Abstract
BACKGROUND.
Prognostic factors associated with clinical outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with a novel androgen receptor-directed therapies (ARDT) in the second line setting has not been formally evaluated.
PATIENTS AND METHODS.
We retrospectively reviewed and analyzed medical records of all patients with mCRPC who received sequential treatment with ARDT. We analyzed potential clinical factors associated with post treatment endpoints including 50% decline in prostatic-specific antigen (PSA), PSA-progression-free survival (PFS), clinical or radiographic PFS and overall survival (OS). Prognostic univariate and multivariate Cox proportional hazard models were developed and assessed.
RESULTS.
One hundred twenty-six patients with mCRPC treated with a second-line novel ARDT were included. Overall, 50% decline in PSA was observed in 22% of patients and a median PSA-PFS of 2.9 months and a PFS of 3.6 months. After adjusting for potential confounders including prior exposure to docetaxel and number of prior antiandrogen agents, time to development of CRPC was an independent factor associated with PSA-PFS (hazard ratio [HR]: 0.99; 95% confidence interval [CI]: 0.99–1; P = 0.02) and PFS (HR: 0.99; CI: 0.98–1; P = 0.01). PSA response (50% decline) to first-line novel ARDT correlated negatively with PSA-PFS with second-line novel ARDT (HR: 1.7; 95% CI: 1.14–2.53; P = 0.009) and lower pre-treatment levels of albumin were associated with shorter PFS (HR: 0.56; 95% CI: 0.32–0.97; P = 0.03). Performance status, pre-treatment levels of albumin, extent of disease and time to development CRPC were associated with OS.
CONCLUSIONS.
Second-line ARDT is associated with modest outcomes in patients with mCRPC. Time to development of CRPC is the strongest predictor of PSA response, PSA-PFS and OS which suggest that intrinsic resistance to AR directed treatment is the major treatment outcome factor in these patients. Future studies in patients receiving long term ARTD should include the identification of predictive biomarkers to facilitate treatment selection.
Keywords: castration-resistant prostate cancer, androgen receptor, prognostic factors, enzalutamide and abiraterone
INTRODUCTION
The androgen receptor (AR) remains a key driver of tumor growth in castration-resistant prostate cancer. Based on this rationale, a new generation of AR-directed therapies has been successfully developed: abiraterone acetate, a CYP17 inhibitor which prevents testicular, adrenal and intratumoral androgen synthesis and enzalutamide, a second generation AR antagonist with a higher affinity for the AR compared with first generation antiandrogens. Both agents have yielded an improvement in OS when compared to placebo in patients with mCRPC [1–4].
The four pivotal phase III studies with abiraterone and enzalutamide were restricted to patients previously untreated with novel AR-targeted therapies. Treatment with second-line novel ARDT has not been prospectively evaluated to date. However, small retrospective series have demonstrated that the effectiveness of second-line ARDT is low in patients pre-treated with abiraterone/enzalutamide, docetaxel, or both [5–8]. Collectively, these series have reported PSA decline (≥50%) in 5–38% of patients and a median PFS/time to PSA progression ranging from 2.5 to 4 months. Despite these modest results and the lack of prospective evaluation of sequential AR-targeted therapies, second-line therapy with abiraterone and enzalutamide is commonly used in clinical practice. Various mechanism of resistance to novel second-line ARDT including AR splice variant AR-V7, AR point mutations, AR phosphorylation or post-translational modifications to the AR among others have been to focus of major studies and are currently being evaluated [9] as potential molecular biomarkers in tumor cells of patients with mCRPC that may facilitate treatment selection. In the meantime, the identification of prognostic clinical factors and risk groups to accurately assess the clinical benefit of sequential AR targeted treatment and potentially guide clinical management is of paramount importance.
We explored the effect of pre-treatment clinical factors and their relationship with outcomes in patients with metastatic CRPC treated with second-line ARDT. The ultimate aim of this analysis is to define potential prognostic factors associated with PSA-PFS, PFS and OS in patients with metastatic CRPC using a novel ARDT in the second line setting. This study specifically includes mCRPC patients treated with sequential novel AR targeted treatments (abiraterone and enzalutamide).
PATIENTS AND TREATMENTS
This was a retrospective, single-institution analysis that included all consecutive patients with mCRPC who were treated with sequential novel ARDT. The population comprised patients with histologically confirmed prostate adenocarcinoma, progressive disease despite “castration levels” of serum testosterone (<50 ng per deciliter [dl]) with continuous LHRH agonist/antagonist therapy, and documented metastatic lesions. For this study, baseline demographic characteristics, as well as, clinical and analytic factors prior to second-line ARDT irrespective of the agent administered were recorded.
