Impact of Abiraterone Therapeutic Drug Monitoring on Cortisol as a Surrogate Biomarker of CYP17 Inhibition in Metastatic Prostate Cancer Treatment

Abstract

Background:

Prostate cancer is driven by androgen receptor activation caused by (dihydro)testosterone. Abiraterone, which is used against metastatic castration-resistant prostate cancer (mCRPC), improves survival by irreversibly inhibiting CYP17 to reduce androgen and cortisol synthesis. As such, cortisol is a potential biomarker for androgen suppression. This study assessed the impact of pharmacokinetically (PK)–guided interventions after therapeutic drug monitoring (TDM) of abiraterone on cortisol plasma concentrations as a biomarker for CYP17 inhibition in patients with mCRPC.

Methods:

In this retrospective cohort study, patients with mCRPC receiving abiraterone with TDM based on abiraterone plasma concentrations were compared with a historical cohort receiving standard care. The primary end point was adequate CYP17 inhibition, defined as cortisol plasma concentration <6.18 nmol/L. Secondary end points included the time course of cortisol plasma concentrations and the impact of PK-guided interventions.

Results:

A total of 103 patients were included in the TDM population, and 99 were included in the historical cohort. Median cortisol plasma concentrations were lower in the TDM population [1.9 (95% confidence interval 1.1–5.8) versus 3.9 (95% confidence interval 1.4–12.4] nmol/L, P = 0.01), with more patients achieving adequate CYP17 inhibition (75.7% versus 62.6%, P = 0.06). Of the 32 patients with evaluable data before and after PK-guided intervention, 96.9% reached adequate abiraterone concentrations; however, no significant improvement in adequate CYP17 inhibition was observed when comparing cortisol before and after PK-guided intervention (81.3% versus 71.9%, P = 0.45).

Conclusions:

In the TDM population, lower cortisol plasma concentrations were observed. However, it is unclear whether increasing abiraterone exposure through PK-guided interventions decreased cortisol plasma concentrations.

INTRODUCTION

Prostate cancer is the second most common cancer in men and is hormonally driven by androgens. After binding testosterone and dihydrotestosterone, the androgen receptor drives tumor growth and increases prostate-specific antigen (PSA) levels.¹ In the treatment of metastatic castration-resistant prostate cancer (mCRPC), abiraterone acetate (Zytiga; Janssen Biotech, Inc, Horsham, PA) prolongs overall survival and progression-free survival (PFS).^2–4 Abiraterone acetate, a prodrug of abiraterone, inhibits androgen and glucocorticoid synthesis through irreversible inhibition of the enzyme 17α-hydroxylase/C17,20-lyase (CYP17), which is expressed in the testes, adrenal glands, and prostate tumours.⁵

The registered fixed dose of abiraterone, 1000 mg once daily (OD) in modified fasted state, leads to high interindividual variability in pharmacokinetic exposure (coefficient of variation 45%–70%).^3,4,6–8 Previously, abiraterone trough levels (C_min) of ≥8.4 ng/mL, as a surrogate for abiraterone exposure, have been associated with significantly longer PFS and an exposure–toxicity relationship has not been established.^7,8 At the registered fixed dose of 1000 mg OD in modified fasting state, 35%–42% of patients fail to achieve this efficacy target.^7,8 A recent study demonstrated that pharmacokinetically (PK)–guided interventions (with the first intervention being intake of abiraterone with food and a second-dose escalation to 1500 mg OD) in patients with low abiraterone exposure are feasible and effective, increasing the proportion of patients with adequate target exposure from 33.5% to 81.4%.⁹ Patients receiving PK-guided interventions due to low exposure of abiraterone exhibited similar treatment durations to those with adequate abiraterone exposure, supporting the use of therapeutic drug monitoring (TDM).⁹

