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A Phase I Study of Capivasertib in Combination With Abiraterone Acetate in Patients With Metastatic Castration-Resistant Prostate Cancer

Open AccessPublished:November 25, 2022DOI:https://doi.org/10.1016/j.clgc.2022.11.017

      Highlights

      • Capivasertib + abiraterone acetate treatment had an acceptable tolerability profile.
      • No dose-limiting toxicity was observed.
      • Adverse events were consistent with the known safety profile of each agent.
      • Combination pharmacokinetics were similar to previous monotherapy dosing results.
      • Supports further studies in patients with metastatic prostate cancer.

      Abstract

      Background

      Although androgen receptor-targeted agents prolong the lives of patients with metastatic prostate cancer, patients develop therapy resistance and most ultimately succumb to the disease. The PI3K/AKT/PTEN pathway has been associated with the development of resistance, raising the possibility that pathway inhibitors may produce a clinical benefit. This open-label phase Ib study examined the safety, tolerability, pharmacokinetics (PK) and preliminary clinical activity of adding capivasertib – a potent, selective inhibitor of AKT1/2/3 – to approved abiraterone acetate therapy.

      Methods

      Twenty-seven patients with metastatic castration-resistant prostate cancer who had undergone at least 1 prior line of systemic therapy received abiraterone acetate 1000 mg (orally administered once daily), plus oral prednisone 5 mg (twice daily) with capivasertib 400 mg (orally, twice daily, with an intermittent schedule of 4 days on, 3 days off).

      Results

      No dose-limiting toxicity was observed. The most frequent adverse events (all grade) were diarrhea (30%), anemia (26%), asthenia (22%), and nausea (22%). The most frequent grade 3 or higher adverse events were acute kidney injury (19%), hyperglycemia (7%), rash (7%), abdominal pain (7%), and asthenia (7%). Capivasertib and abiraterone PK were consistent with previously reported results from monotherapy dosing. Nine participants (33%) showed a 20% or greater decrease in prostate-specific antigen during study treatment.

      Conclusion

      The combination of capivasertib and abiraterone acetate had an acceptable tolerability profile consistent with the known profile of each agent. These data support further evaluation of capivasertib and abiraterone acetate in patients with advanced prostate cancer.

