Efficacy and Safety Exposure-Response Relationships of Apalutamide In

Home , Apalutamide

Author Manuscript Published OnlineFirst on June 19, 2020; DOI: 10.1158/1078-0432.CCR-20-1041 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.

Efficacy and safety exposure-response relationships of apalutamide in

patients with non-metastatic castration-resistant prostate cancer

Authors: Carlos Perez-Ruixo,1 Oliver Ackaert,1# Daniele Ouellet,2 Caly Chien,2 Hiroji

Uemura,3 David Olmos,4 Paul Mainwaring,5 Ji Youl Lee,6 Margaret K. Yu,7 Juan-Jose Perez-

Ruixo,1 Matthew R. Smith,8 Eric J. Small⁹

Author affiliations

1Janssen Research & Development, Antwerp, Belgium; 2Janssen Research & Development, Spring House, PA,

USA; 3Yokohama City University Medical Center, Yokohama, Japan; 4Spanish National Cancer Research

Centre (CNIO), Madrid, and Hospitales Universitarios Virgen de la Victoria y Regional, Institute of Biomedical

Research in Málaga (IBIMA), Spain; 5Centre for Personalised Nanomedicine, University of Queensland,

Brisbane, Australia; 6Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, South Korea;

7Janssen Research & Development, Los Angeles, CA, USA;8Massachusetts General Hospital Cancer Center and

Harvard Medical School, Boston, MA, USA; 9Helen Diller Family Comprehensive Cancer Center, University of

California San Francisco, San Francisco, CA, USA

Running title: Exposure-response relationships of apalutamide in nmCRPC

Keywords: Prostate cancer, pharmacokinetics and pharmacodynamics

Corresponding author: Oliver Ackaert, PhD. Janssen Research & Development, Clinical

Pharmacology and pharmacometrics, Turnhoutseweg 30, B‑2340 Beerse, Belgium. Phone:

+32 485 521247; Email: [email protected]

Conflict of interest statement: M.R. Smith: Grants: Janssen; Personal fees: Janssen,

Astellas, Bayer. C. Perez-Ruixo, O. Ackaert, D. Ouellet, C. Chien, M.K. Yu, J-J. Perez-

Ruixo: Employee: Janssen Research & Development at time of conduct of the study; D.

Ouellet, C. Chien, M.K. Yu, J-J. Perez-Ruixo: Stock owner: Johnson & Johnson at time of

Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 19, 2020; DOI: 10.1158/1078-0432.CCR-20-1041 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.

conduct of the study. H. Uemura: Personal fees: Janssen, Astellas, Takeda, Sanofi, Bayer,

Astra-Zeneca. D. Olmos: Personal fees: Janssen, Bayer, Genentech/Roche, outside the submitted work. Travel support: AstraZeneca, Astellas, Bayer, Genetech/Roche, Ipsen,

Janssen, outside the submitted work. Grants: Janssen, Astellas, Bayer, Sanofi, Astra-Zeneca,

Bayer, outside the submitted work. P.N. Mainwaring: Personal fees: XING Technologies P/L,

Ipsen, Janssen, Merck, Novartis, Pfizer, Roche; Grants: Merck; E.J. Small: stock owner:

Fortis Therapeutics, Harpoon Therapeutics; Personal fees: Janssen, Fortis, Beigene and

Tolero. All other authors have declared no conflicts of interest.

TRANSLATIONAL RELEVANCE

ERLEADA® (apalutamide) is an orally administered selective androgen receptor inhibitor,

which was the first approved therapy in the United States and European Union for treatment

of patients with non-metastatic castration-resistant prostate cancer (nmCRPC) based on the pivotal phase 3 SPARTAN study. Differences in apalutamide and N-desmethyl-apalutamide

exposures after the administration of 240 mg once daily do not result in clinically relevant

differences in metastasis-free survival. Based on the relatively narrow exposure range, apalutamide at 240 mg once daily provides similarly efficacious exposure in most patients

with nmCRPC. Skin rash and weight loss were identified to have a statistically significant

association with apalutamide exposure, with patients who had higher exposures being more

likely to experience skin rash or weight loss. Because of the exposure-response relationship with these AEs, patients who experience them may benefit from a dose reduction without compromising efficacy.

ABSTRACT

Purpose: To evaluate the relationship between exposure of apalutamide and its active

metabolite, N-desmethyl-apalutamide, and selected clinical efficacy and safety parameters in

men with high risk non-metastatic castration-resistant prostate cancer.

