An open-label, multicenter, phase Ib study investigating the effect of apalutamide on ventricular repolarization in men with castration-resistant prostate cancer

Belderbos, Bodine P.S.; Wit, Ronald de; Chien, Caly; Mitselos, Anna; Hellemans, Peter; Jiao, James; Yu, Margaret K.; Attard, Gerhardt; Bulat, Iurie; Edenfield, William J.; Saad, Fred

doi:10.1007/s00280-018-3632-6

Cited by 22 publications

(16 citation statements)

References 17 publications

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“…The pharmacokinetic characteristics of apalutamide and M3 in patients who received niraparib 300 mg with apalutamide were not summarized, because data were available for only two patients (Supplementary Table 3). These results were consistent with apalutamide monotherapy exposures in patients with prostate cancer [31].…”

Section: Pharmacokinetics Of Apalutamide and Its Metabolite M3 (Nirapsupporting

confidence: 87%

“…It is plausible that both variability in pharmacokinetics (limited data; no niraparib-alone arm) and P-gp induction by apalutamide contributed to the observed reduced niraparib exposure when combined with apalutamide. The exposures of apalutamide and its metabolite were consistent with apalutamide monotherapy exposures in patients with prostate cancer [ 31 ].…”

Section: Discussionmentioning

confidence: 83%

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Niraparib with androgen receptor-axis-targeted therapy in patients with metastatic castration-resistant prostate cancer: safety and pharmacokinetic results from a phase 1b study (BEDIVERE)

Saad

N.²,

Shore

et al. 2021

Cancer Chemother Pharmacol

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Purpose To assess the safety and pharmacokinetics and determine the recommended phase 2 dose (RP2D) of niraparib with apalutamide or abiraterone acetate plus prednisone (AAP) in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods BEDIVERE was a multicenter, open-label, phase 1b study of niraparib 200 or 300 mg/day with apalutamide 240 mg or AAP (abiraterone acetate 1000 mg; prednisone 10 mg). Patients with mCRPC were previously treated with ≥ 2 lines of systemic therapy, including ≥ 1 androgen receptor-axis-targeted therapy for prostate cancer. Results Thirty-three patients were enrolled (niraparib-apalutamide, 6; niraparib-AAP, 27). No dose-limiting toxicities (DLTs) were reported when combinations included niraparib 200 mg; five patients receiving niraparib 300 mg experienced DLTs [niraparib-apalutamide, 2/3 patients (66.7%); niraparib-AAP, 3/8 patients (37.5%)]. Although data are limited, niraparib exposures were lower when given with apalutamide compared with historical niraparib monotherapy exposures in patients with solid tumors. Because of the higher incidence of DLTs, the niraparib–apalutamide combination and niraparib 300 mg combination with AAP were not further evaluated. Niraparib 200 mg was selected as the RP2D with AAP. Of 19 patients receiving niraparib 200 mg with AAP, 12 (63.2%) had grade 3/4 treatment-emergent adverse events, the most common being thrombocytopenia (26.3%) and hypertension (21.1%). Five patients (26.3%) had adverse events leading to treatment discontinuation. Conclusions These results support the choice of niraparib 200 mg as the RP2D with AAP. The niraparib–AAP combination was tolerable in patients with mCRPC, with no new safety signals. An ongoing phase 3 study is further assessing this combination in patients with mCRPC. Trial registration no. NCT02924766 (ClinicalTrials.gov).

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Section: Pharmacokinetics Of Apalutamide and Its Metabolite M3 (Nirapsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 83%

Niraparib with androgen receptor-axis-targeted therapy in patients with metastatic castration-resistant prostate cancer: safety and pharmacokinetic results from a phase 1b study (BEDIVERE)

Saad

N.²,

Shore

et al. 2021

Cancer Chemother Pharmacol

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“…The pharmacokinetic profiles of apalutamide and N-desmethyl apalutamide following administration of apalutamide 240 mg once daily together with AA-P were similar to those previously reported for apalutamide monotherapy (Fig. 1D) (21).…”

Section: Pharmacokinetic Parameterssupporting

confidence: 87%

Pharmacokinetics, Safety, and Antitumor Effect of Apalutamide with Abiraterone Acetate plus Prednisone in Metastatic Castration-Resistant Prostate Cancer: Phase Ib Study

