FormalPara Key Points

Regular-strength (RS) and lower-strength (LS) dual-action tablets (DATs) [niraparib and abiraterone acetate (AA)] were developed and investigated for metastatic castration-resistant prostate cancer.

RS-DAT (niraparib 200 mg/AA 1000 mg) is bioequivalent to single-agent combination under modified fasting conditions.

LS-DAT is considered bioequivalent to single-agent combination under modified fasting conditions.

1 Introduction

Prostate cancer is the most commonly diagnosed cancer in men in 112 countries [1], with an estimated 1.4 million cases newly diagnosed and 375,000 associated deaths globally in 2020 [1]. While overall survival (OS) of early stage prostate cancer is increasing because of early detection and effective therapies for localized and regional disease [2,3,4], patients with metastatic prostate cancer (mPC) have worse outcomes, primarily because of the eventual development of castration-resistant prostate cancer (CRPC) caused by resistance to androgen deprivation therapy [3, 4]. In at least one study, the incidence of mCRPC in the USA remained relatively constant over an 8-year study period (1.1%; 2010–2017) but prevalence more than doubled, suggesting patients with the disease are living longer [5].

The poly[adenosine diphosphate (ADP)]-ribose polymerase (PARP) pathway is a potential drug target in prostate cancers that have homologous recombination repair (HRR) gene alterations [6], which may be present in up to approximately 30% of patients with mPC [7,8,9]. Patients with mCRPC and HRR gene defects have a significantly shorter life expectancy (median overall survival: 28.5 months) than patients with mCRPC and no HRR gene defects (36 months) [10]. Furthermore, patients with metastatic castration (hormone)-sensitive prostate cancer (mCSPC) and HRR gene alterations progress to mCRPC significantly faster than those without such mutations [11, 12]. Therefore, targeting the PARP pathway, in addition to androgen deprivation therapy in patients with mCRPC, presents a potential therapeutic strategy for improved survival.

Niraparib—which is approved for the treatment of advanced epithelial ovarian, fallopian tube, or primary peritoneal cancers [13, 14]—is an orally available, highly selective PARP inhibitor (PARPi) with potent activity against PARP-1 and PARP-2 DNA-repair polymerases [15]. Taken orally, niraparib is rapidly absorbed and has a bioavailability of 73%, with primarily hepatic metabolism via carboxylesterase-catalyzed amide hydrolysis [13, 14]. The apparent volume of distribution for niraparib is approximately 1311 L in patients with cancer, suggestive of extensive distribution given its relatively high oral bioavailability [13]. Niraparib has a terminal half-life of approximately 2 days and is eliminated primarily through the hepatobiliary and renal routes, with an average recovery of 86.2% in urine and feces over 21 days [14]. In an open-label single-arm phase 2 study (GALAHAD), niraparib monotherapy showed promising clinical activity in patients with treatment-refractory mCRPC and DNA-repair gene defects, including breast cancer gene (BRCA) alterations and certain non-BRCA alterations [16].

Abiraterone acetate (AA) is a prodrug of abiraterone. AA is approved in combination with prednisone/prednisolone for the treatment of patients with mCRPC and metastatic high-risk castration-sensitive prostate cancer [17, 18]. Taken orally, AA is rapidly hydrolyzed to abiraterone, which then undergoes metabolism, including sulfation, hydroxylation, and oxidation, primarily in the liver [18]. AA is used on the basis of the mechanism of action of abiraterone, which selectively inhibits cytochrome P450 17 α-hydroxylase/17,20 lyase (CYP17) [19]. All androgen synthesis pathways rely on CYP17; thus, abiraterone inhibits adrenal, testicular, and intratumoral androgen production. CYP17 inhibition does not affect the pharmacokinetics (PK) of niraparib.

In the fasted state, time to reach maximum plasma abiraterone concentration is approximately 2 h. Administration with food significantly increases exposure based on fat content; therefore, AA should only be taken under modified fasting conditions (no food for 2 h before or 1 h after). The apparent volume of distribution for abiraterone is approximately 5630 L, suggestive of extensive distribution. The mean half-life of abiraterone in plasma is approximately 15 h based on data from healthy subjects. Following oral administration of 14C-AA 1000 mg, approximately 88% of the radioactive dose is recovered in feces and approximately 5% in urine.