Patients and Methods: An exploratory exposure-response analysis was undertaken using

data from the 1207 patients (806 apalutamide and 401 placebo) enrolled in the SPARTAN

study, including those who had undergone dose reductions and dose interruptions. Univariate

and multivariate Cox regression models evaluated the relationships between apalutamide and

N-desmethyl-apalutamide exposure, expressed as area under the concentration-time curve at

steady state, and metastasis-free survival (MFS). Univariate and multivariate logistic

regression models assessed the relationship between apalutamide and N-desmethyl-

apalutamide exposure and common treatment-emergent adverse events including fatigue, fall,

skin rash, weight loss, and arthralgia.

Results: A total of 21% of patients in the apalutamide arm experienced dose reductions

diminishing the average daily dose to 209 mg instead of 240 mg. Within the relatively narrow exposure range, no statistically significant relationship was found between MFS and apalutamide and N-desmethyl-apalutamide exposure. Within apalutamide treated subjects, skin rash and weight loss had a statistically significant association with higher apalutamide exposure.

Conclusions: The use of apalutamide at the recommended dose of 240 mg once daily

provided a similar delay in metastases across the SPARTAN patient population, regardless of

exposure. The exploratory exposure-safety analysis supports dose reductions in patients

experiencing adverse events.

INTRODUCTION

ERLEADA® (apalutamide) is an orally administered, specific inhibitor of the androgen

receptor (AR), which is approved in the United States and European Union for the treatment

of patients with non-metastatic castration-resistant prostate cancer (nmCRPC). Apalutamide

acts via inhibition of AR nuclear translocation and of AR binding to androgen response

elements (1). The efficacy and safety of apalutamide versus placebo in men with high risk

nmCRPC have been evaluated in a multicenter phase 3 study (ARN-509-003; SPARTAN;

NCT01946204), as described previously (2). Addition of apalutamide 240 mg once daily to

ADT resulted in a 72% decrease in the risk of developing metastatic disease or death (hazard

ratio [HR] = 0.28, 95% confidence interval [CI], 0.23 to 0.35; P<0.001), compared with

placebo plus ADT (3). This study also confirmed the tolerability and acceptable safety profile

of apalutamide observed in earlier studies.

An understanding of the relationship between dose, exposure, and response is important

to assess the benefit-risk profile and individualize the appropriate dose (4). This exploratory

exposure-response (ER) analysis was undertaken to explore the relationships between exposure to apalutamide and its active metabolite, N-desmethyl-apalutamide, and selected

clinical efficacy and safety endpoints.

PATIENTS AND METHODS

Clinical Study Design and Patient Population

The ER analysis was performed with data collected from all patients enrolled in the

phase 3 SPARTAN study (2, 3). Patients with nmCRPC were randomized in a 2:1 ratio to

receive apalutamide 240 mg or matched placebo administered orally on a continuous daily

dosing regimen. After the first dose on cycle 1 day 1 0.5-4 hours post-dose PK samples were

collected while pre-dose samples were available for cycles 2, 3, 6, 12, 18, and 24. All

patients who not had bilateral orchiectomy had to continue medical ADT with a GnRH

agonist or antagonist. Two formulations of apalutamide were used, leading to dosing of 240

mg first as (8 × 30 mg) capsules then as (4 × 60 mg) tablets, with no previously identified

clinically relevant exposure differences between these 2 formulations (5).

For patients who experienced treatment-emergent adverse events (TEAEs), dose

interruptions and/or reductions were permitted if study discontinuation criteria had not been

met. When patients experienced an AE of grade 3 or higher, apalutamide was to be held until

symptoms improved to grade 1 or lower. Re-initiation of apalutamide therapy was allowed at

the same or lower dose (maximum of 2 dose level reductions [240 mg to 180 mg; 180 mg to

120 mg]).

Metastasis-free survival (MFS) was the primary endpoint of the SPARTAN trial, and

was defined as the time from randomization to first evidence of detectable bone or soft tissue

distant metastasis as identified by independent central review or death due to any cause

(whichever occurred earlier). The MFS data for patients without metastasis or death were

censored on the date of the last tumor assessment (or, if no tumor assessment was performed

after the baseline visit, at the date of randomization). Patients continued with study treatment

until blinded independent central review confirmed the detection of distant metastatic disease,

development of unacceptable toxicity, or withdrawal of consent.