Despite the successful use of TDM with a cost-neutral option to increase plasma concentrations, the variability in treatment response is not fully explained by abiraterone pharmacokinetics.¹⁰ Moreover, abiraterone plasma levels do not directly reflect the degree of CYP17 inhibition and subsequent androgen suppression. Ideally, androgen suppression should be assessed by measuring testosterone levels. However, residual testosterone levels are typically undetectable with current analytical methods.¹¹ However, further reduction of testosterone levels in this undetectable range can improve clinical outcomes.^11–13 Since CYP17 inhibition also reduces cortisol production, cortisol has been proposed as a surrogate biomarker for undetectable systemic testosterone concentrations to assess androgen suppression by abiraterone. In a previous observational study, cortisol plasma concentrations below 6.18 nmol/L were associated with better PFS and overall survival, even in patients with adequate abiraterone exposure.¹⁴

To date, it is unclear whether abiraterone TDM leads to adequate cortisol suppression, as the previous observational study on cortisol as a biomarker was conducted before the clinical implementation of abiraterone TDM. Therefore, this study aims to evaluate the impact of abiraterone TDM on cortisol plasma concentrations as a surrogate for CYP17 inhibition in the treatment of mCRPC.

MATERIALS AND METHODS

Study Design and Patients

This retrospective cohort study compared a TDM population with a historical cohort. Patients with mCRPC starting treatment with abiraterone between June 2017 and December 2021 at the Netherlands Cancer Institute were eligible for the TDM population if they were included in the multicenter prospective trial on TDM of oral target therapies used in oncology [The Dutch Pharmacology Oncology Group—Therapeutic Drug Monitoring study (DPOG-TDM study), trial number NTR6886].¹⁵ Patients who started treatment with abiraterone at 1000 mg OD in a fasted state were eligible for inclusion with at least one plasma sample used within the DPOG-TDM study for abiraterone plasma concentration analyses and available for cortisol analysis. The inclusion criteria for the historical cohort were patients with the same abiraterone starting dose for whom plasma samples were collected as part of routine clinical care between June 2016 and December 2020 who had no objection to the use of data for research and who were not included in the DPOG-TDM study. The use of the patient data in this cohort study was approved by the Institutional Review Board (IRBdm19-309).

In the DPOG-TDM cohort, the initial dose was 1000 mg OD in a fasted state, and abiraterone concentrations were measured at weeks 4, 8, and 12 and every 12 weeks thereafter. Concentration measurement frequency in the historical cohort was defined by the treating clinician and was most often aligned with routine outpatient clinic visits. If unavailable, C_min was calculated through log-linear extrapolation (for data from before February 2020) or by using the ratio of the measured pharmacokinetic level and the typical population concentration and multiplying this ratio with the typical population C_min value (from February 2020 onward).¹⁶

Data were stored in an electronic case report form for the DPOG-TDM study and collected as part of routine clinical care for the historical cohort. Data on baseline characteristics, abiraterone dose, abiraterone plasma concentrations, and PK-guided interventions were obtained. Cortisol plasma concentrations were measured retrospectively in available samples used for abiraterone analysis by a previously validated Liquid Chromatography-tandem Mass Spectrometry (LC-MS/MS) method with a validated range of 0.14–14 nmol/L, and intra-assay and interassay coefficient of variations of <13% and <3.6%, respectively.¹¹ Correction for the timing of sample collection considering the circadian rhythm of cortisol was not required, as the circadian rhythm of cortisol was undetectable when abiraterone was used.¹⁴ Abiraterone suppresses cortisol synthesis by inhibiting CYP17, the key enzyme in its biosynthetic pathway. The low-dose corticosteroids (prednisolone 5 mg twice daily or dexamethasone 0.5 mg OD) administered did not further reduce cortisol levels, as the enzymatic blockade already limits production.^5,17 Consequently, no correction for chronic corticosteroid use was necessary in this context. Switching from prednisolone to dexamethasone at the time of asymptomatic PSA progression was also not considered to affect cortisol plasma concentrations.^18,19

Study End Points

The primary end point of this study was to evaluate the proportion of patients achieving cortisol plasma concentrations below 6.18 nmol/L as a surrogate for adequate CYP17 inhibition, based on a previous study.¹⁴ The median cortisol plasma concentrations across all time points were compared between the TDM population and the historical cohort. Secondary end points included the time course of CYP17 inhibition and the impact of PK-guided interventions on cortisol plasma concentrations. To study the time course of CYP17 inhibition as measured by cortisol plasma concentrations, the proportion of patients achieving adequate CYP17 inhibition at weeks 4, 8, and 12 after the start of treatment with abiraterone was compared between the TDM population and the historical cohort. To evaluate the impact of PK-guided interventions on cortisol plasma concentrations, cortisol plasma concentrations before and after PK-guided interventions were compared within the TDM population.