      Keywords

      Introduction

      Prostate adenocarcinoma is a common malignancy, with an estimated 1.4 million cases worldwide each year.
      • Ferlay J
      • Ervik M
      • Lam F
      • et al.
      Global Cancer Observatory: Cancer Today.
      Around 80% of patients with metastatic prostate cancer will die from the disease.
      • Elmehrath AO
      • Afifi AM
      • Al-Husseini MJ
      • et al.
      Causes of death among patients with metastatic prostate cancer in the US From 2000 to 2016.
      While androgen deprivation therapy is foundational for advanced prostate cancer, nearly all patients with metastatic prostate cancer experience progression to metastatic castration-resistant prostate cancer (mCRPC), which is still incurable. Ongoing therapies focus on slowing progression and minimizing disease burden, while prolonging survival.
      Next-generation androgen receptor-targeting agents (ARTAs), including abiraterone acetate (an inhibitor of the CYP17A1 androgen synthesis enzyme) and enzalutamide (an androgen receptor [AR] antagonist) have demonstrated improvements in progression-free survival (PFS) and overall survival for mCRPC.
      • Beer TM
      • Armstrong AJ
      • Rathkopf DE
      • et al.
      Enzalutamide in metastatic prostate cancer before chemotherapy.
      • de Bono JS
      • Logothetis CJ
      • Molina A
      • et al.
      Abiraterone and increased survival in metastatic prostate cancer.
      • Ryan CJ
      • Smith MR
      • de Bono JS
      • et al.
      Abiraterone in metastatic prostate cancer without previous chemotherapy.
      Abiraterone acetate and enzalutamide are frequently preferred as first-line therapy over docetaxel, given their safety profile and oral route of administration. However, mCRPC invariably develops resistance to ARTAs,
      • Nuhn P
      • De Bono JS
      • Fizazi K
      • et al.
      Update on systemic prostate cancer therapies: management of metastatic castration-resistant prostate cancer in the era of precision oncology.
      and there is an unmet need for new treatments that slow or prevent resistance.
      The PI3K/AKT/PTEN pathway that promotes cell proliferation and resistance to apoptosis has been associated with ARTA resistance. It is estimated that 40% to 60% of mCRPC tumors have lost expression of the negative pathway regulator, PTEN.
      • Jamaspishvili T
      • Berman DM
      • Ross AE
      • et al.
      Clinical implications of PTEN loss in prostate cancer.
      Preclinical studies have demonstrated reciprocal cross-talk between the AR and PI3K/AKT/PTEN pathway, whereby AR inhibition upregulates PI3K/AKT/PTEN pathway signaling, and PI3K/AKT/PTEN pathway inhibition activates AR signaling. Consistent with this, simultaneous inhibition of both pathways has demonstrated preclinical antitumor activity, particularly in PTEN-deficient models.
      • Carver BS
      • Chapinski C
      • Wongvipat J
      • et al.
      Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer.
      ,
      • Mulholland DJ
      • Tran LM
      • Li Y
      • et al.
      Cell autonomous role of PTEN in regulating castration-resistant prostate cancer growth.
      This has focused interest on the use of PI3K/AKT/PTEN pathway inhibitors to counter ARTA resistance.
      Capivasertib is a potent, selective inhibitor of all 3 AKT isoforms (AKT1/2/3)
      • Davies BR
      • Greenwood H
      • Dudley P
      • et al.
      Preclinical pharmacology of AZD5363, an inhibitor of AKT: pharmacodynamics, antitumor activity, and correlation of monotherapy activity with genetic background.
      that has been investigated in numerous cancers, including prostate cancer.
      • Coleman N
      • Moyers JT
      • Harbery A
      • Vivanco I
      • Yap TA.
      Clinical development of AKT inhibitors and associated predictive biomarkers to guide patient treatment in cancer medicine.
      The phase I/II ProCAID study showed that addition of capivasertib to docetaxel significantly extended the secondary endpoint of overall survival in patients with mCRPC, and a follow-on phase III trial (CAPItello-280; NCT05348577) has begun.
      • Crabb SJ
      • Griffiths G
      • Marwood E
      • et al.
      Pan-AKT inhibitor capivasertib with docetaxel and prednisolone in metastatic castration-resistant prostate cancer: a randomized, placebo-controlled phase II trial (ProCAID).
      The ongoing phase III CAPItello-281 (NCT04493853) study is examining adding capivasertib to abiraterone acetate in patients with PTEN-deficient, de novo, metastatic, hormone-sensitive prostate cancer.
      • Fizazi K
      • George DJ
      • Santis MD
      • et al.
      A phase III trial of capivasertib and abiraterone versus placebo and abiraterone in patients with de novo metastatic hormone-sensitive prostate cancer characterized by PTEN deficiency (CAPItello-281).
      Additionally, the phase III IPATential150 trial demonstrated that the AKT inhibitor ipatasertib improved radiological PFS when added to abiraterone acetate in patients with PTEN-deficient mCRPC, albeit at the expense of additional toxicity.
      • Sweeney C
      • Bracarda S
      • Sternberg CN
      • et al.
      Ipatasertib plus abiraterone and prednisolone in metastatic castration-resistant prostate cancer (IPATential150): a multicentre, randomised, double-blind, phase 3 trial.
      Here we report findings from a phase Ib, open-label, multicohort, multicenter study (NCT04087174) that examined the safety, tolerability, pharmacokinetics (PK) and preliminary signs of clinical activity from adding capivasertib to abiraterone acetate therapy in patients with mCRPC.

      Materials and Methods

      Patient Population

      Eligible patients had documented evidence of mCRPC, a World Health Organisation performance status of 0 to2, life expectancy of at least 12 weeks or longer, and had received at least one line of systemic therapy for mCRPC (either chemotherapy or an ARTA, which could include abiraterone), unless no alternative approved therapy was available. Patients had to be eligible to receive abiraterone acetate treatment.
      Patients were ineligible if they had received enzalutamide in the 8 weeks before the first dose of study treatment, or had received nitrosourea or mitomycin C within 6 weeks, major surgery or radiotherapy with a wide field of radiation within 4 weeks, any other anti-cancer agent (with the exception of luteinizing hormone-releasing hormone analogues) within 3 weeks, potent inhibitors, inducers or substrates of CYP3A4 within 2 weeks, and/or any investigational agent within 30 days before the first dose. Prior abiraterone was allowed. Other exclusion criteria included clinically significant abnormalities of glucose metabolism (defined as type 1 or type 2 diabetes mellitus that required insulin treatment or HbA1c ≥ 8.0% [63.9 mmol/mol]), previously identified brain metastases or spinal cord compression unless treated and considered stable over the 3 weeks leading up to the study, clinically significant cardiac disease, or any evidence of severe or uncontrolled systemic disease as judged by the investigator.

