (53)0.18Fisher exact
 Unknown96 (18)56 (18)40 (20)
Disease sites, no. (%):
 Bone416 (80)249 (78)167 (83)0.21Fisher exact
 Lymph node193 (37)119 (37)74 (37)0.93Fisher exact
 Visceral81 (16)42 (13)39 (19)0.06Fisher exact
Prior therapy:
 Time from start of ADT, mean in mo (range)Docetaxel, no. (%)59 (3–262)64 (4–262)52 (3–251)0.004t test
 No. cycles, median (range)334 (64)210 (66)124 (62)0.35Fisher exact
7 (1–24)8 (1–24)6 (1–22)
Laboratory:
 LDH, mean, U/l (range)243 (106–2035)292 (119–1972)384 (105–2635)0.001t test
  Elevated, no. (%)231 (45)129 (41)102 (51)
  Normal, no. (%)255 (49)173 (54)82 (41)
  Unknown, no. (%)33 (6)16 (5)17 (9)
 ALP, mean, U/l (range)121 (30–2189)193 (30–1897)262 (34–2189)0.006t test
  Elevated, no. (%)195 (38)102 (32)93 (47)
  Normal, no. (%)316 (61)212 (67)104 (52)
  Unknown, no. (%)8 (2)4 (1)4 (1)
 Albumin, mean, g/l (range)37 (13–52)37 (17–52)35 (13–48)<0.001t test
  Low, n (%)171 (33)88 (28)83 (41)
  Normal, no. (%)296 (57)204 (64)92 (46)
  Unknown, no. (%)52 (10)26 (8)26 (13)

ADT = androgen-deprivation therapy; ALP = alkaline phosphatase; ECOG = Eastern Cooperative Oncology Group; LDH = lactate dehydrogenase.

3.2. Treatment outcomes

As of 1 November 2013, 410 (79%) patients had ceased abiraterone treatment. In these patients, 391 (95%), 266 (65%), and 150 (29%) had PSA, clinical, and objective disease progression, respectively (more than one mode of progression could apply for any one patient). Treatment outcomes with abiraterone in ECOG PS 0–1 and ≥2 patients are presented in Table 2. ECOG PS 0–1 patients were significantly more likely to attain a PSA decline ≥50% and had significantly longer median time to PSA progression, median treatment duration, and median OS (Fig. 1A). Notably, an OS benefit for ECOG PS 0–1 patients was seen in both postdocetaxel (19.2 mo vs 8.7 mo; Fig. 1B) and docetaxel-naïve patients (26.0 mo vs 10.3 mo; Fig. 1C). No significant difference was seen in the proportion of ECOG PS ≥2 and 0–1 patients who had PSA (72% vs 77%; p = 0.21) or objective disease progression (25% vs 31%; p = 0.31), but clinical progression was significantly more frequent in the ECOG PS ≥2 cohort (63% vs 44%; p < 0.001).

Table 2

Outcomes with abiraterone acetate stratified by Eastern Cooperative Oncology Group performance status

CharacteristicECOG 0–1ECOG ≥2p valueTest
PSA decline ≥50%:
 All patients, no. (%)142 (45)63 (31)0.003Fisher exact
  95% CI39.2–50.025.5–38.2
 Postdocetaxel, no. (%)92 (44)35 (28)0.005Fisher exact
  95% CI37.3–50.621.0–36.7
 Docetaxel naïve, no. (%)50 (46)28 (36)0.23Fisher exact
  95% CI37.2–55.726.5–47.5
Duration of treatment:
 All patients, mo, median7.44.5<0.001Log-rank
  95% CI6.5–8.33.8–5.2
 Postdocetaxel, mo, median7.14.0<0.001Log-rank
  95% CI6.0–8.33.1–4.8
 Docetaxel naïve, mo, median7.94.90.003Log-rank
  95% CI5.6–10.23.4–6.3
Time to PSA progression:
 All patients, mo, median5.24.10.023Log-rank
  95% CI4.8–5.93.3–5.0
 Postdocetaxel, mo. median4.73.50.012Log-rank
  95% CI4.0–5.52.3–4.8
 Docetaxel naïve, mo, median5.94.60.534Log-rank
  95% CI5.2–6.74.3–4.9
OS:
 All patients, mo, median20.09.1<0.001Log-rank
  95% CI17.1–22.97.7–10.4
 Postdocetaxel, mo, median19.28.7<0.001Log-rank
  95% CI16.4–22.07.1–10.3
 Docetaxel naïve, mo, median26.010.3<0.001Log-rank
  95% CI9.0–43.07.9–12.7

