Abiraterone is a new hormonal drug for metastatic castration resistant prostate cancer. In a retrospective analysis, neutrophil/lymphocyte ratio (NLR) ≤ 5 and restricted metastatic spread to either bones or lymph nodes were associated with PSA response to abiraterone. These two variables were combined to a score that was associated with PSA response and OS, in both a training and a validation cohort.
Keywords: prostate cancer, abiraterone acetate, NLR, mCRPC, response
Abstract
Background
Abiraterone acetate (abiraterone) prolongs overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC). This study's objective was to retrospectively identify factors associated with prostate-specific antigen (PSA) response to abiraterone and validate them in an independent cohort. We hypothesized that the neutrophil/lymphocyte ratio (NLR), thought to be an indirect manifestation of tumor-promoting inflammation, may be associated with response to abiraterone.
Patients and methods
All patients receiving abiraterone at the Princess Margaret (PM) Cancer Centre up to March 2013 were reviewed. The primary end point was confirmed PSA response defined as PSA decline ≥50% below baseline maintained for ≥3 weeks. Potential factors associated with PSA response were analyzed using univariate and multivariable analyses to generate a score, which was then evaluated in an independent cohort from Royal Marsden (RM) NHS foundation.
Results
A confirmed PSA response was observed in 44 out of 108 assessable patients (41%, 95% confidence interval 31%–50%). In univariate analysis, lower pre-abiraterone baseline levels of lactate dehydrogenase, an NLR ≤ 5 and restricted metastatic spread to either bone or lymph nodes were each associated with PSA response. In multivariable analysis, only low NLR and restricted metastatic spread remained statistically significant. A score derived as the sum of these two categorical variables was associated with response to abiraterone (P = 0.007). Logistic regression analysis on an independent validation cohort of 245 patients verified that this score was associated with response to abiraterone (P = 0.003). It was also associated with OS in an exploratory analysis.
Conclusions
A composite score of baseline NLR and extent of metastatic spread is associated with PSA response to abiraterone and OS. Our data may help understand the role of systemic inflammation in mCRPC and warrant further research.
introduction
Several new agents were shown to prolong survival of patients with metastatic castration-resistant prostate cancer (mCRPC) after chemotherapy, including cabazitaxel [1], abiraterone [2], enzalutamide [3] and radium-223 [4]. Abiraterone, a CYP17 inhibitor, was shown to improve survival in the post-chemotherapy setting [2]. Subsequently, it was shown to prolong radiographic progression-free survival (PFS) in the chemotherapy-naïve setting, with a trend toward improved overall survival (OS) [5].
Currently, there are no predictive markers of response to abiraterone, and the optimal drug sequencing in mCRPC is unknown. The decision between docetaxel and abiraterone upon disease progression with conventional androgen deprivation is based on clinical factors and practical considerations pertaining drug availability and reimbursement. It is unlikely that sequential administration of these treatments will be studied in a prospective randomized trial.
A retrospective analysis of 156 ketoconazole-treated patients demonstrated that a baseline NLR of above 3 was associated with shorter PFS [6]. The objective of the present study was to identify variables associated with prostate-specific antigen (PSA) response in patients treated with abiraterone. Due to the similar mechanisms of action of abiraterone and ketoconazole (CYP-17 inhibition), we hypothesized that NLR may also be associated with response to abiraterone.
patients and methods
study population
All mCRPC patients treated with abiraterone at the PM in Toronto, Canada, from November 2009 (first drug availability) until March 2013 were reviewed (the training cohort). This study was approved by the PM Research Ethics Boards.
All mCRPC patients treated with abiraterone at the RM NHS Foundation in Sutton, Surrey, UK, served as the validation cohort. Informed consent was obtained on institutional research board approved protocols.
data collection and definitions
Patients in the training cohort were identified through the PM electronic patient record (EPR) using keyword ‘abiraterone’, but only included if treatment was initiated for any period of time. All data were extracted from EPR.