      Study Design

      The study had 2-parts. Part A examined whether the selected dosing regimen had acceptable safety and tolerability. Part B allowed for dose expansion and additional recruitment based on Safety Review Committee (SRC) examination of Part A data. The study was conducted according to Good Clinical Practice guidelines, the Declaration of Helsinki, and followed national ethics and regulatory approvals. Informed consent was obtained from all participants.

      Study Objective

      The primary objective was to investigate the safety and tolerability of capivasertib when given in combination with abiraterone acetate to patients with mCRPC. Other objectives were to characterize the PK of capivasertib and abiraterone under combination dosing, and to examine preliminary signs of clinical activity of combined capivasertib plus abiraterone acetate therapy. Adverse event (AE) and PK data were recorded for all patients who received capivasertib and abiraterone acetate. Clinical efficacy data were collected from 14 patients: 2 in Part A and 12 in Part B.

      Treatment

      Eight participants were recruited in Part A to receive capivasertib (400 mg, oral twice daily [BD]) by an intermittent schedule (4 days on, 3 days off) in combination with abiraterone acetate (1000 mg oral, once daily), together with prednisone or prednisolone 10 mg. Intermittent capivasertib administration was previously shown to maximize therapeutic benefit and reduce toxicities by allowing nontarget tissues to recover during dosing breaks and, based on accumulated efficacy and safety data, is being used in phase III trials.
      The SRC examined Part A data to confirm the dosing level before expanding the study to additional participants (Part B). 10 participants received a 1-week pretreatment with abiraterone acetate before study treatment to allow within-subject comparison of abiraterone PK parameters in the presence and absence of capivasertib. Study treatment was continued until unacceptable toxicity, disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, confirmed progression in bone according to Prostate Cancer Working Group 3 (PCWG-3) criteria,
      • Scher HI
      • Morris MJ
      • Stadler WM
      • et al.
      The Prostate Cancer Working Group 3 (PCWG3) consensus for trials in castration-resistant prostate cancer (CRPC).
      any skeletal-related event, or the decision of the participant to discontinue for any reason.

      Assessments

      Blood samples were collected for clinical laboratory testing on day 1 of study treatment, at a second visit that occurred before day 14, and weekly thereafter until withdrawal from the study. AEs were characterized by the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.
      Radiological PFS (according to RECIST 1.1 and PCWG-3 criteria) was defined as the time from the first dose of study therapy until objective disease progression (soft tissue or bone) or death (by any cause), regardless of whether the participant withdrew from study therapy or received another anti-cancer therapy before progression. Circulating prostate-specific antigen (PSA) levels were measured before study initiation, on day 1 of study treatment, and at the end of each 28-day cycle thereafter. Tumor assessments by bone scans and computed tomography or magnetic resonance imaging were performed on day 1 and then every 8 weeks for the first 24 weeks, and every 12 weeks thereafter until disease progression. The baseline for efficacy measurements was defined as the value recorded on the day that treatment commenced or, if not available, the most recent value recorded before the start of study treatment.

      PK

      A predose blood sample was collected on day 1, 11, 18, and 29 of the study. Serial blood samples were collected on day 25 or day 29 (predose, 0.5, 1, 2, 4, 6, 8, and 12-hours postdose), with day 25 values used to calculate PK parameters. Plasma samples (25 µL) were analyzed for capivasertib, after the addition of 13C-labelled internal standard, by solid phase extraction followed by reversed phase HPLC-MS/MS. For abiraterone, plasma samples (50 µL) were analyzed, after the addition of abiraterone-d4 internal standard, by liquid-liquid extraction followed by HPLC-MS/MS. A series of calibration standards containing known amounts of each compound (1.00-1000 ng/mL and 1.00–500 ng/mL for capivasertib and abiraterone, respectively) added to control human plasma were processed in parallel with trial samples. Both pre- and peri-study validation for all methods was successfully conducted according to the United States Food and Drug Administration Guidance for Industry Bioanalytical Method Validation.

      US. Food and Drug Administration. Bioanalytical Method Validation Guidance for Industry. 2018: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/bioanalytical-method-validation-guidance-industry. 16/06/2022.