Abiraterone was administered orally at a starting dose of 1,000 mg once a day with prednisone 5 mg twice a day and enzalutamide was also administered continuously at a starting dose of 160 mg daily. Treatment continued until disease progression, lack of clinical benefit or unacceptable toxicity.
While this is a retrospective analysis, all follow-up assessments were prospectively defined as follows: PSA measurements were obtained every 1–2 months, and CT of the chest, abdomen, and pelvis and technetium-99m bone scanning were performed every 2–4 months. Therapy with enzalutamide or abiraterone was continued until disease progression, lack of clinical benefit, or the occurrence of drug-related unacceptable toxicity. Institutional review board approval was obtained prior to data collection.
DATA COLLECTED
Electronic medical records were reviewed to record patient age, race, Gleason score, extent of disease, details of the prior treatments including initial treatment, number of prior first-generation androgen-receptor antagonist (bicalutamide, flutamide, and/or nilutamide), ketoconazole and docetaxel regimens administered. Disease status at androgen deprivation therapy (ADT)-initiation, absolute PSA value at the end of a 7-month ADT period, time to development of castration-resistant disease, disease status at time of development of CRPC and sites of metastasis at time to ADT progression was collected. Castration-resistant disease was defined as two increases in the PSA level at least 1 month apart or evidence of new clinical disease while the patient was receiving ADT and the testosterone was at castrate levels.
Eastern Cooperative Oncology Group performance status (ECOG-PS), baseline hemoglobin (g/dl), alkaline phosphate (UI/l), albumin (g/dl), PSA (ng/ml) levels, presence of pain-related symptoms (≥3 on the visual analogue pain scale) and the extent of the disease (minimal disease vs. extensive disease) as previously defined in the CHAARTED study [10].
ENDPOINTS
Clinical outcomes of interest included PSA response rates, PSA-PFS, clinical/radiographic PFS and OS. PSA response was defined as a reduction in the PSA level from baseline by ≥50%. PSA-PFS was defined as a rising PSA level while on abiraterone or enzalutamide that was ≥25%, with the last value being 2.0 ng per milliliter or higher (Prostate Cancer Working Group 2 [PCWG2] definition) [11]. Those that remained alive without PSA progression were censored at the time of last PSA assessment. For PSA-related outcomes, PSA level was confirmed at a subsequent date in most instances; however, confirmation was not consistently performed on all patients. PFS was defined as the time interval from second-line ARDT initiation until radiographic or clinical progression or death, whichever came first [11]. Soft tissue progression was evaluated per Response Evaluation Criteria in Solid Tumors criteria (RECIST, version 1.1) and bone scan progression was assessed per PCWG2 criteria. Confirmatory scans were not generally performed since patients were treated per regular clinical practice [11,12]. PSA elevations alone were not considered in the definition of PFS. Subjects were censored upon initiating a new therapy subsequent to second-line novel ARDT if they did not display evidence of clinical/radiographic progression by that time. Patients with insufficient imaging data available for evaluation of PFS were still evaluated for PSA response. OS with second-line novel ARDT was also measured, and was defined as the interval from the initiation of second-line novel ARDT to death from any cause. For outcomes with first-line novel ARDT treatment period, PSA response, PSA-PFS and PFS were also assessed and were defined from the initial date of first-line novel ARDT to the corresponding event occurrence, or censored on the initial date of next therapy.
STATISTICAL ANALYSIS
Patient’s demographics are summarized descriptively. Median PSA-PFS, PFS, and OS with second-line novel ARDT were reported for each category and probabilities of PSA-PFS, PFS, and OS were estimated based on Kaplan–Meier method. An analysis was performed investigating the impact of a pre-specified set of clinical and analytic factors on PSA-response, PSA-PFS, and PFS. Univariate and multivariate Cox proportional hazard models were accessed for evaluating the risks of interested outcomes. Multivariate models for the interested outcomes were performed including variables with P-value ≤0.15 in univariate analysis, then backward procedures selected based on AIC. The threshold of significant level was set up as 0.05 without considering multiplicity.
Age at diagnosis, PSA level at diagnostic, time to development of CRPC, PSA, hemoglobin, alkaline phosphatase, and albumin levels prior to second-line novel ARDT, were considered continuous variables. Time to first-line novel ARDT PSA-progressed and PFS were also included in the list of risk factors to assess the effect on PSA-PFS and PFS with second-line novel ARDT. Continuous factors were investigated assuming a linear effect and investigating for a potential nonlinear effect.