PK-Guided Intervention

For patients in the TDM population with an abiraterone plasma concentration <8.4 ng/mL, a PK-guided intervention was recommended when feasible. The first PK-guided intervention was to add a light snack or low-fat meal at the time of abiraterone intake. The second PK-guided intervention was to increase the abiraterone dose to 1500 mg OD (with food). Further dose increases were not recommended. Intervention recommendations were provided to the treating clinician.

Statistical Analyses

Baseline characteristics were described with descriptive statistics and compared between the TDM population and the historical cohort using a Mann–Whitney test for continuous data or a Fisher exact test for categorical data. Patients with median cortisol plasma concentrations <6.18 nmol/L were considered to have adequate CYP17 inhibition. Differences in the proportion of patients with adequate CYP17 inhibition were analyzed using a χ² test, and the median cortisol plasma concentrations were compared using a Mann–Whitney U test. This analysis was also performed at 4, 8, and 12 weeks for patients with available data at these time points. Within the TDM population, the median cortisol plasma concentrations per patient before and after PK-guided intervention were compared using a Wilcoxon signed-rank test. The proportion of patients with adequate CYP17 inhibition, defined as median cortisol plasma concentrations <6.18 nmol/L, was compared using a NcNemar test. A P-value <0.05 was considered statistically significant. Statistical analyses were performed with R version 4.2.2 (R Foundation for Statistical Computing, Vienna, Austria).

RESULTS

Study Population

A total of 103 patients were included in the TDM population and 99 in the historical cohort (Table 1). Abiraterone was the first-line treatment for mCRPC in 53.5% of patients in the historical cohort, compared with 89.3% in the TDM population. Prior treatments in the historical cohort primarily included docetaxel (39.4%) and enzalutamide (25.3%). In addition, the 2 populations differed in baseline PSA levels. The median C_min of abiraterone was 16.5 ng/mL in the TDM population and 9.2 ng/mL in the historical cohort. In the TDM population, a PK-guided intervention was recommended and implemented in 59 patients (57.3%), most commonly involving the intake of abiraterone with food (Table 2).

TABLE 1.

Baseline Characteristics

	TDM Population (n = 103)	Historical Cohort (n = 99)
Age [mean (range)]	72 (53–89)	71 (57–92)
WHO performance status (n (%))
WHO 0	32 (31.1)	36 (36.4)
WHO 1	45 (43.7)	52 (52.5)
WHO 2	7 (6.8)	10 (10.1)
Unknown	19 (18.4)	1 (1.0)
PSA at baseline (ng/mL) [median (IQR)]	18.9 (7.0–59.1)	44.3 (19.5–135.6)
Switch to dexamethasone [n (%)]	63 (61.2)	54 (54.5)
Number of previous lines of systematic treatment in CRPC phase (n (%))
0	92 (89.3)	53 (53.5)
1	5 (4.9)	19 (19.2)
2	1 (1)	18 (18.2)
3	2 (1.9)	7 (7.1)
≥4	3 (2.9)	2 (2.0)
Previous systematic treatments in CRPC phase (n (%))
Docetaxel	5 (4.9)	39 (39.4)
Enzalutamide	8 (7.8)	25 (25.3)
Radium	1 (1)	9 (9.1)
Cabazitaxel	5 (4.9)	9 (9.1)
Abiraterone	1 (1)	2 (2.0)
Other therapies	6 (5.8)	4 (4.0)

IQR, interquartile range; WHO, World Health Organization.

TABLE 2.