      PK parameters were derived using non-compartmental analysis. Capivasertib plasma concentrations were compared to those from previous studies in patients with solid tumors receiving capivasertib 480 mg BD (4 days on, 3 days off) as monotherapy, after dose-normalization that assumed dose-proportionality.
      • Banerji U
      • Dean EJ
      • Pérez-Fidalgo JA
      • et al.
      A phase I open-label study to identify a dosing regimen of the pan-AKT inhibitor AZD5363 for evaluation in solid tumors and in PIK3CA-mutated breast and gynecologic cancers.
      ,
      • Dean E
      • Banerji U
      • Schellens JHM
      • et al.
      A Phase 1, open-label, multicentre study to compare the capsule and tablet formulations of AZD5363 and explore the effect of food on the pharmacokinetic exposure, safety and tolerability of AZD5363 in patients with advanced solid malignancies: OAK.
      Abiraterone plasma concentrations were compared to model-predicted concentrations using a previously published population PK model.
      • Stuyckens K
      • Saad F
      • Xu XS
      • et al.
      Population pharmacokinetic analysis of abiraterone in chemotherapy-naïve and docetaxel-treated patients with metastatic castration-resistant prostate cancer.

      Results

      Participants

      Thirty-four patients with mCRPC were enrolled. Seven did not pass screening procedures (Supplemental Table 1). The characteristics of participants who received study treatment (N = 27; the safety analysis set) are summarized in Table 1. Median age was 68 years (range 49-82 years). Eleven participants (41%) had received abiraterone acetate before entering the study, 18 participants (67%) had received enzalutamide, 22 (81%) had received docetaxel, 9 (33%) had received cabazitaxel, and 13 (48%) had previously received an immunotherapy, most commonly sipuleucel-T (7 participants) and/or pembrolizumab (5 participants).
      Table 1Patient Demographics, Disease Characteristics, and Previous Cancer Therapies
      Total Patients (N = 27)
      Age (years); median (range)68 (49-82)
      Country; n (%)
      Spain11 (41)
      USA16 (59)
      Time from diagnosis to enrolment (years); median (range)6.4 (0.1-17.1)
      ECOG performance status, n (%)
      012 (44)
      115 (56)
      PSA at screening (μg/L); median (range)83.4 (0.40-593)
      Prior therapies; n (%)
      Abiraterone11 (41)
      Enzalutamide18 (67)
      Bicalutamide9 (33)
      Docetaxel22 (81)
      Cabazitaxel9 (33)
      Carboplatin5 (19)
      Immunotherapy13 (48)
      PARP inhibitor7 (26)
      Radiotherapy4 (15)
      Prior chemotherapy regimens; n (%)
      04 (15)
      113 (48)
      26 (22)
      32 (7.4)
      ≥ 41 (3.7)
      Abbreviations: ECOG = Eastern Cooperative Oncology Group; PARP = poly (ADP-ribose) polymerase; PSA = prostate-specific antigen.

      Safety

      No dose-limiting toxicities were observed during Part A (8 participants) and the study was expanded to Part B (19 participants) without altering the treatment regimen. All participants in Part A (100%) and 17 participants (90%) in Part B discontinued treatment, most commonly owing to disease progression (14 participants total [52%]). AEs leading to permanent discontinuation of capivasertib (irrespective of relationship) were reported for 11 participants (41%), and AEs leading to permanent discontinuation of abiraterone acetate (irrespective of relationship) were reported for 9 participants (33%) (Supplemental Table 1). Two participants in Part B (11%) continued treatment at the time of data cut-off (Supplemental Table 1).
      Participants received a median number of three 28-day treatment cycles. Five participants (63%) in Part A and 8 participants (42%) in Part B experienced an interruption and/or reduction to the planned capivasertib dosing. There were no abiraterone acetate treatment interruptions or dose reductions in Part A, although 6 participants in Part B (32%) experienced an interruption and/or reduction (Supplemental Table 2).
      All participants experienced at least 1 AE. The most common AEs were diarrhea, anemia, nausea, asthenia, and fatigue (Table 2). AEs of CTCAE grade 3 or higher were reported for 16 participants (59%; Table 2 and Supplemental Table 3). Serious AEs were reported for 10 participants (37%; Supplemental Table 4). Two participants (7.4%) died during the study. In both cases the investigator identified the cause of death as disease-related and not treatment-related.
      Table 2Adverse Events That Occurred in ≥ 10% of Patients
      Patients Who Experienced Any Adverse Event (N = 27), n (%)Patients Who Experienced CTCAE Grade ≥ 3 (N = 27), n (%)
      Any adverse event27 (100)16 (59.3)
      Diarrhea16 (59)1 (3.7)
      Anemia8 (30)0
      Nausea7 (26)0
      Asthenia6 (22)2 (7.4)
      Fatigue6 (22)1 (3.7)
      Acute kidney injury5 (19)5 (19)
      Decreased appetite5 (19)0
      Hyperglycemia5 (19)2 (7.4)
      Rash maculopapular5 (19)2 (7.4)
      Abdominal pain4 (15)2 (7.4)
      Constipation4 (15)0
      Dehydration4 (15)1 (3.7)
      Headache4 (15)0
      Hypokalemia4 (15)1 (3.7)
      Hypomagnesemia4 (15)0
      Hypophosphatemia4 (15)0
      Pyrexia4 (15)0
      Back pain3 (11)0
      Dysphagia3 (11)0
      Dyspnea3 (11)0
      Hematuria3 (11)0
      Hyperkalemia3 (11)1 (3.7)
      Edema peripheral3 (11)0
      Urinary tract infection3 (11)1 (3.7)
      Vomiting3 (11)0
      Abbreviation: CTCAE = Common Terminology Criteria for Adverse Events.