Race (Caucasian vs. non-Caucasian), disease status at diagnosis (M0 vs. M1), Gleason sum (<8 vs. ≥8), initial treatment (radical prostatectomy vs. radiation therapy vs. initial ADT), neoadjuvant/adjuvant ADT (yes vs. no), disease status at ADT initiation (M0 vs. M1), PSA-response to ADT (≤4 vs. >4 ng/ml), disease status at the time of CRPC development (M0 vs. M1), sites of metastasis at time to ADT progression (bones vs. lymph nodes vs. visceral involvement), # of prior first-generation androgen-receptor antagonist (0, 1 vs. ≥2), prior ketoconazole (yes vs. no), prior docetaxel (yes vs. no), ECOG-PS (0 vs. ≥1), presence of bone pain (yes vs. no), extension of disease (minimal vs. extensive) and PSA response to first-line novel ARDT (yes vs. no) were considered categorical variables. Comparisons between patient subgroup and PSA-response were performed using χ2 test for categorical data, Wilcoxon rank test for continuous data, or logic regression models in the multivariable analysis.
RESULTS
Patient’s Characteristics
We identified 126 patients with mCRPC who received a second-line novel ARDT, either abiraterone (13%) or enzalutamide (87%), between March 13, 2012 and March 13, 2015. At the data cutoff for this analysis, the median duration of follow-up after initiation of second-line novel ARDT was 1.6 years (range 0.08–2.9 years). Patient’s baseline demographic and pretreatment clinical and laboratory characteristics are summarized in Table I. One third of the patients were newly-diagnosed metastatic prostate cancer patients. Sites of metastasis at time to ADT progression included bone in 96 patients (76.2%), lymph nodes in 27 patients (21.4%), and lung (visceral) in three patients (2.4%).
TABLE I.
Summary Table of Patient’s Characteristics: Overall Population and Stratified by PSA Response to Second-Line Novel ARDT
| Overall population (n = 126) | <50% decline PSA (n = 98) | >50% decline PSA (n = 28) | P-value | |
|---|---|---|---|---|
|
| ||||
| Baseline characteristics | ||||
| Age, years, mean (SD) | 62.03 (8.4) | 62.21 (8.3) | 61.39 (8.7) | 0.65 |
| Race | ||||
| No-Caucasian | 20 (15.9) | 17 (17.4) | 3 (10.7) | 0.56 |
| Caucasian | 106(84.1) | 81 (82.6) | 25 (89.3) | |
| Gleason score | ||||
| 6, 7 | 45 (35.7) | 37 (37.8) | 8 (28.6) | 0.65 |
| ≥8 | 76 (60.3) | 59 (60.2) | 17 (60.7) | |
| Missing | 5 (4) | 2 (2.1) | 3 (10.7) | |
| PSA level at diagnostic, ng/ml, median (range) | 11.4 (1.4–3514) | 10.8 (1.4–3514) | 14.85 (1.7–1874) | 0.28 |
| Disease status at diagnostic | ||||
| M0 | 90 (71.4) | 72 (73.5) | 18 (64.3) | 0.35 |
| M1 | 36 (28.6) | 26 (26.5) | 10 (35.7) | |
| Initial treatment | ||||
| Radical prostatectomy | 59 (46.8) | 49(50) | 10 (35.7) | 0.40 |
| Radiation therapy | 31 (24.6) | 22 (22.5) | 9 (32.2) | |
| Primary ADT | 36 (28.6) | 27 (27.5) | 9 (32.1) | |
| Neo-/Adjuvant therapy | ||||
| No | 87 (69) | 68 (69.4) | 19 (67.9) | 1 |
| Yes | 39 (31) | 30 (30.6) | 9 (32.1) | |
| Disease status at initiation of ADT | ||||
| M0 | 56 (44.4) | 42 (42.9) | 14 (50) | 0.52 |
| M1 | 70 (55.6) | 55 (57.1) | 14 (50) | |
| PSA response to initial ADT | ||||
| ≤4 ng/ml | 102 (80.9) | 79 (80.6) | 23 (82.2) | 0.76 |
| >4 ng/ml | 19 (15.1) | 16 (16.3) | 3 (10.7) | |
| Missing | 5 (4) | 3 (3.1) | 2 (7.1) | |
| Disease status at time of development of CRPC | ||||