Targeting the PARP pathway, in addition to androgen deprivation therapy in patients with mCRPC, presents a potential therapeutic strategy for improved survival. Therefore, the combination of niraparib and AA plus prednisone/prednisolone is under investigation for the treatment of patients with mCRPC, with a proposed dosing regimen of niraparib 200 mg/AA 1000 mg plus 10 mg prednisone/prednisolone daily and a lower dosing regimen of niraparib 100 mg/AA 1000 mg plus 10 mg prednisone/prednisolone daily if dose reduction is needed due to niraparib-related toxicity. This dose was based on the results from two studies: BEDIVERE, a two-part open-label phase 1b study of patients with previously treated mCRPC [20] and MAGNITUDE, a randomized double-blind placebo-controlled multicenter pivotal phase 3 study designed to evaluate the safety and efficacy of niraparib/AA plus prednisone/prednisolone 10 mg daily as first-line therapy in patients with mCRPC, with or without certain HRR gene alterations [21]. In MAGNITUDE, the combination of niraparib/AA plus prednisone/prednisolone had a safety profile consistent with the known safety profile of the single agents and significantly improved radiographic progression-free survival in patients with mCRPC and HRR gene alterations, particularly the BRCA subset [21].

The proposed dosing regimen for niraparib/AA would require patients to take six pills (two niraparib 100 mg and four AA 250 mg) per day, in addition to prednisone/prednisolone [22, 23]. Patients with prostate cancer often take multiple oral medications for comorbid conditions; therefore, the likelihood of polypharmacy—defined as regular use of ≥ 5 medications—is high. Furthermore, the prescribed number of doses per day is inversely related to compliance [22], and polypharmacy may be a cause of nonadherence in patients who feel they are taking too many pills or who get confused about which pills to take and when to take them [23]. In this regard, fixed-dose combination drug products offer the practical benefits of decreased pill burden and a simplified dose regimen, as well as the added benefit of minimizing chances of accidental under-/over-dosing, which may lead to unintended effects and/or drug–drug interactions. These benefits have been associated with increased patient compliance and convenience, improved clinical effectiveness, and reduced cost to patients [24].

Two combined dual-action tablets (DATs) of niraparib/AA—100/500 mg (regular-strength [RS]-DAT) and 50/500 mg (lower-strength [LS]-DAT)—were developed to reduce the pill burden for niraparib and AA from six to two tablets per day, providing patients with a more simplified dosing regimen, and enabling the use of a combination product with dose reduction due to niraparib-related toxicity. As niraparib and AA were administered as single agents in MAGNITUDE, results of a bioavailability (BA)/bioequivalence (BE) study and accompanying analyses are presented herein to support the use of both formulations in patients.

2 Methods

2.1 Objectives

The primary objective of this BA/BE study was to determine the BE of the RS-DAT formulation of niraparib/AA with respect to single-agent combination (SAC) at steady state under modified fasting conditions in patients with mCRPC (periods 2 and 3). The secondary objective was to determine the relative BA (rBA) of the LS-DAT formulation of niraparib/AA with respect to SAC after a single-dose administration under modified fasting conditions in patients with mCRPC (period 1).

2.2 Study Design and Treatments

This open-label randomized multicenter study in patients with mCRPC was conducted at 14 sites in the USA and Europe between 10 December 2020 and 15 October 2021. The genotoxic potential of niraparib precluded conduct of this study in healthy participants. For evaluation of the BE of the RS-DAT with respect to SAC, we used a randomized two-way crossover, multiple-dose design followed by a multiple-dose extension phase to ensure therapeutic intent in patients with mCRPC. A similar BE study design for the evaluation of LS-DAT was not considered acceptable for ethical reasons: the dosing regimen (niraparib 100 mg/AA 1000 mg) has not been established as an effective therapeutic regimen. Thus, a single-dose run-in period was used to evaluate the LS-DAT bioavailability relative to SAC. The resulting study design included a 21-day screening phase, a PK assessment phase, an extension phase, and a follow-up phase (Fig. 1). Data only from the PK assessment phase were used for PK, pharmacodynamic, and safety assessments presented herein.

Fig. 1
figure 1

Study design with treatment sequences for randomization. Period 1: niraparib 100 mg and AA 1000 mg. Period 2 and 3: niraparib 200 mg and AA 1000 mg. During repeated dosing (periods 2, 3, and extension), all patients received niraparib and AA once daily in combination with prednisone/prednisolone 5 mg twice daily. AA abiraterone acetate, D day, LS-DAT lower-strength dual-action tablet (niraparib 100 mg/AA 1000 mg), RS-DAT regular-strength dual-action tablet (niraparib 200 mg/AA 1000 mg), SAC single-agent combination, seq sequence

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Following confirmation of eligibility during the screening phase, patients were randomly assigned before first administration of study treatment in period 1 to one of the four treatment sequences based on a computer-generated randomization schedule that was prepared before the start of the study. The niraparib 200 mg/AA 1000 mg dose was administered orally as two RS-DATs, which each contained niraparib 100 mg and AA 500 mg, and the niraparib 100 mg/AA 1000 mg dose was administered orally as two LS-DATs, which each contained niraparib 50 mg and AA 500 mg. Study drugs were administered under modified fasting conditions, consistent with clinical recommendations [21], defined as study treatment intake on an empty stomach only (intake 1 h before or ≥ 2 h after a meal). On intensive PK sample collection days −7, 11, and 22, patients were required to fast overnight and were allowed to eat a standard breakfast at exactly 1 h after dosing. Strong CYP3A4 inducers and p-glycoprotein inhibitors/inducers were prohibited during the PK assessment phase on the basis of interaction with niraparib and/or abiraterone.