      PK

      At least 1 capivasertib and 1 abiraterone plasma concentration was determined for all 27 participants. Some serial PK samples were collected on day 29 (after 3 days without capivasertib dosing) instead of on day 25 (day 4 of 4 days receiving capivasertib). Plasma capivasertib concentrations over time are shown in Figure 1A. Table 3 presents a summary of PK parameters calculated from day 25 plasma concentrations in participants who received capivasertib 400 mg BD without dose interruptions or reductions that might affect capivasertib PK. The geometric mean (gMean) area under the time-concentration curve over the dosing interval (AUCτ) and maximum plasma concentration (Cmax) for capivasertib were 10 300 ng·h/mL and 1934 ng/mL, respectively, and the median time to reach the maximum observed concentration (Tmax) was 2 hours. The between-subject variability in capivasertib exposure was moderate, with geometric coefficient of variation percentages of 39% for AUCτ and 36% for Cmax. Figure 1B shows participant abiraterone plasma concentrations over time, and Table 4 shows PK parameters. The variability in abiraterone exposure was in line with previous abiraterone PK analyses that showed high between- and within-subject variability.
      • Stuyckens K
      • Saad F
      • Xu XS
      • et al.
      Population pharmacokinetic analysis of abiraterone in chemotherapy-naïve and docetaxel-treated patients with metastatic castration-resistant prostate cancer.
      A predose gMean abiraterone concentration (Cmin) was calculated at 13 ng/mL for the 10 participants who received abiraterone acetate for a 1-week run-in before commencing study treatment. This value was similar to the gMean abiraterone Cmin values calculated for these participants under combination dosing (gMean Cmin values on days 12, 18, 25, and 29 of study treatment were 7, 11, 16, and 18 ng/mL, respectively).
      Figure 1
      Figure 1Capivasertib and abiraterone plasma concentrations versus time on day 25 or day 29. Black plots show plasma concentrations of (A) capivasertib (n = 18) and (B) abiraterone (n = 18) in individual participants following drug administration on day 25 (or day 29 for abiraterone). Grey plots (with triangles) in (A) show capivasertib plasma concentrations after dosing on day 29. These were not directly comparable to day 25 values as they followed a 3-day off-dose period. Note that abiraterone was dosed continuously. Red plots show the geometric mean for the study population. Capivasertib and abiraterone acetate were administered at 0 hours. Predose concentrations are plotted for 0 hours. Data from patients with dose interruptions or reductions were not included. Blue shading indicates the 95% prediction interval derived from (A) capivasertib dosed as monotherapy in previous studies
      • Banerji U
      • Dean EJ
      • Pérez-Fidalgo JA
      • et al.
      A phase I open-label study to identify a dosing regimen of the pan-AKT inhibitor AZD5363 for evaluation in solid tumors and in PIK3CA-mutated breast and gynecologic cancers.
      ,
      • Dean E
      • Banerji U
      • Schellens JHM
      • et al.
      A Phase 1, open-label, multicentre study to compare the capsule and tablet formulations of AZD5363 and explore the effect of food on the pharmacokinetic exposure, safety and tolerability of AZD5363 in patients with advanced solid malignancies: OAK.
      and (B) a published population PK model of abiraterone acetate monotherapy.
      • Stuyckens K
      • Saad F
      • Xu XS
      • et al.
      Population pharmacokinetic analysis of abiraterone in chemotherapy-naïve and docetaxel-treated patients with metastatic castration-resistant prostate cancer.
      PK = pharmacokinetics.
      Table 3Capivasertib Pharmacokinetic Parameters on day 25
      Parameter (units); nStatisticValues
      AUCτ (ng·h/mL); n = 10gMean10 300
      CV%39
      Min–Max6400–18 400
      Cpredose (ng/mL); n = 11gMean304
      CV%73
      Min–Max104–795
      Cmax (ng/mL); n = 11gMean1934
      CV%36
      Min–Max1050–3250
      Cmin (ng/mL); n = 11gMean275
      CV%59
      Min–Max104–629
      C12 (ng/mL); n = 10gMean316
      CV%57
      Min–Max156–717
      Tmax (h); n = 11Median2.0
      Min–Max1.0–4.1
      CL/F (L/h); n = 10Mean41.3
      SD14.3
      Min–Max21.8–62.5
      Abbreviations: AUCτ = area under the time-concentration curve over the dosing interval; C12 = plasma concentration at 12 hours after dosing; CL/F = apparent total body clearance of drug from plasma; Cmax = maximum plasma concentration; Cmin = minimum plasma concentration; Cpredose = plasma concentration obtained before administering a dose; CV = coefficient of variation; gMean = geometric mean; Max = maximum; Min, minimum; SD = standard deviation; Tmax = time to reach peak observed concentration following drug administration.
      Table 4Abiraterone Pharmacokinetic Parameters on day 25 or day 29
      Parameter (units); nStatisticValues
      AUC0–24 (ng·h/mL); n = 15gMean780
      CV%65
      Min–Max281–2130
      AUClast (ng·h/mL); n = 18gMean566
      CV%116
      Min–Max28.4–1280
      Cmax (ng/mL); n = 19gMean117
      CV%124
      Min–Max4.37–334
      Tlast (h); n = 18Median12.0
      Min–Max11.0–12.2
      Tmax (h); n = 19Median2.1
      Min–Max0.5–5.8
      Abbreviations: AUC0–24 = area under the plasma concentration-time curve over 24 hours; AUClast = area under the concentration-time curve from the time of administration to final quantifiable concentration; Cmax = maximum plasma concentration; CV, coefficient of variation; gMean = geometric mean; Max, maximum; Min, minimum; Tlast = time to the last quantifiable capivasertib measurement; Tmax, time to reach the maximum observed concentration following administration.