SPARTAN was conducted in accordance with principles for human experimentation as defined in the Declaration of Helsinki and was approved by the Human Investigational

Review Board of each study center and by the Competent Authority of each country. Written informed consent was obtained from each patient before enrollment in the study, after the patient was advised of the potential risks and benefits, as well as the investigational nature of the study.

Data Analysis

Exposure metrics for apalutamide, N-desmethyl-apalutamide and active moiety

The observed PK data was used as input in the population PK model to derive model- based exposure metrics (6). Individual steady-state exposure metrics (area under the concentration curve after 24 hours [AUC0-24h,ss], pre-dose concentration [Cmin,ss], and maximum concentration [Cmax,ss]) were computed at steady state for apalutamide and N- desmethyl-apalutamide. The active moiety was calculated as the sum of apalutamide and N- desmethyl-apalutamide exposures weighted by their relative potency considering that N- desmethyl apalutamide, exhibits one-third of the activity of apalutamide in an in vitro

transcriptional reporter assay (7). After 4 weeks of treatment, more than 95% of patients had reached steady state exposure of apalutamide and N-desmethyl-apalutamide, well before the first visit scheduled for MFS assessment at 16 weeks after start of treatment. The exposure metrics were derived based on the maximum a posteriori estimates of the individual pharmacokinetic model parameter for apalutamide and N-desmethyl-apalutamide, which were obtained from the plasma concentrations collected in the SPARTAN study and the reference population pharmacokinetic model, described in a separate article (6). Given the

option of dose modifications for AEs, the average taken daily dose up to the event of interest

(either MFS or first occurrence of AE) was used to compute the exposure metrics. The exposure metrics (AUC0-24h,ss, Cmin,ss and Cmax,ss), adjusted by the average daily dose, reflect

the average exposure of a subject up to the time of the first event of interest, considering

possible dose reductions, dose interruptions or missed doses prior to first time of the event.

Scatterplots and linear regression analyses were performed between individual steady-

state AUC0-24h,ss, Cmin,ss, and Cmax,ss to select the exposure metrics for the exposure-response

analysis. If a variance inflation factor higher than 5 (r2>0.80) was detected among the

exposure metrics, the exposure response analysis was performed with the steady-state AUC0-

24h,ss only; if not, Cmin,ss and Cmax,ss were also considered. The assessment of the correlation between exposure metrics was performed separately for apalutamide and N-desmethyl- apalutamide.

Efficacy endpoint data

MFS was the primary endpoint included in the ER analysis. The effects of the stratification factors prostate-specific antigen doubling time (PSADT) (> 6 months vs. ≤ 6 months), the presence of loco-regional disease (N0 vs. N1), and the co-administration of a bone-sparing agent (yes vs. no) on MFS were considered in the efficacy analysis (3). Since age and Eastern Cooperative Oncology Group (ECOG) performance status were identified to have a statistically significant (P<0.05) association with overall survival in SPARTAN, these prognostic factors were also included in the exposure-MFS analysis.

Safety data

The exposure-safety analysis focused on TEAEs of clinical relevance (ie classified as

TEAEs of special interest or related to the drug), with occurrence higher than 10%, at any grade. Based on these criteria, fatigue (30.4% apalutamide vs. 21.1% placebo), falls (15.6% apalutamide vs. 9.0% placebo), skin rash (23.8% apalutamide vs. 5.5% placebo), weight loss

(16.1% apalutamide vs. 6.3% placebo), and arthralgia (15.9% apalutamide vs. 7.5% placebo) were included in the exposure safety analysis.

ER Analysis

Software

Pharmacokinetic analysis and the maximum a posteriori estimates of the individual pharmacokinetic model parameters for apalutamide and N-desmethyl-apalutamide were obtained using NONMEM® software (Icon Development Solutions, Ellicott City, MD, USA)

(8). The data management, diagnostic graphics, post-processing of NONMEM® analysis

results, and statistical analysis were carried out using R Project for Statistical Computing,

Version 3.4.1 or higher for Windows (Comprehensive R Network, http://cran.r-project.org/)

(9).

Exposure-efficacy analysis.