PK-Guided Intervention and Cortisol Data in the TDM Population and Historical Cohort

	TDM Population (n = 103)	Historical Cohort (n = 99)	P
Number of abiraterone samples	946	425
Abiraterone samples per patient [median (IQR)]	9 (6–12)	3 (2–6.5)
Cmin abiraterone (ng/mL) [median (IQR)]	16.5 (11.6–25.0)	9.2 (6.1–18.9)
Toxicity [yes, n (%)]	20 (19.4)	14 (14.1)
Successful PK-guided intervention (n (%))
Intake with food	55 (53.4)	—
Dose increase	4 (3.9)	—
No PK-guided intervention	43 (41.7)	99 (100)
Not evaluable	1 (1)	—
Number of cortisol samples	402	425
Cortisol samples per patient [median (IQR)]	4 (3–5)	3 (2–7)
Median cortisol plasma concentration (nmol/L) [median (IQR)]
Overall	1.9 (1.1–5.8)	3.9 (1.4–12.4)	0.01*
Week 4	3.0 (1.7–9.4)	6.9 (2.2–23.7)	0.01*
Week 8	2.5 (1.1–5.5)	5.5 (2.2–15.7)	0.01*
Week 12	2.2 (1.4–4.4)	3.9 (2.2–9.1)	0.03*
Patients with median cortisol <6.18 nmol/L [n (%) (patients with available samples, n)]
Overall	78 (75.7)	62 (62.6)	0.06
Week 4	29 (72.5), (n = 40)	23 (48.9), (n = 47)	0.04*
Week 8	32 (74.4), (n = 43)	22 (56.4), (n = 39)	0.14
Week 12	28 (87.5), (n = 34)	15 (60.0), (n = 25)	0.11

^*Statistically significant (P < 0.05).

C_min, trough concentration; IQR, interquartile range.

CYP17 Inhibition Between Populations

A median of 4 and 3 samples for cortisol analysis were available for members of the TDM population and historical cohort, respectively. The median cortisol plasma concentration in the TDM population was significantly lower than that in the historical cohort (1.93 versus 3.86 nmol/L, respectively; P = 0.01). The TDM population trended toward a higher proportion of patients with cortisol plasma concentrations <6.18 nmol/L, considered to represent adequate CYP17 inhibition, but the difference was not statistically significant (75.7% versus 62.6%, respectively; P = 0.06) (Table 2, Fig. 1). To study the time course of CYP17 inhibition, cortisol plasma concentrations at weeks 4, 8, and 12 were compared between the TDM population and the historical cohort for patients with available samples (Table 2 and Fig. 1). Cortisol plasma concentrations were lower at weeks 4, 8, and 12 in the TDM population, with significantly more patients showing adequate CYP17 inhibition at week 4 (Table 2 and Fig. 1). After the start of abiraterone therapy, a decrease in cortisol plasma concentrations was observed and was more evident in the historical cohort (Fig. 1).

FIGURE 1.

Median cortisol plasma concentration in the TDM population and historical cohort. The dashed line represents the cutoff value for cortisol at 6.18 nmol/L. *P < 0.05; **P < 0.01.

Impact of PK-Guided Intervention on CYP17 Inhibition

For 32 of the 59 patients who underwent a PK-guided intervention due to low abiraterone exposure, plasma samples taken before and after the intervention were available for cortisol analyses. The PK-guided intervention was successful in 96.9% of these patients, resulting in an adequate median abiraterone concentration after intervention without toxicity for at least 1 month. No significant differences were observed in median cortisol plasma concentrations before and after PK-guided intervention (2.21 versus 2.76 nmol/L, respectively; P = 0.27) nor in the proportion of patients with adequate CYP17 inhibition (81.3% versus 71.9%, respectively; P = 0.45) (Table 3 and Fig. 2).

TABLE 3.

Cortisol Data Before and After PK-Guided Intervention in the TDM Population

	TDM Population With PK-Guided Intervention and Cortisol Samples Before and After PK-Guided Intervention (n = 32)
Cmin abiraterone (ng/mL) [median (IQR)]	13.5 (10.6–18.6)
Before PK-guided intervention	7.9 (4.3–13.25)
After PK-guided intervention	18.5 (12.0–24.3)
PK-guided intervention (n (%))
Intake with food	30 (93.8)
Dose increase	2 (6.2)
PK-Guided intervention successful [n (%)]	31 (96.9)
Number of cortisol samples	155
Before PK-guided intervention	56
After PK-guided intervention	99
Cortisol samples per patient [median (IQR)]	5 (3.8–6)
Median cortisol (nmol/L) [median (IQR)]
Overall	1.9 (1.4–4.4)
Before PK-guided intervention	2.2 (1.1–5.2)
After PK-guided intervention	2.8 (1.4–8.3)
Patients with median cortisol <6.18 nmol/L [n (%)]
Overall	25 (78.1)
Before PK-guided intervention	26 (81.3)
After PK-guided intervention	23 (71.9)

C_min, trough concentration; IQR, interquartile range.