| M0 | 29 (23) | 20 (20.4) | 9 (32.1) | 0.20 |
| M1 | 97 (77) | 78 (79.6) | 19 (67.9) | |
| Disease sites at the time of progression to ADT | ||||
| Bone metastasis + bone and nodal metastasis | 96 (76.2) | 79 (80.6) | 17 (60.7) | 0.04 |
| Nodal metastasis | 27 (21.4) | 18 (18.4) | 9 (32.2) | |
| Visceral metastasis (lung) | 3 (2.4) | 1 (1.0) | 2 (7.1) | |
| Number of prior first generation antiandrogen therapy*; n (%) | ||||
| 0 | 11 (8.7) | 8 (8.2) | 3 (10.7) | 0.43 |
| 1 | 84 (66.7) | 68 (69.4) | 16 (57.1) | |
| ≥2 | 31 (24.6) | 22 (22.4) | 9 (32.2) | |
| Ketoconazole; n (%) | ||||
| No | 83 (65.87) | 64 (65.31) | 19 (67.86) | 1 |
| Yes | 43 (34.13) | 34 (34.69) | 34 (34.69) | |
| Prior docetaxel therapy; n (%) | ||||
| No | 56 (46.8) | 45 (45.9) | 14 (5) | 0.83 |
| Yes | 67 (53.2) | 53 (54.1) | 14 (5) | |
| Patient’s characteristics at the time of novel second AR-targeted therapy | ||||
| Performance status; n (%) | ||||
| 0 | 67 (53.2) | 48 (49) | 19 (67.9) | 0.89 |
| ≥1 | 59 (46.8) | 50 (51) | 9 (32.1) | |
| Presence of bone pain; n (%) | ||||
| No | 75 (59.5) | 54 (55.1) | 21 (75) | 0.08 |
| Yes | 51 (40.5) | 44 (44.9) | 7 (25) | |
| Extent of disease; n (%) | ||||
| Minimal | 20 (15.9) | 14(14.3) | 6 (21.4) | 0.38 |
| Extensive | 106 (83.1) | 84 (85.7) | 22 (78.6) | |
| PSA level, ng/ml, mean (SD) | 156.11 (373.01) | 145.32 (279.24) | 193.47 (599.88) | 0.68 |
| Alkaline phosphatase level, IU/l, mean (SD) | 150.7 (145.51) | 161.16 (152.95) | 115.21 (111.98) | 0.086 |
| Hemoglobin level, g/dl, mean (SD) | 11.89 (1.63) | 11.71 (1.58) | 12.5 (1.67) | 0.031 |
| Albumin level, g/dl, mean (SD) | 4.02 (0.38) | 3.99 (0.38) | 4.14 (0.35) | 4.14 (0.35) |
| Type of novel second AR-targeted therapy; n (%) | ||||
| Abiraterone | 17 (13.49) | 14 (14.29) | 3 (10.71) | 0.76 |
| Enzalutamide | 109 (86.51) | 84 (85.71) | 25 (89.29) | |
| Time to development CRPC, mean (SD) | 26.65 (29.34) | 24.27 (21.99) | 35.19 (46.82) | 0.24 |
| Correlation with outcomes with first novel AR-targeted therapy | ||||
| PSA Response novel 1AR; n (%) | ||||
| No | 64 (50.79) | 48 (48.98) | 16 (57.14) | 0.52 |
| Yes | 61 (48.41) | 49 (50) | 12 (42.86) | |
| No evaluable | 1 (0.79) | 1 (1.02) | 0 (0) | |
| PSA-PFS, median (range) | 5.61 (0.46, 23.61) | 6.31 (0.82, 23.61) | 3.72 (0.46, 13.87) | 0.10 |
| Rx-PFS, median (range) | 7.26 (0.82, 27.51) | 7.79 (0.82, 27.51) | 5.2 (1.25, 15.61) | 0.15 |
ARDT, Androgen receptor-directed therapy; ADT, androgen deprivation therapy; CRPC, castration-resistant prostate cancer; AR, androgen receptor; PSA, prostatic specific antigen; PFS, progression free survival; Rx, radiographic.
Bicalutamide, nilutamide, flutamide.
Abiraterone was the most common choice for first ARDT (n = 109; 87%) and only 13% (n = 17) had initial enzalutamide. Clinical outcomes according to the type of novel ARDT are summarized in Table II. This difference likely reflects historical trends, as the majority of patients receiving abiraterone as their first AR-targeted therapy started therapy after the Food and Drug Administration (FDA) approval and became available in 2011. Fifty-three percent of patients also had prior docetaxel. Other prior regimens included first-generation androgen-receptor antagonists in about 90% and ketoconazole in 34% of the patients.
TABLE II.