The PK assessment phase comprised three periods: period 1, single dose of niraparib 100 mg/AA 1000 mg on study day −7 as either LS-DAT or SAC; period 2, daily dose of niraparib 200 mg/AA 1000 mg from study days 1–11 as either RS-DAT or SAC; and period 3, daily dose of niraparib 200 mg/AA 1000 mg from study days 12–22 as either SAC or RS-DAT (whichever was not taken in period 2). This scenario resulted in four possible treatment sequences to which patients may have been randomized. In the extension phase, both niraparib and AA as a SAC or AA alone were continued (study day 23 to discontinuation). From period 2 onward, and throughout the study, niraparib/AA was given in combination with prednisone/prednisolone 5 mg twice daily (once in the morning and once in the evening with food, except on study days 11 and 22 when it was taken with lunch and dinner). Patients received study treatment until disease progression, withdrawal of consent, loss to follow-up, lack of clinical benefit in the opinion of the investigator, start of subsequent anticancer therapy, or until the sponsor ended the study.

The study protocol and amendments were reviewed by an independent ethics committee or institutional review board and were conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements. Patients or their legally acceptable representatives provided written consent to participate in the study.

2.3 Patients

The study population consisted of patients with mCRPC who, in the opinion of the investigator, may derive benefit from study treatment. Other inclusion criteria included age ≥ 18 years, Eastern Cooperative Oncology Group Performance Status scale score of ≤ 1, and acceptable organ function as defined per study protocol. Patients who received prior therapy with apalutamide or enzalutamide were required to have had ≥ 8-week or ≥ 6-week wash-out, respectively, before first dose of study treatment. Patients who previously had progressed on AA alone or AA in combination with a PARPi, or who previously discontinued treatment with AA or PARPi due to related toxicity, were excluded. Other exclusion criteria included history or current diagnosis of myelodysplastic syndromes/acute myeloid leukemia, ongoing serious systemic infection, disorders affecting gastrointestinal absorption, clinically significant cardiovascular disease, uncontrolled hypertension, moderate or severe hepatic impairment, active hepatitis B or C infection, and inadequately controlled human immunodeficiency virus infection. All patients were tested at baseline for presence of an HRR gene alteration using archived tumor material and blood testing. Results were communicated to investigators before the end of the PK assessment phase to guide continuation of therapy with the combination of niraparib and AA or AA alone during the extension phase. The planned total sample size, based on statistical assumptions to power BE based on a crossover study design, was approximately 120 patients. The study was not powered to support BE with parallel design (LS-DAT). Additional patients could be enrolled to replace patients who withdrew during the PK assessment phase.

2.4 PK Sample Collection and Analysis

Venous blood samples were collected for measurement of niraparib and abiraterone plasma concentrations. PK samples were collected up to 3 days post-dose (72 h post-dose) during period 1 and under steady state conditions from pre-dose up to 24 h post-dose on study days 11 and 22 during periods 2 and 3. Plasma samples were analyzed for niraparib and abiraterone concentrations using a validated, specific, and sensitive liquid chromatography mass spectrometry/mass spectrometry method. For niraparib, separation was done with a C18 1.7 µm × 2.1 mm × 50 mm column, and detection was done on an API-5500 [25]. For abiraterone, separation was done with a C18 column 1.7 µm × 2.1 mm × 50 mm column, and detection was done on an API-4000 [26]. Plasma concentrations of niraparib and abiraterone were determined using a lower limit of quantification of 5.00 ng/mL and 0.200 ng/mL, respectively.

Primary PK parameters for LS-DAT evaluation were maximum observed analyte concentration (Cmax) and area under the plasma concentration–time curve (AUC) from time 0 to 72 h post-dosing (AUC0–72h) as calculated by a linear up-log down method using Phoenix™ WinNonlin® (version 8.1; Certara LP, USA). Primary PK parameters for RS-DAT evaluation were Cmax at steady state (Cmax,ss) and AUC from time 0–24 h at steady state (AUC0–24h,ss). For both evaluations, if ≥ 1 PK parameter of interest was not estimable for a given patient in ≥ 1 treatment periods, the patient’s data were not included in statistical analyses of that PK parameter.