      Treatment Efficacy

      Tumor response was evaluated with RECIST 1.1 criteria in soft tissue and PCWG-3 criteria in bone, which required measurable disease at baseline; however not all participants had measurable and evaluable soft tissue lesions at baseline. None of the 14 evaluable participants showed an objective response to study treatment. Median radiological PFS (according to RECIST 1.1 and PCWG-3 criteria) was 9.7 months (95% confidence interval [CI]: 2.1-15.6 months) in Part A and 2.3 months (1.7–3.8 months) in Part B. In an exploratory analysis, the change from baseline PSA levels was examined in all participants (Figure 2). Of the 27 evaluable patients, 1 patient (3.7%; 80% CI 0.39–13.66) had a 50% or greater reduction in PSA from baseline after 12 weeks of treatment. Nine showed a 20% or greater decrease in PSA concentration compared to day 1 of study treatment, including 1 participant where PSA remained low for the 306 days that they were in the study. The subset of participants whose PSA levels decreased on study treatment had a higher proportion of individuals without previous ARTA treatment (4 of 9 [44%]), compared with those whose PSA levels remained stable or increased (2 of 19 [11%] had no previous ARTA treatment).
      Figure 2
      Figure 2Prostate-specific antigen levels. Plot shows the fold change in PSA levels for each participant relative to PSA levels on day 1 of the study. Black plots show values from participants who had received prior abiraterone, enzalutamide and/or apalutamide (ARTA) therapy. Red plots show values from participants with no prior ARTA therapy (at least 1 month of prior therapy). Dashed blue line indicates the threshold of a 20% decrease in PSA levels.
      ARTA = androgen receptor-targeted agent; PSA = prostate-specific antigen.