Clinical Outcomes by Type of Novel ARDT
| Second-line ARDT | 50% PSA decline | Median PSA-PFS (months) | Median PFS (months) |
|---|---|---|---|
|
| |||
| Abiraterone | 17.6% (3/17) | 2.6 (2.1-NA) | 4.8 (3.1-NA) |
| Enzalutamide | 22.9% (25/109) | 2.9 (2.3–3.4) | 3.4 (3.0–5.2) |
| Overall | 22.5% (28/124) | 2.9 (2.3–3.3) | 3.6 (3.1–5.0) |
ARDT, androgen receptor directed therapy; PSA, prostatic specific antigen; PFS, progression free survival.
The median PSA level at the time of second-line ARDT initiation was 50.6 ng/ml (range 1–3204 ng/ml). The majority of these patients had extensive disease (84%) at the time of Second-AR initiation.
Efficacy of Second-Line Novel AR-Targeted Therapy
PSA-related outcomes.
A total of 126 patients were evaluable for PSA-response. PSA-response with second-line novel ARDT was observed in 28 of 126 (22.4%) patients. Waterfall plots depicting maximum PSA changes with second-line novel ARDT are presented in Figure 1. PSA-response to second-line novel ARDT was more likely observed in patients with ECOG-PS of 0 or absence of bone pain (P = 0.08 and P = 0.03, respectively). Patients who achieve PSA-response had also higher baseline hemoglobin and albumin levels (P = 0.03 and P = 0.05, respectively). There was no significant association noted between PSA-response and extent of the disease, PSA level prior to second-line novel ARDT or the type of second-line novel ARDT administered (abiraterone vs. enzalutamide). PSA-response with first-line novel ARDT was not significantly associated with PSA response to second-line novel ARDT. Only, 20% percent (n = 12/61) of patient who responded by PSA to first-line novel ARDT were also PSA responders to second-line novel ARDT, whereas 25% (n = 16/64) of non-PSA responders to first-line novel ARDT achieved a PSA response with second-line novel ARDT. In the multivariate analysis, hemoglobin levels (OR 0.89; 95%CI: 0.78–0.99; P = 0.04) and PSA-PFS to first-line ARDT (OR 0.89; 95%CI: 0.78–0.99; P = 0.04) were weakly associated to PSA response to second-line ARDT.
Fig. 1.
Waterfall plot of maximal PSA change (%) from baseline of second-line novel androgen receptor therapies.
The median PSA-PFS for second-line novel ARDT was 2.9 months (95% CI, 2.3–3.3 months) (Fig. 2). A multivariable proportional hazard Cox regression model was constructed to control for potential confounding factors. In this analysis, longer time to development of CRPC was associated with improved PSA-PFS (HR 0.99; 95%CI: 0.99–1; P = 0.02) and PSA response to first-line novel ARDT was associated to shorter PSA-PFS (HR 1.7; 95%CI: 1.14–2.53; P = 0.009). Detailed results and the hazard ratios of the multivariable analysis are listed in Table III.
Fig. 2.
Kaplan–Meier curves of overall survival, PFS, and PSA-PFS with second-line androgen receptor-directed therapy for the entire cohort.
TABLE III.
Multivariable Cox Proportional Hazard Model for PSA-PFS and PFS With Second-Line Novel ARDT
| PSA-PFS | PFS | |||
|---|---|---|---|---|
|
|
|
|||
| HR (95%CI) | P-value | HR (95%CI) | P-value | |
|
|
||||
| Baseline albumin level prior Second-line novel ARDT | 0.56 (0.32–0.97) | 0.03 | ||
| Prior docetaxel (yes vs. no) | 1.47 (0.93–2.32) | 0.1 | ||
| Bone pain (yes vs. no) | 1.53 (0.97–2.42) | 0.06 | ||
| Time to development CRPC (months) | 0.99 (0.99–1) | 0.02 | 0.99 (0.98–1) | 0.01 |
| Response to first-line novel ARDT (yes vs. no) | 1.7 (1.14–2.53) | 0.009 | 1.37 (0.89–2.09) | 0.14 |
PSA, prostatic-specific antigen; PFS, progression-free survival; ARDT, Androgen receptor directed therapies; HR, Hazard Ratio; CI, Confidence Interval; CRPC, castration-resistant prostate cancer.
Progression-Free Survival to Second-Line Novel AR-Directed Therapy
Median PFS for second-line novel ARDT therapy was 3.6 month (95%CI, 3.1–5.0 months) which was shorter than the median PFS for first-line novel ARDT therapy (8.5 months; 95%CI: 6.2–9.7 months) (Fig. 2). Overall, the probability of PFS at 6 and 12 months after initiation of second-line novel ARDT was 35% (95% CI: 0.27–0.45) and 17% (95% CI: 0.11–0.28), respectively. Longer time to CRPC development (HR 0.99; 95%CI 0.98–1; P = 0.01) and higher levels of albumin at the initiation of second-line novel ARDT (HR = 0.56; 95%CI 0.32–0.97; P = 0.04) were correlated with improved PFS to second-line novel ARDT. No other clinical characteristics included in our multivariable model were found to be statistically associated with differences in PFS. Detailed results and the hazard ratios of the multivariable analysis are listed in Table III.