2.5 Statistical Analyses

Descriptive statistics, including arithmetic mean, standard deviation (SD), coefficient of variation (CV), geometric mean (GM), median, minimum, and maximum were calculated for plasma concentrations for each study treatment at each sampling time and for all PK parameters using Phoenix™ WinNonlin® (version 8.1; Certara LP, USA). The PK-evaluable population was composed of all patients who completed ≥ 1 PK period and had sufficient concentration data to accurately estimate ≥ 1 PK parameter. The BE evaluable population was composed of all patients who completed both periods 2 and 3 with sufficient PK sample collection to accurately estimate ≥ 1 PK parameter and without events deemed to affect PK.

A descriptive PK analysis and a primary statistical analysis to determine the BE of the RS-DAT with respect to SAC were performed on log-transformed PK parameters data (Cmax,ss, AUC0–24h,ss, and observed trough analyte concentration at steady state [Ctrough,ss]) for niraparib and abiraterone from the PK and BE evaluable populations, respectively, from periods 2 and 3. A linear mixed-effect model that included treatment, period, and sequence as fixed effects, and patient within sequence as a random effect, was used to estimate the least squares mean and intrapatient variance. Using these parameters, the point estimate and 90% confidence intervals (CIs) for the difference in means on a log scale between test and reference were constructed. Limits of the CIs were retransformed using antilogarithms to obtain 90% CIs for the GM ratios (GMRs) of Cmax,ss and AUC0–24h,ss between the RS-DAT and SAC for niraparib and abiraterone. BE between the RS-DAT versus SAC was concluded if the 90% CIs for the GMRs of RS-DAT over SAC for the primary PK parameters of both compounds fell simultaneously between 80% and 125%.

A descriptive PK analysis and the rBA assessment of the LS-DAT versus SAC were performed on PK parameters data for niraparib and abiraterone from the PK evaluable population from period 1. An analysis of variance (ANOVA) model with treatment as a fixed effect was applied to construct 90% CIs for the GMRs of primary PK parameters between the LS-DAT and SAC for niraparib and abiraterone.

To further assess the rBA of abiraterone in the LS-DAT versus SAC within the same patients and to improve precision of the estimates, a paired analysis using abiraterone PK from treatment sequences 3 and 4 was performed. Specifically, since abiraterone PK at the 1000 mg dose is linear and stationary, Cmax,ss of the LS-DAT was obtained from the corresponding single-dose Cmax (observed in period 1) via nonparametric superposition and by applying accumulation factors (from single dose to steady state) derived from the abiraterone pre-final population PK (PPK) model (described in more detail below).

Each patient in the analysis received both the LS-DAT and SAC; therefore, this analysis was a paired comparison for Cmax,ss (Cmax,ss for LS-DAT extrapolated from single-dose Cmax observed in period 1 versus Cmax,ss for SAC from periods 2 and 3) and AUC0–24h,ss (AUC0–∞ from period 1 used as AUC0–24,ss for the LS-DAT versus AUC0–24h,ss for SAC from periods 2 and 3). A linear mixed-effects model that included treatment as a fixed effect and patient as a random effect was applied to construct 90% CIs for the GMRs of Cmax,ss and AUC0–∞ for the LS-DAT and AUC0–24h,ss for SAC between the LS-DAT and SAC for abiraterone.

2.6 Model-Based BE Assessment for the LS-DAT

Because BA assessment of the LS-DAT was conducted as a parallel-group design and was not intended to formally demonstrate BE between LS-DAT and SAC, a preplanned clinical trial simulation was conducted to evaluate the BE of LS-DAT versus SAC using a crossover design. First, the characteristics of niraparib and abiraterone PPK, based on available PK data of the RS-DAT, the LS-DAT, and SAC, were determined [27]. For model-based BE assessment of the LS-DAT versus SAC, PPK simulations of 1000 replicates of the BA/BE study design in periods 2 and 3 (i.e., two-way steady-state crossover PK assessment phase) were performed using R version 3.4.1 with a sample size of 120, which was approximately the sample size at final analysis of the BA/BE study.