      Discussion

      This phase Ib, multicenter, open-label study assessed the safety, tolerability and PK of capivasertib given in combination with abiraterone acetate in patients with mCRPC. The AEs that are most commonly associated with capivasertib (diarrhea, fatigue, hyperglycemia, and rash) occurred with a similar frequency and severity as previously reported for capivasertib monotherapy.
      • Banerji U
      • Dean EJ
      • Pérez-Fidalgo JA
      • et al.
      A phase I open-label study to identify a dosing regimen of the pan-AKT inhibitor AZD5363 for evaluation in solid tumors and in PIK3CA-mutated breast and gynecologic cancers.
      ,
      • Dean E
      • Banerji U
      • Schellens JHM
      • et al.
      A Phase 1, open-label, multicentre study to compare the capsule and tablet formulations of AZD5363 and explore the effect of food on the pharmacokinetic exposure, safety and tolerability of AZD5363 in patients with advanced solid malignancies: OAK.
      ,
      • Hyman DM
      • Smyth LM
      • Donoghue MTA
      • et al.
      AKT inhibition in solid tumors with AKT1 mutations.
      Abiraterone acetate therapy has been most commonly associated with mineralocorticoid-related AEs, including fluid retention, hypertension and hypokalemia;
      • de Bono JS
      • Logothetis CJ
      • Molina A
      • et al.
      Abiraterone and increased survival in metastatic prostate cancer.
      these were also detected at a similar frequency as for abiraterone acetate monotherapy.
      • de Bono JS
      • Logothetis CJ
      • Molina A
      • et al.
      Abiraterone and increased survival in metastatic prostate cancer.
      Unusually, the relatively high prevalence of acute kidney injuries seen in participants has not been previously associated with capivasertib or abiraterone acetate
      • de Bono JS
      • Logothetis CJ
      • Molina A
      • et al.
      Abiraterone and increased survival in metastatic prostate cancer.
      ,
      • Banerji U
      • Dean EJ
      • Pérez-Fidalgo JA
      • et al.
      A phase I open-label study to identify a dosing regimen of the pan-AKT inhibitor AZD5363 for evaluation in solid tumors and in PIK3CA-mutated breast and gynecologic cancers.
      ,
      • Dean E
      • Banerji U
      • Schellens JHM
      • et al.
      A Phase 1, open-label, multicentre study to compare the capsule and tablet formulations of AZD5363 and explore the effect of food on the pharmacokinetic exposure, safety and tolerability of AZD5363 in patients with advanced solid malignancies: OAK.
      ,
      • Hyman DM
      • Smyth LM
      • Donoghue MTA
      • et al.
      AKT inhibition in solid tumors with AKT1 mutations.
      ; it is an AE that should be monitored and evaluated in ongoing and future clinical trials. This includes the phase III CAPItello-281 study that examines capivasertib addition to abiraterone acetate in patients with de novo metastatic, hormone-sensitive prostate cancer that features PTEN deficiency.
      • Sweeney C
      • Bracarda S
      • Sternberg CN
      • et al.
      Ipatasertib plus abiraterone and prednisolone in metastatic castration-resistant prostate cancer (IPATential150): a multicentre, randomised, double-blind, phase 3 trial.
      The PK parameters calculated for capivasertib and abiraterone given in combination are similar to those reported for capivasertib and abiraterone acetate administered alone.
      • Banerji U
      • Dean EJ
      • Pérez-Fidalgo JA
      • et al.
      A phase I open-label study to identify a dosing regimen of the pan-AKT inhibitor AZD5363 for evaluation in solid tumors and in PIK3CA-mutated breast and gynecologic cancers.
      ,
      • Dean E
      • Banerji U
      • Schellens JHM
      • et al.
      A Phase 1, open-label, multicentre study to compare the capsule and tablet formulations of AZD5363 and explore the effect of food on the pharmacokinetic exposure, safety and tolerability of AZD5363 in patients with advanced solid malignancies: OAK.
      ,
      • Lubberman FJE
      • Benoist GE
      • Gerritsen W
      • et al.
      A prospective phase I multicentre randomized cross-over pharmacokinetic study to determine the effect of food on abiraterone pharmacokinetics.
      ,
      • Szmulewitz RZ
      • Peer CJ
      • Ibraheem A
      • et al.
      Prospective international randomized phase II study of low-dose abiraterone with food versus standard dose abiraterone in castration-resistant prostate cancer.
      Additionally, the Cmin of abiraterone in this study was similar when administered alone versus when administered with capivasertib. These data suggest that there is no drug–drug interaction between capivasertib and abiraterone, which further supports testing this combination in prostate cancer.
      The efficacy analysis was limited by the small number of participants with evaluable tumor responses, limited information on the genetic status of tumors, as well as heterogeneity in the type and number of treatments received before the study. Thus, although no participant showed an objective response to study treatment, this does not necessarily reflect that patients with mCRPC will not benefit from adding capivasertib to abiraterone acetate therapy. Notably, capivasertib plus abiraterone acetate appeared to lower PSA levels in approximately one-third of participants, including 4 of the 6 with no prior ARTA exposure. Future studies should examine capivasertib in combination with abiraterone acetate for mCRPC, especially in patients who have not received an ARTA. It will also be important to examine if efficacy varies by whether tumors carry alterations in the PI3K/AKT/PTEN pathway.