Overall Survival to Second-Line Novel AR-Directed Therapy
Median OS was 1 year (95% CI: 0.9–1.2 years) after second-line novel ARDT. At 18 months after second-line therapy, the survival probability was 30% (95% CI: 0.22–0.41). The significant prognostic factors in the univariate analysis (defined as P < 0.15) were considered in the proportional hazards Cox regression model. Number of prior first-generation androgen-receptor antagonist, Gleason sum score, ECOG-PS, extent of disease, albumin levels prior to second-line novel ARDT and time to development of CRPC were included in the final model. After adjusting for potential confounding factors, patients with longer time to develop CRPC (HR = 0.98; 95% CI: 0.97–0.99; P = 0.0028) and higher levels of albumin (HR 0.35; 95% CI 0.19–0.63; P = 0.00054) had lower risk of death. Those patients who had an ECOG-PS score greater or equal to 1 (HR = 1.67; 95% CI: 1.01–2.77; P = 0.046) and extensive disease (HR 3.23; 95% CI 1.16–9.04; 0.025) were associated with worse OS when compared to patients with ECOG-PS of 0 and minimal disease at the initiation of second-line novel ARDT, respectively. Detailed results and the hazard ratios of the multivariable analysis are listed in Table IV.
TABLE IV.
Multivariable Cox Proportional Hazard Model for OS Mith Second-Mine Novel ARDT
| OS |
||
|---|---|---|
| HR (95%CI) | P-value | |
|
| ||
| Number of prior first generation antiandrogen therapy | 0.65 (0.42–1.00) | 0.049 |
| Baseline alkaline phosphatase prior second-line novel ARDT | 1.00 (1.00–1.002) | 0.08 |
| Performance status 0 versus ≥1 | 1.91 (1.16–3.13) | 0.01 |
| Baseline albumin level prior Second-line novel ARDT | 0.37 (0.21–0.67) | 0.0009 |
| Extent of disease (minimal vs. extensive) | 2.53 (1.00–6.42) | 0.05 |
| Time to development CRPC (months) | 0.99 (0.98–1.00) | 0.01 |
OS, Overall Survival; ARDT, Androgen receptor-directed therapies: HR, Hazard Ratio; CI, Confidence interval; CRPC, Castration-resistant prostate cancer.
DISCUSSION
Four pivotal trials have previously examined the benefit of ARDT in the pre- and post-chemotherapy setting. However, none of these trials allowed patients previously treated with novel ADRTs and many questions regarding the optimal sequencing of treatment remain unanswered. Recent small series suggest poor anti-tumor activity with second-line ADRT in unselected patients with mCRPC in the second-line setting.
This analysis represents the largest evaluation in patients treated with second-line ARDT in a standard prospective fashion in single institution with data collected off study. Our study looked at all consecutive patients who received prior ARDT or chemotherapy with the focus defining potential clinical parameters impacting on outcome. Results either with second-line enzalutamide or abiraterone were generally poor. It is important to note that the 22% PSA-response rate, a median PSA-PFS of 2.9 months and a PFS of 3.6 months found, is consistent with the published experience in other retrospective cohorts [5–8].
In our study, common prognostic factors such as ECOG-PS, presence of bone pain, extent of disease or alkaline phosphatase levels were not associated with outcome endpoints such as PSA-PFS or PFS. However, time to development CRPC was associated both with PSA-PFS and PFS. Recently, other investigators reported that previous duration of response to ADT was significantly associated with outcomes to a broad spectrum of AR-axis targeted drugs, including antiandrogens, abiraterone, ketoconazole, oestrogens, and enzalutamide [13]. We focused our study on only on patients who received sequential abiraterone and enzalutamide in view of the lack of prospective data on sequencing these two agents. We also observed significant improved PSA-PFS and PFS with second-line ARDT in those patients who benefited longer from ADT. Our findings suggest that time to development CRPC may represent a surrogate of the degree of AR-addicted biology of prostate cancer, even at a later time of the disease when adaptive mechanisms may have changed the sensitivity to AR manipulations.