CI = confidence interval; ECOG = Eastern Cooperative Oncology Group; OS = overall survival; PSA = prostate-specific antigen.

gr1

Fig. 1

Kaplan-Meier analysis of overall survival stratified by Eastern Cooperative Oncology Group performance status in (A) all, (B) postdocetaxel, and (C) chemotherapy-naïve metastatic castration-resistant prostate cancer patients treated with abiraterone acetate.

ECOG = Eastern Cooperative Oncology Group.

3.3. Postabiraterone treatment

A total of 207 patients (40%) patients received at least one systemic agent after abiraterone, with 57 receiving more than two lines. The most common treatments delivered were enzalutamide (n = 130), docetaxel (n = 77), mitoxantrone (n = 19), and cabazitaxel (n = 15). ECOG PS 0–1 patients were significantly more likely than PS ≥2 patients to receive postabiraterone systemic treatment (50% vs 24%, p < 0.001; Fisher exact test).

3.4. Multivariable analyses

Multivariable analysis for OS was performed using factors from a prognostic index recently developed from a post hoc analysis of the COU-AA-301 trial [8] (see the “Patients and methods” section for details of how this index was constructed). The six factors in this index are serum LDH (above the upper limit of normal [ULN; 250 IU/l]) vs less than or equal to the ULN), ECOG PS (2 vs 0–1), visceral metastases (present vs absent), serum albumin (≤4 g/dl vs >4 g/dl), serum ALP (above the ULN [160 IU/l]) vs less than or equal to the ULN), and time from commencement of ADT to starting abiraterone (≤36 mo vs >36 mo). In addition to these factors, postabiraterone systemic treatment (none vs any) and prior docetaxel treatment (no vs yes) were included as variables in the multivariable analysis. Using these factors, ECOG PS was confirmed as an independent prognostic factor for OS, together with postabiraterone systemic treatment, serum LDH, visceral metastases, and serum albumin (Table 3).

Table 3

Multivariable analysis examining the association between clinicopathologic factors and overall survival in metastatic castration-resistant prostate cancer patients treated with abiraterone acetate

VariableHR95% CIp value
Duration of ADT prior to abiraterone (≤36 mo vs >36 mo)1.3060.985–1.7310.063
ECOG PS (2 vs 0–1)2.1661.624–2.888<0.001
Serum LDH (greater than the ULN [250 IU/l] vs less than or equal to the ULN)1.4831.113–1.9770.007
Serum ALP (greater than the ULN [160 IU/l] vs less than or equal to the ULN)1.3430.999–1.8050.051
Visceral metastases (present vs absent)1.9151.381–2.657<0.001
Serum albumin (≤4 g/dl vs >4 g/dl)1.6661.089–2.5470.019
Postabiraterone systemic treatment (none vs any)2.9112.159–3.927<0.001
Prior docetaxel treatment (no vs yes)0.7750.558–1.0760.127

ALP = alkaline phosphatase; ADT = androgen-deprivation therapy; CI = confidence interval; ECOG = Eastern Cooperative Oncology Group; HR = hazard ratio; LDH = lactate dehydrogenase; PS = performance status; ULN = upper limit of normal.

Multivariable analysis was also performed for time to PSA progression and PSA decline ≥50% using all of the aforementioned factors, with the exception of postabiraterone systemic treatment (which would not be expected to affect PSA progression or PSA decline while on abiraterone). Using the remaining seven factors, ECOG PS and time from commencement of ADT to starting abiraterone were identified as independent prognostic factors for time to PSA progression (Table 4). A significant correlation between ECOG PS and PSA decline ≥50% was also demonstrated (Table 5).