The relationships between apalutamide, N-desmethyl-apalutamide and active moiety exposure and MFS were first evaluated using Kaplan-Meier curves of MFS by quartiles of exposure. Placebo was included as a separate group. Additionally, a multivariate Cox regression analysis for apalutamide and N-desmethyl-apalutamide exposure was performed, covariates included were treatment arm (apalutamide vs. placebo), the pre-specified stratification factors (PSADT [ 6 months vs. > 6 months], presence of locoregional disease

[N1 vs. N0], and bone-sparing agent used [yes vs. no]) and prognostic factors including age and ECOG performance status (1 vs. 0).

Patients randomized to the placebo group had apalutamide and N-desmethyl- apalutamide exposure assigned to zero. The impact of apalutamide and N-desmethyl- apalutamide exposure on MFS, after adjusting for the covariates, was assessed by the HR and its 95% CI. The P-values as well as the change in –2 loglikelihood (LL) after the inclusion of each exposure metric were used for model comparison.

Exposure-safety analysis.

The selected safety endpoints (fatigue, fall, skin rash, weight loss, and arthralgia) were dichotomized into presence or absence of any TEAEs regardless of grade. Patients with multiple occurrences of events were only counted once, when the first event was experienced.

As half of fractures were preceded by falls, and causality was hard to determine, falls

(regardless if this was followed by a fracture or not), but not fractures were included in the exposure-safety analysis.

Univariate and multivariate logistic regression analysis were conducted to assess any

possible association between treatment (apalutamide vs. placebo) and apalutamide and N-

desmethyl-apalutamide exposure on the selected safety endpoints. The corresponding odds

ratio (OR), 95% CI, χ², and P-values were calculated. The P-values as well as the change in –

2LL were used for model comparison. Additionally, a sensitivity analysis was conducted by including and excluding placebo patients in the exposure-safety analysis.

The ER analyses described above were exploratory and hypothesis-generating and were performed under the assumption that there was a sufficient number of events for a meaningful analysis. P-values lower than 0.05 were considered statistically significant. No correction for

multiple statistical testing was implemented.

RESULTS

Analysis Dataset

Data from all 1207 randomized patients (806 in the apalutamide group and 401 in the

placebo group) were included in the exposure-safety analysis while 1 patient from the

apalutamide treatment group was excluded in the exposure-efficacy analysis because of

missing values in a significant prognostic factor (ECOG performance status).

Apalutamide and N-desmethyl-apalutamide PK Exposure

Consistent with the long half-life of apalutamide, pharmacokinetic data showed that

240 mg QD dosing led to a relatively constant apalutamide plasma concentration during the

dosing interval at steady state, with limited peak-to-trough fluctuation ranging from a mean

Cmax,ss value of 5.81 μg/mL (range: 1.46 to 13.9) to a mean Cmin,ss value of 4.24 μg/mL

(range: 0.60 to 11.1). The peak-to-trough fluctuation of N-desmethyl-apalutamide plasma concentration at steady state is negligible, with relatively constant N-desmethyl-apalutamide plasma concentrations over the dosing interval at a plasma concentration average value of 6.3

μg/mL (range: 1.8 to 12.5). The apalutamide and N-desmethyl-apalutamide exposures,

measured as AUC0-24h,ss, were 115 (range: 19.8 to 291) and 152 (range: 44.1 to 299) μg·h/mL,

respectively. The interindividual variability in apalutamide and N-desmethyl apalutamide

exposure, expressed as coefficient of variation of AUC0-24h,ss was considered low to moderate

(≤27%). In addition, following once-daily oral apalutamide administration of 240 mg, apalutamide and N-desmethyl-apalutamide systemic exposure showed a 5.3- and 85.2-fold accumulation (calculated, based on AUC) in plasma, respectively.

The correlations between the individual exposure metrics at steady-state (AUC0-24h,ss,

2 Cmin,ss, Cmax,ss) for apalutamide and N-desmethyl-apalutamide were high (r >0.95) between all parameters. Because of this high correlation, AUC0-24h,ss was selected as the unique exposure

metric to conduct the ER analysis for efficacy and safety endpoints. In contrast, the

correlation between AUC0-24h,ss of apalutamide and N-desmethyl-apalutamide was estimated

to be below 0.80 (r2=0.646, P<0.001), and therefore both apalutamide and N-desmethyl-

apalutamide AUC0-24h,ss were evaluated in the ER analysis, and the collinearity due to these 2 variables was further monitored.