Our group recently reported that AR-V7 detected in CTCs correlates with lack of response to novel ARDTs [14] but not to chemotherapy [15]. Furthermore, “reversions” from AR-V7-positive to AR-V7-negative status were only observed during taxane therapies [16]. Extensive data with first-line docetaxel in patients with mCRPC [17,18] indicate a (≥50%) PSA response rate and a PFS significantly longer than the same data with second-line ARDT observed in this study and reported by others. These data suggest that taxane-based chemotherapy may be a better treatment option for patients with mCRPC who failed first-line ARDT. Interestingly, our data suggests that a PSA-response to first-line novel ARDT correlated negatively with PSA-PFS with second-line novel ARDT, suggesting that contrary to what one would have intuitively predicted a response to first-line novel ARDT is not necessarily associated with a benefit to subsequent second-line novel ARDT.
Our study must be interpreted in the context of its limitations, such as its retrospective design and its single-institution patient cohort. The decision whether to initiate second-line ADRT or chemotherapy and the type of ARDT was made at the discretion of the treating physician and not by randomization. Although adoption of these strategies was influenced by emerging trends in patient care over the time period of our review, individual patient characteristics may have influenced the treatment decision and could have confounded the outcome. In order to evaluate potential effects of prior treatment (prior to the second line ARDT) we attempted to identify potential confounding effects of prior treatment with docetaxel and use of enzalutamide versus abiraterone. We did not observe significant associations between these parameters and the outcomes described herein.
The OS analysis has several limitations. First, half of the patients had docetaxel-pre-treated; other patients were unfit for chemotherapy and other preferred another hormonal manipulation instead of chemotherapy. Second, the absence of adjustment for subsequent life-prolonging treatments (cabazitaxel, radium-223 and sipulleucel-T) may also have affected our OS analysis although factors usually associated with outcomes in (performance status, albumin, extent of disease and prolonged response to ADT) in our current group were comparable to those reported in the literature in patients receiving docetaxel treatment [19].
CONCLUSION
In this report we describe the results of potential associations of a variety of conventional prognostic factors with PSA response, PSA-PFS, PFS, and OS. Our data suggest that time to development CRPC is associated with PSA-PFS and PFS, and OS. Prospective randomized trials should provide more definitive data to assist in treatment selection for mCRPC patients. Ongoing validation trials assessing the role of molecular biomarkers in the selection of treatment of patients with mCRPC is a critical step for further therapeutic improvements in this disease.
Grant sponsor:
Janssen, Johnson & Johnson, Sanofi, Dendreon, Exelixis, Genentech, Novartis, and Tokai; Grant sponsor: Lilly.
Footnotes
Conflict of Interest: Dr. Antonarakis has served as a paid consultant/advisor for Janssen, Astellas, Sanofi, Dendreon, Essa, and Medivation and is a co-inventor of a technology that has been licensed to Tokai. Dr. Paller has served as a paid consultant for Dendreon. Other authors have declared no conflicts of interest.
REFERENCES
- 1.Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, Fizazi K, Mainwaring P, Piulats JM, Ng S, Carles J, Mulders PF, Basch E, Small EJ, Saad F, Schrijvers D, Van Poppel H, Mukherjee SD, Suttmann H, Gerritsen WR, Flaig TW, George DJ, Yu EY, Efstathiou E, Pantuck A, Winquist E, Higano CS, Taplin ME, Park Y, Kheoh T, Griffin T, Scher HI, Rathkopf DE. COU-AA-302 Investigators Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 2013;368:138–148. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, Iversen P, Bhattacharya S, Carles J, Chowdhury S, Davis ID, de Bono JS, Evans CP, Fizazi K, Joshua AM, Kim CS, Kimura G, Mainwaring P, Mansbach H, Miller K, Noonberg SB, Perabo F, Phung D, Saad F, Scher HI, Taplin ME, Venner PM, Tombal B; PREVAIL Investigators. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014;371(5):424–433. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, Chi KN, Jones RJ, Goodman OB Jr, Saad F, Staffurth JN, Mainwaring P, Harland S, Flaig TW, Hutson TE, Cheng T, Patterson H, Hainsworth JD, Ryan CJ, Sternberg CN, Ellard SL, Fléchon A, Saleh M, Scholz M, Efstathiou E, Zivi A, Bianchini D, Loriot Y, Chieffo N, Kheoh T, Haqq CM, Scher HI; COU-AA-301 Investigators. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011;364:1995–2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, de Wit R, Mulders P, Chi KN, Shore ND, Armstrong AJ, Flaig TW, Fléchon A, Mainwaring P, Fleming M, Hainsworth JD, Hirmand M, Selby B, Seely L, de Bono JS; AFFIRM Investigators. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012;367:1187–1197. [DOI] [PubMed] [Google Scholar]