Table 4

Multivariable analysis examining the association between baseline clinicopathologic factors and time to prostate-specific antigen progression in metastatic castration-resistant prostate cancer patients treated with abiraterone acetate

VariableHR95% CIp value
Duration of ADT prior to abiraterone (≤36 mo vs >36 mo)1.2751.022–1.5910.031
ECOG PS (2 vs 0–1)1.2681.007–1.5970.043
Serum LDH (above the ULN [250 IU/l] vs less than or equal to the ULN)1.1340.901–1.4260.284
Serum ALP (above the ULN [160 IU/l] vs less than or equal to the ULN)1.1750.925–1.4930.187
Visceral metastases (present vs absent)1.1510.848–1.5620.366
Serum albumin (≤4 g/dl vs >4 g/dl)1.2040.917–1.5800.182
Prior docetaxel treatment (no vs yes)0.9660.766–1.2190.771

ALP = alkaline phosphatase; ADT = androgen-deprivation therapy; CI = confidence interval; ECOG = Eastern Cooperative Oncology Group; HR = hazard ratio; LDH = lactate dehydrogenase; PS = performance status; ULN = upper limit of normal.

Table 5

Multivariable analysis examining the association between baseline clinicopathologic factors and prostate-specific antigen decline ≥50% in metastatic castration-resistant prostate cancer patients treated with abiraterone acetate

VariableHR95% CIp value
Duration of ADT prior to abiraterone (>36 mo vs ≤36 mo)1.1150.737–1.6860.607
ECOG PS (0–1 vs 2)2.0131.299–3.1190.002
Serum LDH (less than or equal to the ULN vs above the ULN [250 IU/l])1.3550.888–2.0650.158
Serum ALP (less than or equal to the ULN vs above the ULN [160 IU/l])0.6220.403–0.9620.033
Visceral metastases (absent vs present)1.2430.697–2.2160.462
Serum albumin (>4 g/dl vs ≤4 g/dl)1.0940.658–1.8180.729
Prior docetaxel treatment (yes vs no)0.8800.570–1.3590.564

ALP = alkaline phosphatase; ADT = androgen-deprivation therapy; CI = confidence interval; ECOG = Eastern Cooperative Oncology Group; HR = hazard ratio; LDH = lactate dehydrogenase; PS = performance status; ULN = upper limit of normal.

4. Discussion

In this multicentre, retrospective study, we examined outcomes in ECOG PS 0–1 and ≥2 mCRPC patients treated with abiraterone. Across a cohort of 519 patients, we found that ECOG ≥2 patients had significantly inferior outcomes compared with ECOG 0–1 patients in terms of the proportion of patients who experienced PSA decline ≥50% (45% vs 32%), median time to PSA progression (5.2 mo vs. 4.1 mo) and median OS (20.0 mo vs 9.1 mo). Of note, the survival disadvantage for ECOG PS ≥2 patients in this study was observed in both the postdocetaxel and docetaxel-naïve cohorts. Although no survival data with abiraterone in docetaxel-naïve ECOG PS ≥2 patients has been published, a limited subset (10.6%) of ECOG PS 2 patients were enrolled in the COU-AA-301 trial. Importantly, survival in those patients (median OS of 7.3 mo) was not significantly different from patients in the prednisone monotherapy arm (median OS of 7.0 mo).

The poor survival outcomes seen in ECOG PS ≥2 patients in this study and in ECOG PS 2 patients in the COU-AA-301 trial illustrate the importance of considering patient PS when deciding on the optimal time to initiate systemic anticancer therapy. Although the limited survival of ECOG PS ≥2 patients previously treated with docetaxel was not altogether surprising, it is notable that the median OS in ECOG PS ≥2 docetaxel-naïve patients was only 1.6 mo longer than for the postdocetaxel cohort. Thus, delaying initiation of abiraterone until deterioration of PS may lessen the survival benefit achieved with abiraterone in both docetaxel-naïve and postdocetaxel mCRPC patients. In turn, close monitoring of mCRPC patients for the development or worsening of cancer-associated symptoms to initiate abiraterone prior to a decline in PS may result in improved survival outcomes.