Patients in the validation cohort were identified from pharmacy records, and received abiraterone with prednisolone 10 mg daily or dexamethasone 0.5 mg daily in Phase I, II or III trials (n = 147), expanded access programs (n = 64) or after drug approval (n = 43). Laboratory data were collected from EPR.
Biochemical failure following definitive treatment was defined as a rise in serum PSA of 2 ng/ml above nadir (lowest PSA achieved) according to the Phoenix criteria [7]. Castration-resistance date was defined as the date of first PSA rise or disease progression in the presence of castrate serum testosterone (<1.7 nmol/l).
The primary end point was confirmed PSA response. This was defined according to the Prostate Cancer Working Group 2 criteria as a PSA decline of ≥50% from baseline [8], maintained for ≥3 weeks. Monthly PSA measurements were carried out during the first 3 months of abiraterone, and thereafter every 1–3 months according to physicians' discretion. If no second measurement was available, a decline of ≥50% was considered unconfirmed and inevaluable for the primary end point.
Clinical variables included: age at prostate cancer diagnosis and at the start of abiraterone, times from diagnosis to biochemical failure or mCRPC, and time from mCRPC to abiraterone initiation, Gleason score at diagnosis (≤7 versus 8–10), prior treatment with chemotherapy (yes/no), abiraterone daily dose (1000 mg without food versus 250–500 mg with food) and Eastern Cooperative Oncology Group performance status (ECOG PS).
Laboratory variables included: lactate dehydrogenase (LDH), albumin (ALB), hemoglobin (HGB), alkaline phosphatase (ALP) and PSA. PSA velocity before abiraterone initiation was calculated as the difference between the PSA value on the day of abiraterone initiation and the preceding PSA value divided by the interval between these measurements (ng/ml/month). The NLR before abiraterone initiation was calculated as the ratio of the absolute neutrophil count divided by the absolute lymphocyte count in the blood count, but was not captured for patients with sepsis or those receiving steroids at doses causing leukocytosis (daily steroid equivalence ≥20 mg prednisone [9]).
Radiological variables were metastatic sites before abiraterone initiation, defined on a four-tier scale (1, bone only; 2, lymph node (LN) only; 3, bone and LNs; 4, any visceral involvement).
primary objective and statistical analyses
The primary objective of this study was to identify clinical, laboratory or radiological variables associated with confirmed PSA response to abiraterone, and to generate a score associated with response to abiraterone. As most patients in the PM training cohort were not treated under trial setting, radiological assessment was not carried out at pre-determined intervals. Therefore, radiological PFS could not be assessed for all patients. OS was not used as an end point since most patients in the training cohort were alive at the time of analysis.
Potential variables were analyzed by univariate analysis on the training cohort, using either logistic regression for continuous variables or χ2/Fisher's exact test (depending on cell frequency) for categorical variables. Continuous variables with P-values of <0.1 on univariate analysis were dichotomized by calculating the area under the receiver operating curve (AUC) to identify optimal cutoffs. Multivariable analysis was carried out using logistic regression on all categorical variables with a P-value of <0.1 on univariate analysis. Variables found to be statistically significant were then used to define a categorical score. The association between the score and response or OS was analyzed for the training cohort, and subsequently the validation cohort, using logistic regression.
Odds ratios (OR) and 95% confidence interval (CI) for the different response groups in both cohorts were calculated using logistic regression. All P-values were two-sided and considered significant if <0.05. No correction was made for multiple significance testing. Data analysis was carried out using Statistical Analysis Software (SAS) Version 9.2 (SAS Institute, Inc., Cary, NC).
results
patients and treatment
A total of 116 mCRPC patients received abiraterone with prednisone 5 mg twice daily at PM. Sixty-two patients (53%) received chemotherapy before abiraterone. Twenty patients (17%) received dose-reduced abiraterone (250 or 500 mg daily) with food. The median treatment duration was 5.7 months (range 2 weeks–22.3 months), with 12 patients still receiving abiraterone at the time of analysis. The median follow-up was 13 months, with an estimated median OS of 19.6 months (95% CI 15.3–24.2 months). The NLR at abiraterone initiation was calculated for 108 patients (93%); it was unavailable for four patients, and not calculated for four patients due to sepsis or steroid use. Patient characteristics are shown in Table 1.