FIGURE 2.

Median cortisol plasma concentrations before and after PK-guided intervention. The dashed line represents the cutoff value for cortisol at 6.18 nmol/L.

DISCUSSION

In this cohort study, cortisol plasma concentrations were found to be lower in patients undergoing abiraterone TDM than in a historical cohort without TDM. This reduction, however, did not significantly increase the proportion of patients with cortisol plasma concentrations <6.18 nmol/L, a surrogate for adequate CYP17 inhibition. Moreover, increasing abiraterone exposure through PK-guided interventions did not lower cortisol plasma concentrations.

Previous retrospective analyses have demonstrated that low abiraterone trough levels (C_min <8.4 ng/mL) are associated with poorer clinical outcomes.^7,8,20 Increasing abiraterone exposure beyond this threshold has been linked to improved treatment durations and PSA responses, comparable with those observed in patients with consistently higher abiraterone exposure.⁹ These findings suggest that CYP17 inhibition by abiraterone increases with higher drug exposure, as indicated by greater therapeutic effects. The impact of enhanced CYP17 inhibition on treatment outcomes is further underscored by a study in which cortisol was used as a surrogate pharmacodynamics (PD) biomarker for CYP17 inhibition.¹⁴ Elevated cortisol plasma concentrations, exceeding the defined threshold of 6.18 nmol/L, were associated with worse PFS in mCRPC, observed in both patients with low and adequate median abiraterone exposure.¹⁴

This study aligns with these findings, indicating that higher abiraterone exposure enhances CYP17 inhibition. However, the impact on cortisol suppression appears variable or limited. The observed lower cortisol plasma concentrations in the TDM population may be attributed to TDM resulting in a higher median C_min of abiraterone, consistent with previous findings.¹⁴ Nonetheless, differences in baseline characteristics, such as prior chemotherapy and disease burden, between the cohorts may have influenced cortisol plasma concentrations. Genetic alterations, including mutations in TP53 or the androgen receptor, are more frequently observed in patients with mCRPC than in those with localized or de novo metastatic prostate cancer, leading to a poorer response to abiraterone.^21–27 These alterations may accumulate following androgen deprivation therapy (ADT) and docetaxel treatment.^21–27 Consequently, patients with less advanced disease or fewer prior treatments may be more responsive to abiraterone, resulting in greater CYP17 inhibition. Extended (chemotherapy) pretreatment or more advanced disease may increase the likelihood of mutations affecting CYP17 enzyme activity, potentially leading to abiraterone resistance and elevated cortisol plasma concentrations.^28–30 Since the historical cohort included more patients with prior chemotherapy and higher baseline PSA levels, indicative of more extensive disease, these factors may have contributed to their higher cortisol plasma concentrations. This variability also limits the generalizability of the findings to patients with hormone-sensitive prostate cancer, particularly given the current uncertainty regarding the exposure–response relationship of abiraterone in prechemotherapy patients.²¹

Although lower cortisol plasma concentrations, which are indicative of enhanced CYP17 inhibition, were observed in the TDM population than in the historical cohort, this study was not designed to assess whether this translated into improved clinical outcomes. Treatment response differs significantly between chemotherapy-naïve and pretreated patients, and the cohorts differed in prior treatments.^3,4,31,32 In addition, no comparative analysis of clinical outcomes within the TDM population based on cortisol plasma concentration was conducted, as subgroup sizes were anticipated to be too small to support a meaningful evaluation of PSA response or PFS.¹⁴ Consequently, whether cortisol adequately reflects the degree of CYP17 inhibition and whether increased CYP17 inhibition is the mechanism underlying the improved clinical outcomes observed at higher abiraterone exposure remain unclear.