Although nearly one-third of ECOG PS ≥2 patients in this study had a PSA decline ≥50% in response to abiraterone, the limited survival of these patients supports novel therapeutic strategies for this patient population. Not unexpectedly, we found that patients who had ECOG PS ≥2 had a more aggressive disease phenotype characterised by higher LDH and ALP and lower albumin than ECOG PS 0–1 patients. Drawing a parallel with endocrine receptor–positive metastatic breast cancer, where chemotherapy is favoured over hormone therapy (HT) for rapidly progressive disease [9], it is conceivable that cytotoxic chemotherapy could have greater antitumour efficacy than HT in patients who have aggressive disease. A comparison of these two approaches in a randomised trial would be informative.

A notable aspect of our study is that nearly 40% of patients were ECOG PS ≥2. This particular finding affects the generalizability of the COU-AA-301 and COU-AA-302 trials to the “real-world” nontrial patient population. Interestingly, in other pivotal phase 3 randomised trials of agents shown to increase OS in mCRPC, including docetaxel [10], enzalutamide [11], cabazitaxel [12], radium-223 dichloride [13], and sipuleucel-T [14], ECOG PS ≥2 patients composed no more than 15% of total accrual. Thus, issues regarding the potential generalizability of clinical trial data to mCRPC patients are by no means exclusive to abiraterone.

We acknowledge that this study has several limitations in addition to its retrospective design. Details of comorbid diseases were not available, and we cannot exclude differences between ECOG PS 0–1 and ≥2 patients in this respect. Several other baseline clinicopathologic characteristics differed between ECOG PS 0–1 and ≥2 patients, although PS remained an independent prognostic factor on multivariate analysis for OS, time to PSA progression, and PSA decline ≥50%. Because of the subjective nature of determining PS (in particular, the relatively subtle difference in grading ECOG PS 1 vs 2) and the fact that a large group of physicians at several centres provided care to patients, we also cannot rule out the possibility that some patients may have received an inaccurate ECOG PS classification. Finally, we note that postabiraterone systemic treatment was delivered more frequently in ECOG PS 0–1 patients and was significantly associated with OS. Nevertheless, ECOG PS remained a significant prognostic factor, even with the inclusion of postabiraterone systemic treatment in the multivariate analysis for OS.

5. Conclusions

Using a large cohort of mCRPC patients across three centres, we examined outcomes with abiraterone in a patient population that has been largely excluded from prior reports, namely, ECOG PS ≥2 patients. Our data indicate that mCRPC patients who have better PS derive greater benefit from abiraterone, highlighting the importance of careful patient selection and optimisation of PS prior to commencing abiraterone.


Author contributions: Kim N. Chi had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Chi, Eigl, Azad.

Acquisition of data: Chi, Eigl, Azad, Leibowitz-Amit, Lester, Kollmannsberger, Murray, Clayton, Heng, Joshua.

Analysis and interpretation of data: Chi, Eigl, Azad.

Drafting of the manuscript: Chi, Eigl, Azad, Murray, Heng, Joshua.

Critical revision of the manuscript for important intellectual content: Chi, Eigl, Azad, Murray, Heng, Joshua.

Statistical analysis: Azad.

Obtaining funding: None.

Administrative, technical, or material support: Kollmannsberger, Eigl, Azad, Clayton.

Supervision: Chi, Eigl.

Other (specify): None.

Financial disclosures: Kim N. Chi certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Dr Chi received research funding from OncoGenex Technologies Inc., Astellas, Janssen, and Novartis and is a consultant for Janssen, Astellas, Amgen, Bayer, Millennium, Novartis, and Sanofi. Dr Eigl received an unrestricted educational grant from Janssen. Dr Azad received research funding from Astellas. Dr Joshua received research funding from Janssen-Ortho.

Funding/Support and role of the sponsor: None.

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Footnotes

a Department of Medical Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada

b Division of Medical Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada

c Tom Baker Cancer Centre, University of Calgary, Calgary, Alberta, Canada

Corresponding author. Department of Medical Oncology, BC Cancer Agency, 600 West 10th Avenue, Vancouver, BC, V5Z 4E6 Canada. Tel. +1 604 877 6000; Fax: +1 604 877 0585.