Given the dose modification rate in the phase 3 SPARTAN study (21% dose

reductions in the apalutamide group and 15% in the placebo group), the average daily dose

(instead of the start dose of 240mg) up to the event of interest (either MFS or first occurrence

of TEAEs) was used to compute the exposure metrics. An average daily dose of 209 mg

(apalutamide group) versus 222 mg (placebo group) in patients with one or more dose

reductions was observed (Table 1); however, the relative difference between the derived

AUC0-24h,ss from the average daily dose and the dose-normalized 240 mg (assuming 100%

treatment adherence) was relatively small (<13%). In addition, predicted dose-normalized

AUC0-24h,ss was similar in patients with or without dose reductions.

Exposure-Efficacy Analysis

A summary of the prognostic factor distribution across treatment groups and quartiles

of apalutamide and N-desmethyl-apalutamide exposure is presented in Table 2. These results

suggest that the relevant prognostic factors were balanced among the treatment and exposure

quartiles evaluated, and the potential imbalances that may exist should be controlled by the

multivariate analysis. The Kaplan-Meier curves of MFS stratified by the quartiles of

apalutamide, N-desmethyl apalutamide and the active moiety AUC0-24h,ss are shown in Figure

1. In all pairwise comparisons of the exposure subgroups in the apalutamide group versus the

placebo group, a statistically significant (P<0.0001) increase in MFS was observed for the apalutamide, N-desmethyl-apalutamide and active moiety exposure subgroups.

However, after excluding the patients randomized to placebo, none of the other pairwise

comparisons among the exposure subgroups for apalutamide, N-desmethyl-apalutamide and

active moiety were identified as statistically significant. These findings suggest that all

exposure levels in patients treated with apalutamide experienced benefit. Since the results of

the active moiety are comparable with the results of apalutamide and N-desmethyl

apalutamide, only apalutamide and N-desmethyl apalutamide were carried forward to the

multivariate Cox regression analysis.

The multivariate Cox regression analysis found a statistically significant association

between apalutamide treatment, PSADT, presence of locoregional disease, and ECOG

performance status on MFS. The effect of apalutamide on MFS (HR=0.30, 95% CI, 0.24 to

0.36) was found to be similar after adjusting for the prognostic factors described previously

(3) (HR=0.28, 95% CI, 0.23 to 0.35), suggesting that inclusion of the prognostic factors in the

model did not produce any treatment-effect modification, and consequently the prognostic

factors can be considered independently associated with MFS.

The addition of N-desmethyl-apalutamide AUC0-24h,ss in the model on top of

apalutamide AUC0-24h,ss led to a substantial change of the treatment effect and its uncertainty

(HR=0.205, 95% CI, 0.097 to 0.435), which may be explained by the collinearity between

prognostic factors, apalutamide treatment, and the exposure variables. A multivariate Cox

regression analysis evaluated in the 806 patients treated with apalutamide (i.e. excluding

placebo patients), showed a decrease in the collinearity and confirmed the results of the univariate analysis, that neither apalutamide AUC0-24h,ss nor N-desmethyl-apalutamide AUC0-

24h,ss were statistically associated with MFS.

Exposure-Safety Analysis

A summary of the incidence of the treatment-emergent events for placebo, apalutamide,

and the quartiles of apalutamide and N-desmethyl-apalutamide exposure is presented in Table

The univariate logistic regression analysis for the treatment effect showed that the

probability of experiencing one of the described TEAEs was statistically significantly higher

in the apalutamide group than the placebo group. Moreover, the probability of experiencing one of the described TEAEs significantly increases as apalutamide AUC0-24h,ss increases

(Figure 2). The same effect was observed for N-desmethyl-apalutamide AUC0-24h,ss (Figure

3).

The treatment effect was included together with apalutamide or N-desmethyl-

apalutamide exposure in the multivariate regression analysis. Based on the 95% CI of the OR,

the contribution of apalutamide or N-desmethyl-apalutamide AUC0-24h,ss, when adjusted by

treatment effect differences, was significant for the probability of experiencing skin rash and

weight loss, but not for the probability of experiencing fatigue, fall, or arthralgia at any grade.

The results of the multivariate logistic regression analysis were further confirmed in a

univariate exposure-safety analysis in patients treated with apalutamide, which showed a

statistically significant association between apalutamide treatment and skin rash and weight

loss.