      Conclusions

      The administration of capivasertib in combination with abiraterone acetate had an acceptable tolerability profile, with no dose-limiting toxicities observed, and AEs consistent with the known safety profile of each agent. These data support further studies to evaluate the safety and efficacy of capivasertib and abiraterone acetate in patients with metastatic prostate cancer.

      Clinical Practice Points

      • Next-generation androgen receptor-targeting agents, including abiraterone acetate and enzalutamide, have demonstrated improvements in PFS and overall survival for patients with metastatic prostate cancer. However, these patients can develop resistance to androgen receptor-targeted therapy due to mutations within the PI3K/AKT/PTEN pathway.
      • Capivasertib is a potent, selective inhibitor of all 3 AKT isoforms (AKT1/2/3) that has been investigated in numerous cancers and has demonstrated the potential to prolong overall survival in patients with metastatic prostate cancer.
      • The present phase Ib, open-label, multi-cohort and multicenter study examined the safety, tolerability, PK, and preliminary clinical activity of capivasertib administered in combination with abiraterone acetate.
      • The combination with abiraterone acetate had an acceptable tolerability profile, with no dose-limiting toxicities observed.
      • For AEs, the most frequent, including diarrhea, anemia, asthenia and nausea, were consistent with the known safety profile of each agent, and the PK of the agents in combination were similar to previously reported results for monotherapy dosing, suggesting no drug–drug interaction.
      • Building on previous data, the new findings support the clinical evaluation of capivasertib and abiraterone acetate as an alternative therapy for patients with advanced prostate cancer.

      Data Statement

      Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca's data-sharing policy, described at: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

      CRediT authorship contribution statement

      Neal Shore: Investigation, Project administration, Writing – original draft, Writing – review & editing. Begoña Mellado: Investigation, Project administration, Writing – original draft, Writing – review & editing. Satish Shah: Investigation, Project administration, Writing – original draft, Writing – review & editing. Ralph Hauke: Investigation, Project administration, Writing – original draft, Writing – review & editing. Dan Costin: Investigation, Project administration, Writing – original draft, Writing – review & editing. Nabil Adra: Investigation, Project administration, Writing – original draft, Writing – review & editing. Marie Cullberg: Conceptualization, Formal analysis, Methodology, Writing – original draft, Writing – review & editing. Carlos Fernandez Teruel: Formal analysis, Data curation, Methodology, Visualization, Writing – original draft, Writing – review & editing. Thomas Morris: Data curation, Formal analysis, Funding acquisition, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing.

      Acknowledgments

      Capivasertib was discovered by AstraZeneca subsequent to a collaboration with Astex Therapeutics (and its collaboration with the Institute of Cancer Research and Cancer Research Technology Limited). The authors thank the patients who participated in this clinical trial, their families, and the nursing and medical staff at the trial sites.
      This study (NCT04087174) was funded by AstraZeneca. Medical writing assistance was provided by Rose Goodchild PhD of Oxford PharmaGenesis and was funded by AstraZeneca.

      Disclosure

      The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: N.S has received honoraria and/or grant funding from AbbVie, Astellas, AstraZeneca, Alessa, Bayer, Dendreon, Ferring, Genetech, Janssen, Lilly, Merck, Myovant, Pfizer, Sanofi, and Tolmar, and is a director and owns stock in Photocure. N.A. has received honoraria for advisory roles with Astellas, Aveo Oncology, Bristol Myers Squibb, Exelixis, Merck, and Sanofi, and research funding (to the institute) from Astellas, Bristol Myers Squibb, Exelixis, Genentech, Merck, and Seattle Genetics. M.C, C.F.T., and T.M. are employees of Astra Zeneca and hold stock ownership. Others declare no conflict of interests.

      Appendix. Supplementary materials

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