The niraparib PPK model included the LS-DAT as a covariate in the PPK absorption parameters [27]. Based on the totality of available PK data for abiraterone, no formulation differences in absorption between the LS-DAT and SAC could be demonstrated for abiraterone. Hence, the final abiraterone PPK model did not contain any effect of the LS-DAT on absorption parameters. For this reason, generating BE simulations of LS-DAT versus SAC for abiraterone using the final PPK model would have yielded a 100% probability of meeting BE criteria. To generate a more conservative estimate of the probability of meeting BE criteria, a pre-final abiraterone PPK model [27] was used for the model-based BE assessment of the LS-DAT. This pre-final model included effects of the LS-DAT on first-order absorption rate constant (estimated as −20% for the LS-DAT versus SAC, with 100% relative standard error [RSE]) and duration of zero-order drug release (estimated as −34% for the LS-DAT versus SAC, with 89% RSE). As such, for the purpose of BE simulations, a difference in these two absorption parameters between the LS-DAT and SAC was still assumed (while accounting for their large RSE), even in the absence of a statistically significant difference between formulations.

Using the PPK models [27], individual steady-state (study days 11 and 22) PK profiles were generated from individual PPK parameters, which were obtained by randomly sampling from the uncertainty in the estimation of structural and covariate parameters, the distribution of covariates in the BA/BE study, the interindividual variability, and the residual unexplained variability. Day 11 and 22 individual exposure parameters AUC0–24h,ss and Cmax,ss for the LS-DAT and/or SAC for both niraparib and abiraterone were calculated from the simulated data using noncompartmental analysis, and BE was evaluated as described above for the RS-DAT versus SAC. The probability of demonstrating BE for the LS-DAT versus SAC was calculated as the proportion of simulated clinical trial replicates in which BE criteria (90% CI of estimated GMR within the 80%–125% range) were simultaneously met for both AUC0–24h,ss and Cmax,ss for both niraparib and abiraterone. Additionally, the GMR point estimates and lower and upper 90% CI bounds across the simulated replicates for both AUC0–24h,ss and Cmax,ss for both niraparib and abiraterone were presented graphically.

A similar model-based assessment was additionally conducted to assess the probability of demonstrating BE under a parallel, single-dose design. The same methodology described above was applied, except for the following. A total of 60 patients were simulated for each formulation (the LS-DAT and SAC), which is similar to the sample size for the LS-DAT and SAC in the BA/BE study. Single doses were simulated over the same nominal sampling time grid as defined for niraparib 100 mg/AA 1000 mg given as LS-DAT or SAC in the BA/BE study (i.e., PK sampling up to 72 h). The individual exposure parameters AUC0–72h and Cmax were analyzed with a log linear mixed-effects model with treatment (LS-DAT vs SAC) as a fixed effect. Point estimates and 90% CIs of the estimated GMR for the parallel comparison of LS-DAT versus SAC were then obtained for each of the 1000 simulated study replicates, and the proportion of simulated trials where BE criteria were simultaneously met for both AUC0–24h,ss and Cmax,ss for both niraparib and abiraterone was calculated. The results then were compared with the results from the rBA assessment of the LS-DAT versus SAC on the basis of period 1 data described above.

2.7 Safety Monitoring

All patients were closely monitored at regular intervals during the conduct of the study by monitoring adverse events (AEs), vital signs (blood pressure, heart rate, body temperature), electrocardiograms, and laboratory safety. Special attention was paid to the development of niraparib-related and AA-related events, such as hematological toxicity, hypertension, hypokalemia, and liver toxicity, for which specific management guidelines were provided in the study protocol.

3 Results

3.1 Study Patients

A total of 136 patients were randomized, received ≥ 1 dose of study treatment, and were included in the analyses. Median duration of exposure was 29.0 days (range 1.0–78.0 days). Most patients were white (99.3%), of non-Hispanic or non-Latino ethnicity (99.3%), and ≥ 65 years old (61.0%) [electronic supplementary material (ESM) Table 1]. At baseline, median age was 67 years (range 50–90 years). All patients were medically or surgically castrated before study start, and most patients had high-risk prostate cancer at initial diagnosis: 61.9% of patients had a total Gleason score of ≥ 8 and 70.6% had T3–T4 disease. All patients had metastatic disease (58.8% had M1 stage disease at initial diagnosis) and an Eastern Cooperative Oncology Group Performance Status scale score of 0 (39.7%) or 1 (60.3%) at baseline, and median prostate-specific antigen (PSA) was 46.5 ng/mL (range 0.8–5000.0 ng/mL). No differences were apparent across the treatment sequences.

Of the 136 patients, 117 BE evaluable patients were included in the BE analyses, and 134 PK evaluable patients were included in the rBA analyses (Fig. 2). Overall, six patients (4.4%) permanently stopped study treatment during the PK assessment phase due to patient withdrawal (3 [2.2%]), death due to serious AE (SAE) of cardiac failure (1 [0.7%]), progressive disease (1 [0.7%]), and loss to follow-up (1 [0.7%]). All 136 patients were included in safety analyses.