DISCUSSION

In the phase 3 SPARTAN study, the addition of apalutamide to ADT resulted in

significant improvement over placebo plus ADT in the primary endpoint, MFS, as well as in

other secondary endpoints, including time to symptomatic progression. However,

apalutamide plus ADT was also associated with higher rates of skin rash, fatigue, arthralgia,

weight loss, falls, and fracture (3). Some of these adverse events led to dose adjustments,

which resulted in decreased drug exposure, and which provided the opportunity to undertake

exploratory analyses to elucidate the relationship (if any) between apalutamide and N-

desmethyl-apalutamide exposure and efficacy (MFS) as well as adverse drug reactions of

special interest associated with the use of apalutamide.

The observed high correlation between the 3 exposure parameters selected (Cmax,ss,

Cmin,ss, and AUC0-24h,ss) can be expected considering that the apalutamide and N-desmethyl- apalutamide terminal half-life is substantially longer than the dosing interval; therefore, fluctuations in drug concentration during the dosing interval are low and drug concentrations collected at steady state are highly correlated with AUC. It is useful to correlate long-term drug effects with steady-state AUC0-24h (as was done in this analysis), since AUC0-24h,ss

represents the average drug concentration over a longer time period following multiple

dosing (10-12).

The 240 mg dose of apalutamide used in SPARTAN was selected based on phase 1

data as well as on the inhibition of uptake of fluoro-5α dihydrotestosterone (13), a

pharmacodynamic biomarker for AR inhibition. This dose level also ensured that exposures

were within the range previously identified required for maximum tumor regression in

murine CRPC models. The apalutamide exposure-efficacy analysis presented here revealed

that in the relatively narrow observed exposure range (for both apalutamide and its

metabolite), no statistically significant differences in MFS between exposure quartiles were

determined, further confirming that 240 mg once daily dose of apalutamide provides efficacious exposure in patients with nmCRPC, regardless of dose adjustments. Furthermore, the exposure was similar in patients with and without dose reductions and interruptions.

Therefore, dose reductions/interruptions for the management of TEAEs are not expected to

reduce the efficacy of apalutamide.

These results are in line with those obtained with another AR antagonist used for the

treatment of metastatic CRPC, enzalutamide, which was evaluated in the in the AFFRIM trial

(14). In this analysis, no apparent ER relationship was found for overall survival with an oral

dose of 160 mg/day. The analysis was conducted using Ctrough plasma values as the exposure

metric instead of AUC0-24h,ss, but the exposure-efficacy analysis was also conducted

classifying the Ctrough plasma values into quartiles, as in the current analysis, and no

significant differences in overall survival were seen regarding the quartiles of exposure.

Fatigue, fall, fracture, skin rash, weight loss, and arthralgia were adverse drug reactions that occurred at an incidence greater than 10% in SPARTAN patients receiving apalutamide.

The exposure safety analysis demonstrated that within the observed exposure range in apalutamide-treated patients, the exposure-TEAE relationship was only statistically significant for skin rash and weight loss. Simulations based on the developed exposure-safety relationship demonstrate that dose reductions will likely improve apalutamide tolerability in patients who develop toxicity after starting apalutamide treatment at 240 mg once daily.

Although these results suggest that reductions and interruptions are appropriate to prevent patients from discontinuing apalutamide, this is a relatively small data set, and further study is warranted in real world use regarding the effect of drug holidays and extended use of lower doses.

In summary, ER analyses demonstrated that the MFS benefit in patients with nmCRPC

was similar across the range of apalutamide and N-desmethyl apalutamide exposure

following the recommended apalutamide dose of 240 mg once daily. A significant

association with apalutamide exposure was observed for the incidence of skin rash and

weight loss TEAEs, at any grade. The ER relationship with these AEs suggests that patients

who experience AEs may benefit from reducing the dose of apalutamide without

compromising efficacy.

Disclosure of Potential Conflicts of Interest M.R. Smith: Grants: Janssen; Personal fees: Janssen, Astellas, Bayer. C. Perez-Ruixo, O.

Ackaert, D. Ouellet, C. Chien, M.K. Yu, J-J. Perez-Ruixo: Employee: Janssen Research &

Development at time of conduct of the study; D. Ouellet, C. Chien, M.K. Yu, J-J. Perez-

Ruixo: Stock owner: Johnson & Johnson at time of conduct of the study. H. Uemura:

Personal fees: Janssen, Astellas, Takeda, Sanofi, Bayer, Astra-Zeneca. D. Olmos: Personal

fees: Janssen, Bayer, Genentech/Roche, outside the submitted work. Travel support:

AstraZeneca, Astellas, Bayer, Genetech/Roche, Ipsen, Janssen, outside the submitted work.