Posadas

N.²,

Wit

et al. 2020

Clinical Cancer Research

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Purpose: Apalutamide is a next-generation androgen receptor (AR) inhibitor approved for patients with nonmetastatic castrationresistant prostate cancer (CRPC) and metastatic castrationsensitive prostate cancer. We evaluated the pharmacokinetics, safety, and antitumor activity of apalutamide combined with abiraterone acetate plus prednisone (AA-P) in patients with metastatic CRPC (mCRPC).Patients and Methods: Multicenter, open-label, phase Ib drugdrug interaction study conducted in 57 patients with mCRPC treated with 1,000 mg abiraterone acetate plus 10 mg prednisone daily beginning on cycle 1 day 1 (C1D1) and 240 mg apalutamide daily starting on C1D8 in 28-day cycles. Serial blood samples for pharmacokinetic analysis were collected on C1D7 and C2D8.Results: Systemic exposure to abiraterone, prednisone, and prednisolone decreased 14%, 61%, and 42%, respectively, when apalutamide was coadministered with AA-P. No increase in mineralo-corticoid excess-related adverse events was observed. Patients without prior exposure to AR signaling inhibitors had longer median treatment duration and greater mean decrease in prostate-specific antigen (PSA) from baseline compared with those who had received prior therapy. Confirmed PSA reductions of ≥50% from baseline at any time were observed in 80% (12/15) of AR signaling inhibitor-na€ ve patients and 14% (6/42) of AR signaling inhibitor-treated patients.Conclusions: Treatment with apalutamide plus AA-P was well tolerated and showed evidence of antitumor activity in patients with mCRPC, including those with disease progression on AR signaling inhibitors. No clinically significant pharmacokinetic interaction was observed between abiraterone and apalutamide; however, apalutamide decreased exposure to prednisone. These data support development of 1,000 mg abiraterone acetate plus 10 mg prednisone daily with 240 mg apalutamide daily in patients with mCRPC.

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“…Ischemic heart disease occurred in 23 (4.4%) patients and caused death in two patients. Belderbos et al published an open label, multicentre, phase Ib study, investigating the effect of apalutamide on ventricular repolarization in men with CRPC [27]. A total of 55 patients were enrolled.…”

Section: Renal and Cardiac Toxicitiesmentioning

confidence: 99%

Renal and Cardiovascular Toxicities by New Systemic Treatments for Prostate Cancer

Saltalamacchia

Frascaroli

Bernardo

et al. 2020

Cancers

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Prostate cancer (PC) is the most common male cancer in Western Countries. In recent years, the treatment of relapsed or metastatic disease had benefited by the introduction of a variety of new different drugs. In consideration of the relative long survival of PC patients, side effects of these drugs must be considered and monitored. In this review, we analyzed the newly developed therapies for PC treatment, describing the mechanism of action, the metabolism and latest clinical trials that led to the approval of these drugs in clinical practice. We then evaluated the cardiovascular and renal side effects from pivotal phase III and II studies and meta-analyses. Cardiovascular side effects are the most frequent, in particular hypertension, while renal toxicity is rarer and not well described in literature. Therefore, there is a need to better define the effects of these therapies, in order to personalize patient treatment on the basis of their comorbidities and preferences, in addition to their symptoms and disease load.

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An open-label, multicenter, phase Ib study investigating the effect of apalutamide on ventricular repolarization in men with castration-resistant prostate cancer

Cited by 22 publications

References 17 publications

Niraparib with androgen receptor-axis-targeted therapy in patients with metastatic castration-resistant prostate cancer: safety and pharmacokinetic results from a phase 1b study (BEDIVERE)

Niraparib with androgen receptor-axis-targeted therapy in patients with metastatic castration-resistant prostate cancer: safety and pharmacokinetic results from a phase 1b study (BEDIVERE)

Pharmacokinetics, Safety, and Antitumor Effect of Apalutamide with Abiraterone Acetate plus Prednisone in Metastatic Castration-Resistant Prostate Cancer: Phase Ib Study

Renal and Cardiovascular Toxicities by New Systemic Treatments for Prostate Cancer

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