Table 1.
Patient characteristics of Princess Margaret (PM) cohort
| Median | Range | |
|---|---|---|
| Age at prostate cancer diagnosis (years; n = 116) | 65 | 45–89 |
| Age at the start of abiraterone (years; n = 116) | 74 | 50–91 |
| Time from diagnosis to biochemical failure (years; n = 61) | 3.2 | 0.08–16.0 |
| Time from diagnosis to mCRPC (years; n = 109) | 4.9 | 0.4–21.9 |
| Time from mCRPC to abiraterone start (years; n = 109) | 1.1 | 0–9.3 |
| Hemoglobin (HGB; normal range 140–180 g/l; n = 113) | 119 | 69–146 |
| Albumin (ALB; normal range 38–50 g/l; n = 113) | 39 | 28–47 |
| Lactate dehydrogenase (LDH; normal range 125–220 U/l; n = 113) | 260 | 118–1971 |
| Alkaline phosphatase (ALP; normal range 40–150 U/l; n = 113) | 111 | 40–1897 |
| Neutrophil-to-lymphocyte ratio (NLR; n = 108) | 3.7 | 0.35–20.0 |
| Prostate-specific antigen (PSA; µg/l; n = 112) | 98 | 2.3–4510.0 |
| Value | n (%) | |
| Gleason score | ≤7 | 46 (40) |
| 8–10 | 49 (42) | |
| Unknown | 21 (18) | |
| Eastern cooperative group performance status at the start of abiraterone (ECOG PS) | 0 | 24 (21) |
| 1 | 63 (54) | |
| ≥2 | 28 (24) | |
| Unknown | 1 (1) | |
| Sites of metastasis at the start of abiraterone | 1, Bone only | 48 (41) |
| 2, LN only | 10 (9) | |
| 3, Bone + LN | 35 (30) | |
| 4, Visceral | 18 (16) | |
| Unknown/no mets | 5 (4) | |
| Prior chemotherapy treatment | Yes | 62 (53) |
| No | 54 (47) | |
| Prior hormonal therapies (sub-groups are not mutually exclusive) | Single-agent prednisone | 42 (36) |
| Ketoconazole | 24 (21) | |
| MDV3100 | 3 (3) | |
| DES | 1 (1) | |
| Dose of abiraterone | 1000 mg, fasting | 96 (83) |
| 250–500 mg with food | 20 (17) |
PSA response
Complete PSA data were available for 108 patients. Of these, 44 (41%) had a confirmed PSA response (95% CI 31%–50%). Response characteristics are shown in Table 2.
Table 2.
Response characteristics of PM cohort
| Evaluable (n) | Responders (n) | Response rate (%) | 95% CI (%) | |
|---|---|---|---|---|
| Total | 108 | 44 | 41 | 31–50 |
| Pre-chemotherapy | 51 | 23 | 45 | 31–59 |
| Post-chemotherapy | 57 | 21 | 37 | 24–49 |
clinical variables associated with PSA response
In univariate analysis, higher values of the continuous variables NLR and LDH were associated with a lower likelihood of response to abiraterone (OR<1; P<0.1). There was a higher likelihood of response to abiraterone (OR > 1) in patients with metastases to either bone or LN only compared with visceral involvement or combined bone and LN disease (Table 3).
Table 3.