Grants: Janssen, Astellas, Bayer, Sanofi, Astra-Zeneca, Bayer, outside the submitted work.

P.N. Mainwaring: Personal fees: XING Technologies P/L, Ipsen, Janssen, Merck, Novartis,

Pfizer, Roche; Grants: Merck; E.J. Small: stock owner: Fortis Therapeutics, Harpoon

Therapeutics; Personal fees: Janssen, Fortis, Beigene and Tolero. All other authors have

declared no conflicts of interest.

Acknowledgments

The authors would like to thank the patients, investigators, and their medical, nursing and laboratory staff who participated in the clinical studies included in the present work. The authors acknowledge Jonás Samuel Pérez-Blanco for his support during the exposure- response analysis. This study was funded by Janssen Research and Development.

Author’s Contributions

Conception and design: Margaret K. Yu, Caly Chien

Development of methodology: Carlos Perez-Ruixo, Oliver Ackaert, Daniele Ouellet, Juan-

Jose Perez-Ruixo

Acquisition of data (provided animals, acquired and managed patients, provided

facilities, etc.): Hiroji Uemura, David Olmos, Paul Mainwaring, Ji Youl Lee, Matthew R.

Smith, Eric J. Small

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational

analysis): Carlos Perez-Ruixo, Oliver Ackaert, Daniele Ouellet, Caly Chien, Juan-Jose

Perez-Ruixo

Writing, review, and/or revision of the manuscript: Carlos Perez-Ruixo, Oliver Ackaert,

Daniele Ouellet, Caly Chien, Hiroji Uemura, David Olmos, Paul Mainwaring, Ji Youl Lee,

Margaret K. Yu, Juan-Jose Perez-Ruixo, Matthew R. Smith, Eric J. Small

Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): Carlos Perez-Ruixo, Oliver Ackaert

Study supervision: Margaret K. Yu

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Table 1. Summary statistics for the individual exposure metric (AUC0-24h,ss) for apalutamide and N-desmethyl apalutamide, expressed as mean (CV%).

Average daily N-desmethyl- Percentage of Apalutamide Treatment Dose dose, mg apalutamide subjects AUC0-24h,ss b group Reduction (CV%) AUC0-24h,ss, (% of totala) μg×h/mL (CV%) μg×h/mL (CV%)

No 85% 235 (5.4) - - Placebo Yes 15% 222 (11.5) - -

No 79% 234 (5.5) 113 (23) 149 (18) Apalutamide Yes 21% 209 (17.1) 112 (25.2) 148 (18)

aFor placebo patients, the average daily dose is the equivalent in placebo. bTotal number of patients is those with exposure metrics and average daily dose calculated (n=771 and n=384 for apalutamide and placebo treatment groups, respectively). AUC0-24h,ss, area under the concentration curve after 24 hours at steady state, dose-normalized to 240mg; CV, coefficient of variation.

Table 2. Distribution of the prognostic factors across treatment arms and quartiles of exposure for apalutamide and N-desmethyl-apalutamide.

PSADT Bone- Loco- Age ECOG Age Age N ( 6 sparing regional (65-75 PS (< 65 years) (> 75 years) months) agent use disease (N1) years) (Grade 1)

Placebo 400 283 (70.8) 39 (9.75) 65 (16.3) 190 (47.5) 43 (10.8) 167 (41.8) 89 (22.3)

183 806 576 (71.5) 82 (10.2) 133 (16.5) 341 (42.3) 106 (13.1) 359 (44.5) Apalutamide (22.7) Treatment group

Q1 202 140 (69.3) 20 (9.90) 39 (19.3) 92 (45.5) 34 (16.8) 76 (37.6) 49 (24.3)

Q2 201 139 (69.2) 19 (9.45) 30 (14.9) 105 (52.2) 23 (11.4) 73 (36.3) 40 (19.9)

Q3 201 162 (80.6) 18 (8.96) 33 (16.4) 80 (39.8) 34 (16.9) 87 (43.3) 49 (24.4)

Q4 202 135 (66.8) 25 (12.4) 31 (15.3) 64 (31.7) 15 (7.43) 123 (60.9) 45 (22.3) Apalutamide

Q1 202 139 (68.8) 17 (8.42) 37 (18.3) 97 (48.0) 29 (14.4) 76 (37.6) 58 (28.7)

Q2 201 151 (75.1) 21 (10.5) 35 (17.4) 91 (45.3) 36 (17.9) 74 (36.8) 43 (21.4) apalutamide - Q3 201 141 (70.1) 23 (11.4) 25 (12.4) 84 (41.8) 16 (7.96) 101 (50.2) 44 (21.9)

desmethyl Q4 202 145 (71.8) 21 (10.4) 36 (17.8) 69 (34.7) 25 (12.4) 108 (53.5) 38 (18.8) - N Values are expressed as number of patients (proportion of patients).