- 5.Cheng HH, Gulati R, Azad A, Nadal R, Twardowski P, Vaishampayan UN, Agarwal N, Heath EI, Pal SK, Rehman HT, Leiter A, Batten JA, Montgomery RB, Galsky MD, Antonarakis ES, Chi KN, Yu EY. Activity of enzalutamide in men with metastatic castration-resistant prostate cancer is affected by prior treatment with abiraterone and/or docetaxel. Prostate Cancer Prostatic Dis 2015;18(2):122–127. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Loriot Y, Bianchini D, Ileana E, Sandhu S, Patrikidou A, Pezaro C, Albiges L, Attard G, Fizazi K, De Bono JS, Massard C. Antitumour activity of abiraterone acetate against metastatic castration-resistant prostate cancer progressing after docetaxel and enzalutamide (MDV3100). Ann Oncol 2013;24:1807–1812. [DOI] [PubMed] [Google Scholar]
- 7.Schrader AJ, Boegemann M, Ohlmann CH, Schnoeller TJ, Krabbe LM, Hajili T, Jentzmik F, Stoeckle M, Schrader M, Herrmann E, Cronauer MV. Enzalutamide in castration-resistant prostate cancer patients progressing after docetaxel and abiraterone. Eur Urol 2014;65:30–36. [DOI] [PubMed] [Google Scholar]
- 8.Noonan KL, North S, Bitting RL, Armstrong AJ, Ellard SL, Chi KN. Clinical activity of abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after enzalutamide. Ann Oncol 2013;24:1802–1807. [DOI] [PubMed] [Google Scholar]
- 9.Maughan BL, Antonarakis ES. Androgen pathway resistance in prostate cancer and therapeutic implications. Expert Opin Pharmacother 2015;16(10):1521–1537. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Sweeney CJ, Chen YH, Carducci M, Liu G, Jarrard DF, Eisenberger M, Wong YN, Hahn N, Kohli M, Cooney MM, Dreicer R, Vogelzang NJ, Picus J, Shevrin D, Hussain M, Garcia JA, DiPaola RS. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med 2015;373(8):737–746. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, Eisenberger MA, Higano C, Bubley GJ, Dreicer R, Petrylak D, Kantoff P, Basch E, Kelly WK, Figg WD, Small EJ, Beer TM, Wilding G, Martin A, Hussain M; Prostate Cancer Clinical Trials Working Group. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol 2008;26:1148–1159. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228–247. [DOI] [PubMed] [Google Scholar]
- 13.Loriot Y, Eymard JC, Patrikidou A, Ileana E, Massard C, Albiges L, Di Palma M, Escudier B, Fizazi K. Prior long response to androgen deprivation predicts response to next-generation androgen receptor axis targeted drugs in castration resistant prostate cancer. Eur J Cancer 2015;51(14):1946–1952. [DOI] [PubMed] [Google Scholar]
- 14.Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, Chen Y, Mohammad TA, Chen Y, Fedor HL, Lotan TL, Zheng Q, De Marzo AM, Isaacs JT, Isaacs WB, Nadal R, Paller CJ, Denmeade SR, Carducci MA, Eisenberger MA, Luo J. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med 2014;371:1028–1038. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Antonarakis ES, Lu C, Luber B, Wang H, Chen Y, Nakazawa M, Nadal R, Paller CJ, Denmeade SR, Carducci MA, Eisenberger MA, Luo J. Androgen receptor splice variant 7 and efficacy of taxane chemotherapy in patients with metastatic castration-resistant prostate cancer. JAMA Oncol 2015;1(5):582–591. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Nakazawa M, Lu C, Chen Y, Paller CJ, Carducci MA, Eisenberger MA, Luo J, Antonarakis ES. Serial blood-based analysis of AR-V7 in men with advanced prostate cancer. Ann Oncol 2015;26(9):1859–1865. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, Oudard S, Théodore C, James ND, Turesson I, Rosenthal MA, Eisenberger MA; TAX 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351:1502–1512. [DOI] [PubMed] [Google Scholar]
- 18.Petrylak DP, Tangen CM, Hussain MH, Lara PN Jr, Jones JA, Taplin ME, Burch PA, Berry D, Moinpour C, Kohli M, Benson MC, Small EJ, Raghavan D, Crawford ED. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004;351:1513–1520. [DOI] [PubMed] [Google Scholar]
- 19.Armstrong AJ, Garrett-Mayer E, de Wit R, Tannock I, Eisenberger M. Prediction of survival following first-line chemotherapy in men with castration-resistant metastatic prostate cancer. Clin Cancer Res 2010;16:203–211. [DOI] [PubMed] [Google Scholar]