Univariate analysis of baseline variables associated with confirmed PSA response
| Variable | n | Odds ratio (95% CI) | Response rate (%) | P-value |
|---|---|---|---|---|
| NLR (continuous) | 104 | 0.8 (0.6–0.9) | N/A | 0.005 |
| LDH (continuous) | 107 | 0.99 (0.99–1.0) | N/A | 0.08 |
| Metastatic sites (categorical): | ||||
| Bone only | 103 | 3.1 (1.2–8.4) | 48 | 0.08 |
| LN only | 5.2 (1.0–26.8) | 63 | ||
| Bone + LNs | Ref | 24 | ||
| Visceral | 1.9 (0.5–6.8) | 38 | ||
| PSA velocity (continuous) | 106 | 1.0 (0.99–1.0) | N/A | 0.14 |
| Albumin (continuous) | 105 | 1.1 (0.97–1.2) | N/A | 0.17 |
| Hemoglobin (continuous) | 108 | 1.0 (0.99–1.04) | N/A | 0.19 |
| ECOG PS (categorical): | ||||
| 0–1 | 108 | 1.8 (0.7–4.5) | 43 | 0.24 |
| 2 | Ref | 31 | ||
| ALP (categorical): | ||||
| Normal | 108 | 1.0 (0.99–1) | 41 | 0.18 |
| Above ULN | Ref | 38 | ||
| Gleason score at diagnosis (categorical) | ||||
| ≤7 | 91 | 1.2 (0.5–2.8) | 44 | 0.64 |
| 8–10 | Ref | 42 | ||
| Age at diagnosis (continuous) | 108 | 0.99 (0.95–1.0) | N/A | 0.62 |
| Age at abiraterone start (continuous) | 108 | 1.0 (0.96–1.0) | N/A | 0.8 |
| Prior chemotherapy treatment (categorical): | ||||
| Yes | 108 | 0.7 (0.3–1.5) | 37 | 0.4 |
| No | Ref | 45 | ||
| Lower dose (categorical): | ||||
| no | 102 | 1.5 (0.5–4.4) | 43 | 0.5 |
| Yes | Ref | 28 | ||
| Time from Dx to biochemical failure (continuous) | 59 | 0.6 (0.8–1.1) | N/A | 0.7 |
| Time from diagnosis to mCRPC (continuous) | 101 | 1.0 (0.9–1.1) | N/A | 0.5 |
| Time from mCRPC to abiraterone start (continuous) | 101 | 1.1 (0.9–1.4) | N/A | 0.27 |
The extent of metastases was collapsed to a binary categorical variable, defined as ‘0’ for metastasis to bone or LN only (‘restricted spread’) or ‘1’ for visceral involvement or combined bone and LN disease (‘extensive spread’). The continuous variables LDH and NLR were dichotomized using optimal cutoffs of 5 for NLR and 1.2 times the upper limit of normal (ULN) for LDH. These three binary categorical variables retained association with the primary end point by univariate analysis (supplementary Table S3, available at Annals of Oncology online).
Multivariable analysis showed that an NLR ≤ 5 and restricted spread were independently associated with PSA response (Table 4). A score (designated NLR_MET) was defined based on these two variables. The score was calculated for 99 patients for whom both variables were available, and ranged between 0 (NLR ≤ 5 and restricted spread) and 2 (NLR > 5 and extensive spread). This score was significantly and inversely associated with PSA response to abiraterone (P = 0.007; AUC = 0.697), with higher values associated with lower response rates. The score allowed the categorization of patients to three response groups, with a PSA response rate of 58%, 36% and 6% for score values of 0, 1 and 2, respectively (Table 5).
Table 4.
Multivariable analysis of confirmed prostate-specific antigen response (training cohort)
| Variable | n (%) | OR (95% CI) | RR (%) | P-value |
|---|---|---|---|---|
| NLR ≤ 5 | 72 (69) | 4.3 (1.4–13.3) | 49 | 0.01 |
| NLR > 5 | 32 (31) | Ref | 16 | |
| Bone only/LN only | 54 (52) | 2.8 (1.2–6.9) | 50 | 0.02 |
| visceral or multiple sites | 49 (48) | Ref | 29 | |
| LDH ≤ 1.2 × ULN | 57 (53) | 1.6 (0.6–4) | 47 | 0.31 |
| LDH > 1.2 × ULN | 50 (47) | Ref | 32 |
Table 5.