PSADT, prostate-specific antigen doubling time; ECOG PS, Eastern Cooperative Oncology Group performance status.

Table 3. Summary of the incidence of treatment-emergent adverse events for the placebo group and the apalutamide group and the quartiles of exposure for apalutamide and N-desmethyl- apalutamide in the SPARTAN population.

Skin rash Weight loss Arthralgia N Fatigue (%) N Fall (%) N N N (%) (%) (%)

Placebo 401 84 (20.9) 401 36 (8.98) 401 22 (5.49) 401 25 (6.23) 401 30 (7.48)

Apalutamide 806 244 (30.3) 806 125 (15.5) 806 191 (23.7) 806 129 (16.0) 806 128 (15.9) Group Treatment

Q1 202 55 (27.2) 202 29 (14.4) 202 29 (14.4) 202 14 (6.93) 202 24 (11.9)

Q2 201 63 (31.3) 201 30 (14.9) 201 51 (25.4) 201 32 (15.9) 201 31 (15.4)

Q3 201 63 (31.3) 201 32 (15.9) 201 52 (25.9) 201 31 (15.4) 201 39 (19.4)

Q4 202 36 (31.2) 202 34 (16.8) 202 59 (29.2) 202 52 (25.7) 202 34 (16.8) Apalutamide

Q1 202 49 (24.3) 202 29 (14.4) 202 26 (12.9) 199 17 (8.54) 199 18 (9.05)

Q2 201 64 (31.8) 201 34 (16.9) 201 43 (21.4) 201 23 (11.4) 201 40 (19.9) apalutamide - Q3 201 68 (33.8) 209 31 (14.8) 201 56 (27.9) 208 42 (20.2) 205 33 (16.1)

desmethyl Q4 202 63 (31.2) 194 31 (16.0) 202 66 (32.7) 195 47 (24.1) 198 37 (18.7) - N

Figure Legends

Figure 1. Kaplan-Meier plot for metastasis-free survival (MFS) as a function of placebo and the lowest exposure quartile (Q1) to highest exposure quartile (Q4) of apalutamide (left panel), N- desmethyl apalutamide (Mid panel) and the active moiety (right panel) plasma steady-state

AUC0-24h,ss. Active moiety: sum of apalutamide and N-desmethyl-apalutamide exposures weighted by their relative potency

Figure 2. Logistic regression representing the probability of experiencing fatigue, fall, skin rash, weight loss, and arthralgia as function of apalutamide steady-state AUC0-24h,ss. The upper and lower open circles represent the presence or absence of a given treatment-emergent event across the range of the predicted apalutamide AUC0-24h,ss exposure, respectively. The dots depict the observed incidence for the placebo and the quartiles of exposure for the apalutamide group, respectively, whereas the corresponding vertical bars represent the exact 95% CI. Finally, the middle line and its corresponding shaded area represent model-based exposure–safety relationship and the 95% CI, respectively.

Figure 3. Logistic regression representing the probability of experiencing fatigue, fall, skin rash, weight loss, and arthralgia as function of N-desmethyl apalutamide steady-state AUC0-24h,ss. The upper and lower open circles represent the presence or absence of a given treatment-emergent event across the range of the predicted N-desmethyl apalutamide AUC0-24h,ss exposure, respectively. The dots depict the observed incidence for the placebo and the quartiles of exposure for the N- desmethyl apalutamide group, respectively, whereas the corresponding vertical bars represent the exact 95% CI. Finally, the middle line and its corresponding shaded area represent model-based exposure–safety relationship and the 95% CI, respectively.

Efficacy and safety exposure-response relationships of apalutamide in patients with non-metastatic castration-resistant prostate cancer

Carlos Perez-Ruixo, Oliver Ackaert, Daniele Ouellet, et al.

Clin Cancer Res Published OnlineFirst June 19, 2020.

Updated version Access the most recent version of this article at: doi:10.1158/1078-0432.CCR-20-1041

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