While a trend toward a greater proportion of patients achieving adequate cortisol suppression was observed, statistical significance was not reached. The predefined threshold for adequate CYP17 inhibition was based on an observational study and requires further validation. Lower testosterone levels, despite being undetectable, are thought to correlate with improved clinical outcomes, suggesting that an optimal strategy for maximizing CYP17 inhibition would involve achieving cortisol plasma concentrations as low as possible.¹¹ However, as testosterone levels were not assessed in this study, the actual extent of CYP17 inhibition could not be verified. Notably, current bioanalytical technologies do not allow quantification of these ultralow testosterone levels.

In addition to disease extent and prior treatments, prolonged ADT and tumor adaptation mechanisms could have influenced baseline cortisol plasma concentrations, which were unknown. In vitro studies have shown that CRPC cells can adapt to ADT by synthesizing androgens from cholesterol through enzymes such as CYP17, potentially generating sufficient androgens to activate the androgen receptor and promote tumor growth. Although this phenomenon has not been consistently observed in clinical studies, it may have contributed to higher baseline cortisol plasma concentrations in the historical cohort.^5,33–35 Differences in baseline cortisol could also explain the significant difference in the proportion of patients achieving adequate CYP17 inhibition at week 4, before any PK-guided intervention had taken place.

Despite the observed lower cortisol plasma concentrations in the TDM population, increasing abiraterone exposure in patients with low abiraterone plasma concentrations did not enhance cortisol suppression. Notably, only 6 of the 32 patients in the PK-guided intervention group with available cortisol plasma concentrations before and after intervention exhibited inadequate cortisol suppression during the period of low abiraterone exposure. The majority (81.3%) already had cortisol plasma concentrations below 6.18 nmol/L before intervention. The small sample size for this end point may have limited the ability to detect a significant effect. Alternatively, interpatient variability in the optimal abiraterone concentration required for effective CYP17 inhibition may exist, with some patients achieving maximal CYP17 inhibition at lower abiraterone exposure due to a possible nonlinear, saturable PK/PD relationship, potentially limiting the benefit of further dose increases. Conversely, others may require higher abiraterone exposure due to differences in CYP17 sensitivity. Variability in CYP17 sensitivity may also underlie resistance mechanisms to abiraterone, including overexpression or mutations in CYP17.^33,36 Intratumoral overexpression of CYP17 has been reported in biopsies from patients treated with abiraterone, suggesting that upregulation of CYP17 may contribute to resistance, leading to continued androgen synthesis and disease progression despite adequate abiraterone exposure.^29,33,37 However, other studies have reported no increase in androgen levels, suggesting that abiraterone induces durable and irreversible CYP17 inhibition.^5,38 Notably, cortisol reflects systemic CYP17 activity and may not accurately represent intratumoral steroidogenesis. This dissociation between systemic PD biomarkers and local tumor biology may further explain the absence of a measurable PD response to higher abiraterone exposure.

Further research is warranted to determine whether rising cortisol plasma concentrations during abiraterone treatment could serve as a surrogate marker for intratumoral androgen synthesis and predict resistance or disease progression. In addition, the impact of abiraterone on androgen metabolism should be further elucidated to identify a PD marker that accurately reflects testosterone levels and androgen activity. In addition, whether patients with adequate abiraterone exposure but elevated cortisol plasma concentrations indicative of insufficient CYP17 inhibition would benefit from further increases in abiraterone to overcome reduced CYP17 sensitivity and achieve adequate cortisol suppression remains uncertain. This approach may help determine whether integrating PD-guided dosing based on cortisol monitoring with PK-guided abiraterone monitoring could further optimize treatment of patients with mCRPC.

CONCLUSIONS

To conclude, this study found that cortisol plasma concentrations were lower in patients undergoing abiraterone TDM than in a historical cohort without abiraterone TDM. However, whether increasing abiraterone concentrations following a PK-guided intervention reduces cortisol plasma concentrations remains unclear. This may be attributed to the low proportion of patients with inadequate cortisol suppression before PK-guided intervention or interpatient variability in CYP17 sensitivity.