Fig. 2
figure 2

Patient disposition. *One patient randomized to treatment sequence 1 (Fig. 1) was treated according to treatment sequence 4 (Fig. 1). BE bioequivalence, rBA relative bioavailability

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3.2 RS-DAT (Niraparib 200 mg/AA 1000 mg) BE Assessment

After multiple-dose RS-DAT or SAC, comparable PK profiles with overlapping ranges were observed for niraparib and abiraterone (Fig. 3). Based on 90% CIs of GMRs for Cmax,ss and AUC0–24h,ss for niraparib and abiraterone, the RS-DAT met the a priori BE criteria (range 80%–125%) versus SAC (Table 1).

Fig. 3
figure 3

Mean (SD) plasma concentration–time profiles of niraparib (top) and abiraterone (bottom) at steady state after multiple-dose administrations of niraparib 200 mg/AA 1000 mg given as RS-DAT or single agents under modified fasting conditions in patients with mCRPC. A Niraparib. B Abiraterone. AA abiraterone acetate, conc. concentration, RS-DAT regular-strength dual-action tablets (niraparib 200 mg/AA 1000 mg), SD standard deviation

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Table 1 Statistical analysis of pharmacokinetic parameters for RS-DAT versus SAC
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3.3 LS-DAT (Niraparib 100 mg/AA 1000 mg) rBA Assessment

After single-dose LS-DAT or SAC, comparable PK profiles with overlapping ranges were observed for niraparib and abiraterone (Fig. 4). Mean Cmax of abiraterone and niraparib occurred after 1.5–2 h. For the LS-DAT and SAC, GMRs of Cmax/AUC0–72h were 90.9%/90.1% for niraparib and 132.6%/121.9% for abiraterone, respectively (Table 2). Interpatient variability was notable at 56.2%/41.8% for niraparib and 80.4%/72.9% for abiraterone, respectively.

Fig. 4
figure 4

Mean (SD) plasma concentration–time profiles of niraparib (top) and abiraterone (bottom) at steady state after multiple-dose administrations of niraparib 100 mg/AA 1000 mg given as LS-DAT or single agents under modified fasting conditions in patients with mCRPC. A Niraparib. B Abiraterone. AA abiraterone acetate, LS-DAT lower-strength dual-action tablets (niraparib 100 mg/AA 1000 mg), SD standard deviation

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Table 2 Statistical analysis of pharmacokinetic parameters of niraparib and abiraterone for LS-DAT versus SAC
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Based on the high interpatient variability observed for abiraterone for the LS-DAT versus SAC, an additional analysis using single-sequence data (i.e., patients in treatment sequences 3 and 4) was performed as described in the statistical analysis section. Each patient in the analysis received both the LS-DAT and SAC, resulting in a paired comparison for Cmax and AUC. In this analysis, 90% CIs of GMRs for Cmax and AUC for abiraterone were within the BE range for LS-DAT versus SAC (Table 2).

3.4 LS-DAT (Niraparib 100 mg/AA 1000 mg) Model-Based BE Assessment

Simulations based on PPK model parameters revealed that, for the LS-DAT and SAC, average GMRs for Cmax,ss/AUC0–24h,ss were 88.7%/88.2% for niraparib and 98.7%/100% for abiraterone, respectively. Comparison of the LS-DAT with SAC showed that BE criteria would be simultaneously met for Cmax and AUC of both niraparib and abiraterone following repeated doses in 96.4% of the 1000 simulated studies. Figure 5 shows the distribution of simulated study replicate outcomes as GMRs and 90% CIs for niraparib and abiraterone Cmax,ss and AUC0–24h,ss, where outcomes associated with BE being simultaneously met for all four PK parameters are shown in gray; outcomes where ≥ 1 of the four PK parameters did not meet the BE criteria are shown in red. These findings confirmed results obtained from the aforementioned additional exploratory noncompartmental analysis for abiraterone, where LS-DAT and SAC were compared in the paired-group analysis within patients from sequences 3 and 4 of the BA/BE study (Fig. 5; overlaid in blue for comparison).

Fig. 5
figure 5

Estimated GMR and 90% CIs for niraparib and abiraterone Cmax,ss and AUC0–24h,ss for the simulated BE trials of LS-DAT versus single agents. Dark gray crosses are centered at the point estimates’ GMRs for AUC0–24h,ss and Cmax,ss, while light gray crosses denote the associated 90% CIs. Red lines denote CIs of GMR for either AUC0–24h,ss or Cmax,ss that fall outside the 80%–125% limits. In the abiraterone panel, blue lines denote the 90% CIs of GMR based on the paired analysis using single-sequence data from patients who received niraparib 100 mg/AA 1000 mg as LS-DAT or 200 mg/AA 1000 mg as single agents in the rBA/BE study (AUC: GMR = 102.58, 90% CI 86.51–121.64; Cmax: GMR, 100.54; 90% CI 85.41–118.34 based on nonparametric superposition). Note: the probability to meet BE criteria separately for niraparib and abiraterone is shown in the top-right corner of each panel. AA abiraterone acetate, AUC0–24h,ss area under the plasma concentration–time curve from time 0 to 24 h post-dosing at steady state, CI confidence interval, Cmax,ss maximum observed analyte concentration at steady state, GMR geometric mean ratio, LS-DAT lower-strength dual-action tablets (niraparib 100 mg/AA 1000 mg), rBA/BE relative bioavailability/bioequivalence.