Response rates groups based on NLR_MET score in the training cohort
| Cohort | score | n (%) | RR (%) | OR | 95% CI | P-value (association/trend) | AUC |
|---|---|---|---|---|---|---|---|
| PM | 0 | 38 (38) | 58 | 2.4 | 0.99–5.86 | 0.007/0.0002 | 0.697 |
| 1 | 44 (44) | 36 | Ref | ||||
| 2 | 17 (17) | 6 | 0.11 | 0.01–0.90 | |||
| RM | 0 | 106 (43) | 50 | 1.7 | 0.96–2.97 | 0.003/0.0005 | 0.620 |
| 1 | 94 (38) | 37 | Ref | ||||
| 2 | 45 (18) | 20 | 0.42 | 0.18–0.98 |
validation
The score was validated in an independent cohort (RM). Patient characteristics are given in supplementary Table S1, available at Annals of Oncology online. Two hundred and fifty patients were assessable, of whom 97 (39%: 95% CI 33–45%) had a confirmed PSA response to abiraterone (supplementary Table S2, available at Annals of Oncology online) and 245 had known NLR and disease spread at abiraterone initiation. The NLR_MET score was calculated for 245 patients, and significantly associated with response (P = 0.003; AUC = 0.620). Patients with scores of 0, 1 and 2 had response rates of 50%, 37% and 20%, respectively (Table 5).
exploratory analysis of OS
In an exploratory analysis, we found that the NLR_MET score was significantly associated with OS in both cohorts, with 12-month OS of 84%–90%, 56%–68% and 48%–53% for scores of 0, 1 and 2, respectively (Table 6).
Table 6.
Survival rates at 12 months based on NLR_MET score in the PM and Royal Marsden cohort
| Score | PM cohort |
RM cohort |
||||
|---|---|---|---|---|---|---|
| Survival rate at 12 months (%; 95% CI) | Median OS (months; 95% CI) | P-value | Survival rate at 12 months (%; 95% CI) | Median OS (months; 95% CI) | P-value | |
| 0 | 90 (76–96) | 23 (14.8–32.1) | 0.014 | 84 (75–90) | 29.7 (22.3–38.8) | <0.001 |
| 1 | 68 (52–80) | 18 (14.0–) | 56 (46–65) | 16.3 (10.8–20.2) | ||
| 2 | 53 (28–73) | 14 (2.3–) | 48 (31–63) | 11.2 (6.5–13.9) | ||
discussion
Our results confirm abiraterone as an active drug in mCRPC. In the PM post-chemotherapy subgroup, the confirmed PSA response of 37% is close to that reported in COU-AA-301 (29%) [2]. The higher PSA response rate (45%) in the chemo-naïve subgroup is consistent with higher response rates reported in COU-AA-302 (62%) [5], although direct comparison is inappropriate since PSA response in COU-AA-302 did not include mandatory confirmation [2, 5]. A confirmed PSA decline ≥50% was designated as our primary end point since PSA values before and during abiraterone were available for the entire training cohort, whereas radiological surveillance was not routinely carried out for all. PSA decline was shown to be associated with increased survival in the chemotherapy setting, but does not meet all criteria for surrogacy of OS [10, 11].
Two pre-treatment variables—NLR ≤ 5 and restricted metastases—were associated with higher rates of confirmed PSA response to abiraterone in both cohorts. The score categorizes patients into three response groups—‘high’, with response rates of 50%–58%, ‘intermediate’, with response rates of 36%–37% and ‘low’, with response rates of 6%–20%. This categorization may be useful in estimating the probability of response to abiraterone in routine practice. The score uses readily available clinical data, and merits further evaluation as a way to stratify patients in clinical trials.