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Findings from the simulation exercise using a parallel group design (Fig. 6) showed that meeting the BE criteria for the LS-DAT compared with SAC with such a design would be unlikely—the proportion of simulated studies where BE criteria would be simultaneously met for Cmax and AUC of both niraparib and abiraterone was essentially zero. This finding from the model-based BE assessment was in line with the experimental finding based on noncompartmental analysis (Fig. 6; overlaid in blue for comparison).

Fig. 6
figure 6

Estimated GMR and 90% CIs for niraparib and abiraterone single-dose Cmax and AUC0–72h for the simulated rBA trials of LS-DAT versus single agents. Dark gray crosses are centered at the point estimates’ GMRs for single-dose AUC0–72h and Cmax, while light gray crosses denote the associated 90% CIs. Red lines denote CIs of GMR for either single-dose AUC0–72h or Cmax that fall outside the 80%–125% limits. In the niraparib panel, blue lines denote the 90% CIs of GMR based on the rBA assessment of LS-DAT versus single agents based on period 1 data of patients who received niraparib 100 mg/AA 1000 mg as LS-DAT or 200 mg/AA 1000 mg as single agents in the rBA/BE study (AUC: GMR = 90.11, 90% CI 80.31–101.12; Cmax: GMR = 90.88, 90% CI 78.22–105.59). In the abiraterone panel, blue lines denote the 90% CIs of GMR based on the rBA assessment of LS-DAT versus single agents based on period 1 data of patients who received niraparib 100 mg/AA 1000 mg as LS-DAT or single agents in the BA/BE study (AUC: GMR = 121.9, 90% CI 101.09–147.07; Cmax: GMR = 132.62, 90% CI 108.35–162.32). Note: the probability to meet BE criteria separately for niraparib and abiraterone is shown in the top-right corner of each panel. AA abiraterone acetate, AUC area under the plasma concentration–time curve, AUC0–72h AUC from time 0–72 h post-dosing, BA bioavailability, BE bioequivalence, CI confidence interval, Cmax maximum observed analyte concentration, GMR geometric mean ratio, LS-DAT lower-strength dual-action tablets (niraparib 100 mg/AA 1000 mg), rBA relative BA

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3.5 Safety

Across the three periods of the PK assessment phase, 82 patients (60.3%) experienced ≥ 1 treatment-emergent AE (TEAE), of whom 55 (40.4%) experienced a drug-related TEAE(s) (ESM Table 2). Overall, 16 patients (11.8%) experienced ≥ 1 grade 3 or 4 TEAE, among whom 10 (7.4%) experienced a drug-related grade 3 or 4 TEAE(s) (grade 3: hypertension [3 (2.2%)], anemia [2 (1.5%)], and thrombocytopenia [2 (1.5%)]; grade 4: lymphopenia [1 (0.7%)]). In total, 49 patients (36.0%) experienced ≥ 1 TEAE of special interest (≥ 10% of patients across the three periods), most frequently anemia [24 (17.6%)], and three patients (2.2%) reported coronavirus disease 2019 (COVID-19)-related TEAEs. Ten patients (7.4%) experienced ≥ 1 TEAE leading to study treatment discontinuation or interruption.

Five patients (3.7%) experienced ≥ 1 SAE. The SAEs were considered treatment related by the investigator in one patient who experienced four grade 3 SAEs (hyponatremia, asthenia, mental status change, and nausea). The patient died during the 30-day follow-up after the last dose of study treatment due to a nonrelated grade 5 SAE of cardiac failure. The patient’s medical history included grade 1 stable atrial fibrillation (with no previous thrombotic complications) and grade 2 hypothyroidism.

4 Discussion

Most patients will likely be taking the combination of niraparib and AA at the proposed dosages of 200 mg and 1000 mg daily, respectively. To reduce pill burden, the RS-DAT formulation was developed, and the primary focus of this study was demonstration of BE for the RS-DAT with respect to SAC, supported by a powered study design and statistical analyses demonstrating that the well-defined BE criteria (90% CIs for the GMRs fell between 80% and 125%) were met.

For both niraparib and abiraterone, the study results supported that the combination product was equivalent to each drug administered separately, thereby supporting clinical use of the new DAT formulation.

We recognized, however, that some patients may require a dose reduction of niraparib, while dose reductions due to abiraterone would be less frequent. Thus, the LS-DAT formulation with a low-dose niraparib component was also developed. Since the starting dose of niraparib 100 mg in combination with AA was not considered acceptable for prolonged use, a BE study analogous to that used for the RS-DAT was deemed unethical for the LS-DAT. Therefore, a short run-in with a single dose in a parallel design, which had minimal burden to patients, was used to support comparability between the LS-DAT and SAC, while acknowledging that the study was not powered to support LS-DAT comparison.

For the niraparib component of the LS-DAT, rBA results almost fully met BE criteria. GMRs of niraparib Cmax and AUC0–72h were 90.88% and 90.11%, respectively, and the lower limits of the 90% CI were 78.22% and 80.31%, respectively. Given that niraparib is Biopharmaceutics Classification System Class I at the dose of 200 mg (data on file), the RS-DAT was BE to SAC, and the key difference between the RS-DAT and LS-DAT was primarily the dose of niraparib, the niraparib component of the LS-DAT was considered highly likely to be BE.

For the abiraterone component of the LS-DAT, the point estimates for Cmax (132.62%) and AUC (121.93%) as assessed by the rBA suggest an increase in exposure compared with SAC. However, the observed difference can be attributed to the large intersubject variability in the context of a parallel study design. Notably, interpatient variability of abiraterone was higher for the LS-DAT (Cmax: 80.4%; AUC0–72h: 72.9%) than intrapatient variability of the RS-DAT (Cmax,ss: 48.0%; AUC0–24h,ss: 33.6%). These findings are consistent with results from previous studies of AA monotherapy [28, 29] and suggest that observed differences in Cmax and AUC0–72h GMRs between the DAT and SAC groups in parallel design could be reflective of interpatient differences in PK characteristics of abiraterone (e.g., absolute BA due to low solubility and low permeability as AA is a Biopharmaceutics Classification System Class IV drug, clearance, and volume of distribution), owing to the large difference in group mean rather than indicative of a true difference between formulations.

To better evaluate the comparability of abiraterone between the LS-DAT and SAC, an additional statistical analysis was conducted where the LS-DAT and niraparib 200 mg/AA 1000 mg SAC were compared in a paired fashion. Using this approach, the potential for differences among patients—which could confound the assessment of formulation impact on abiraterone exposure—was removed, and the exposure metrics for abiraterone were compared within the same group of patients. While the LS-DAT was administered as a single dose, the shorter half-life of abiraterone (15 h) meant that the AUC0–inf could be calculated within period 1 and could be compared with the AUC0–24hr,ss of the SAC in period 2 or 3 as abiraterone PK is linear [30]. In this analysis, the 90% CIs for the GMRs of Cmax and AUC for abiraterone between the LS-DAT and SAC were within the 80%–125% criteria for BE. These results support the conclusion that the observed increase in GMR in the parallel-group assessment was most likely due to interpatient variability, and thus the abiraterone component is also considered highly likely to be BE.

To further reinforce the consideration for niraparib and abiraterone, PPK modeling [27] and model-based BE assessment were used to predict whether or not the LS-DAT was BE with SAC. Critical to assessment of BA, the PPK models of niraparib and abiraterone adequately captured the absorption phase of the RS-DAT, LS-DAT, and SAC. For abiraterone, no significant effect for the LS-DAT was observed on the basis of the model parameters of apparent oral availability, first-order absorption rate constant, and duration of zero-order drug release. However, in the simulations, these formulation differences were retained in the abiraterone model to generate a more conservative estimate of the probability to meet BE criteria. The resulting model-predicted AUC0–24h and Cmax for the LS-DAT versus respective single-agent dosing met BE criteria for Cmax and AUC of both niraparib and abiraterone following repeated doses in 96.4% of the 1000 simulated studies based on a multiple-dose crossover design at steady state.

BE is a key criterion for the RS-DAT and LS-DAT being able to help reduce pill burden for patients. By using such a study design and analysis strategy, not only was the RS-DAT demonstrated to be BE, but the LS-DAT was also considered BE to SAC based on the multifaceted evaluation of niraparib exposure (parallel rBA and model-based BE assessment) and abiraterone exposure (paired rBA and model-based BE assessment). In addition, the safety profile of the LS-DAT and RS-DAT was consistent with the known safety profile of niraparib and AA when administered as single agents in patients with mCRPC. No new safety signals were identified.