The NLR has been found to be prognostic in many solid tumors, with high NLR associated with worse OS and higher recurrences [12, 13]. The biological basis of this remains unclear, but is likely related to altered tumor-inflammatory cell interactions. Tumor-promoting inflammation is considered a hallmark of progressive malignancy [14]. A high NLR can be caused by a relatively high neutrophil count or a relatively low lymphocyte count. The former may represent an increased neutrophil-dependent inflammation, which is potentially pro-tumorigenic [15]. Circulating inflammatory cells produce cytokines, which may contribute to cancer progression [16]. A relative lymphopenia may reflect a suboptimal lymphocyte-mediated response to malignancy, although intra-tumoral, rather than systemic lymphopenia, may be more important in tumor promotion [17]. An expression signature associated with B- and T-lymphocyte function is associated with OS [18]. Our new data associating NLR with PSA response to abiraterone support further examination of altered immune responses with treatment outcomes.
Less is known about the potential of NLR to predict response to anti-neoplastic treatment. High NLR is associated with lower responses to gefitinib in EGFR-mutated lung cancer [19]. An NLR > 3 is associated with worse PFS in mCRCP patients receiving ketoconazole, a drug whose mechanism of action is similar to abiraterone [6].
The extent of metastases is associated with response to docetaxel, with or without OGX-011 [20]. The underlying pathophysiology is unknown, although patients with restricted metastases probably have less aggressive or lower volume disease.
The times between diagnosis and biochemical failure or castration-resistance, and between castration resistance and abiraterone initiation were not associated with PSA response. This suggests that response to abiraterone is a biological tumor characteristic, rather than it being associated with prolonged disease course or a prolonged previous response to biochemical castration.
This study has several limitations. It is a retrospective study of a varied patient population. Unequal distribution of unidentified clinicopathological parameters in our training cohort may have biased the results; however, our score was validated. Secondly, our patient numbers were small; factors not found to be significantly associated with outcome here might be important in a larger population. Thirdly, leukocyte counts may be influenced by infection or drugs unaccounted for in this analysis, although when such factors were known, the NLR was excluded. Finally, although our analysis suggests there is a group of patients with a disappointingly low response rate (≤20%) to abiraterone, it cannot determine whether these patients have a higher chance of responding to chemotherapy or other hormonal drugs. Therefore, it would be premature to use this study as a guide for drug sequencing in mCRPC.
Notwithstanding the above limitations, our analysis supports further clinical and translational research to elucidate the relationship between systemic inflammation, mCRPC and its treatment.
funding
This work was supported by funds from the Princess Margaret Prostate Cancer Research Program (PMH Foundation).
disclosure
AO, CP, GA and JSB were all employed, at the time of manuscript preparation, by the Institute of Cancer research, Sutton, Surrey, UK, that has commercial interest in abiraterone. AJT received honoraria from Janseen-Cilag. CP received lecture fees from Sanofi-Aventis and travel support from Sanofi-Aventis and Janssen-Cilag. SSS has a consultant role with Janssen-Ortho, received Honoraria from Janssen-Ortho, Pfizer and Sanofi, and received research funding from Janssen-Ortho, Pfizer and Sanofi. GA has a consultant role with Janssen-Cilag, Veridex, Roche/Ventana, Astellas, Novartis and Millenium Pharmaceuticals, received Honoraria from Janssen-Gilag, Ipsen, Takeda and Sanofi-Aventis and received other remuneration from Janssen-Cilag, Veridex, Roche/Ventana, Astellas, Novartis and Millenium Pharmaceuticals. JSB has a consultant role with Johnson & Johnson, and received honoraria from Johnson & Johnson. AMJ has received research funding from Janssen-Ortho. All remaining authors have declared no conflicts of interest.
Supplementary Material
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