Dataset Information

Dual Blockade of c-MET and the Androgen Receptor in Metastatic Castration-resistant Prostate Cancer: A Phase I Study of Concurrent Enzalutamide and Crizotinib.

ABSTRACT:

Purpose

Androgen receptor (AR) inhibition can upregulate c-MET expression, which may be a resistance mechanism driving progression of castration-resistant prostate cancer (CRPC). We conducted a phase I trial investigating the safety and pharmacokinetics of a potent c-MET inhibitor, crizotinib, with the AR antagonist, enzalutamide, in CRPC.

Patients and methods

Employing a 3+3 dose-escalation design, we tested three dose levels of crizotinib (250 mg daily, 200 mg twice a day, and 250 mg twice a day) with standard-dose enzalutamide (160 mg daily). The primary endpoint was rate of dose-limiting toxicities (DLTs). Tolerability and pharmacokinetics profile were secondary endpoints.

Results

Twenty-four patients were enrolled in the dose-escalation (n = 16) and dose-expansion (n = 8) phases. Two DLTs occurred in dose escalation (grade 3 alanine aminotransferase elevation). The MTD of crizotinib was 250 mg twice a day. Most frequent treatment-related adverse events were fatigue (50%), transaminitis (38%), nausea (33%), and vomiting, constipation, and diarrhea (21% each). Grade ?3 events (25%) included transaminitis (n = 2), fatigue (n = 1), hypertension (n = 1), pulmonary embolism (n = 1), and a cardiac event encompassing QTc prolongation/ventricular arrhythmia/cardiac arrest. Median progression-free survival was 5.5 months (95% confidence interval, 2.8-21.2). Pharmacokinetics analysis at the MTD (n = 12) revealed a mean C _max ^ss of 104 ± 45 ng/mL and AUC_? ^ss of 1,000 ± 476 ng•h/mL, representing a 74% decrease in crizotinib systemic exposure relative to historical data (C _max ^ss, 315 ng/mL and AUC_? ^ss, 3,817 ng•h/mL).

Conclusions

Concurrent administration of enzalutamide and crizotinib resulted in a clinically significant 74% decrease in systemic crizotinib exposure. Further investigation of this combination in CRPC is not planned. Our results highlight the importance of evaluating pharmacokinetics interactions when evaluating novel combination strategies in CRPC.

SUBMITTER: Tripathi A

PROVIDER: S-EPMC7935424 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Publications

Dual Blockade of c-MET and the Androgen Receptor in Metastatic Castration-resistant Prostate Cancer: A Phase I Study of Concurrent Enzalutamide and Crizotinib.

Tripathi Abhishek A Supko Jeffrey G JG Gray Kathryn P KP Melnick Zachary J ZJ Regan Meredith M MM Taplin Mary-Ellen ME Choudhury Atish D AD Pomerantz Mark M MM Bellmunt Joaquim J Yu Channing C Sun Zijie Z Srinivas Sandy S Kantoff Philip W PW Sweeney Christopher J CJ Harshman Lauren C LC

Clinical cancer research : an official journal of the American Association for Cancer Research 20200917 23

<h4>Purpose</h4>Androgen receptor (AR) inhibition can upregulate c-MET expression, which may be a resistance mechanism driving progression of castration-resistant prostate cancer (CRPC). We conducted a phase I trial investigating the safety and pharmacokinetics of a potent c-MET inhibitor, crizotinib, with the AR antagonist, enzalutamide, in CRPC.<h4>Patients and methods</h4>Employing a 3+3 dose-escalation design, we tested three dose levels of crizotinib (250 mg daily, 200 mg twice a day, and 2 ...[more]

PMID: 32943461

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Project description:BackgroundThe effect of enzalutamide in patients with non-metastatic castration-resistant prostate cancer after combined androgen blockade, which represents a patient profile similar to real-world clinical practice in Japan, remains unknown. Therefore, we investigate the efficacy and safety of enzalutamide after combined androgen blockade for recurrence following radical treatment in Japanese patients with non-metastatic castration-resistant prostate cancer.MethodsWe analyzed 66 patients with non-metastatic castration-resistant prostate cancer after combined androgen blockade for recurrence following radical prostatectomy or radiation therapy who were prospectively enrolled from October 2015 to March 2018. They received enzalutamide 160 mg orally once daily until the protocol treatment discontinuation criteria were met. The primary endpoint was prostate-specific antigen-progression-free survival, defined as the time from enrollment to prostate-specific antigen-based progression or death from any cause. The secondary endpoints included overall survival, progression-free survival, metastasis-free survival, time to prostate-specific antigen progression, prostate-specific antigen response rate, chemotherapy-free survival, and safety assessment.ResultsThe median observation period was 27.3 months. The median prostate-specific antigen-progression-free survival was 35.0 months (95% confidence interval, 17.5 to not reached). The median overall survival, median progression-free survival, median metastasis-free survival, and chemotherapy-free survival were not reached, with the corresponding 2-year rates being 91.6%, 67.1%, 72.4%, and 85.8%, respectively. The 50% prostate-specific antigen response rate was 88.9%, with the median time being 2.8 months. In total, 42.2% of the patients experienced adverse events, with malaise being the most common.ConclusionsEnzalutamide effectively manages non-metastatic castration-resistant prostate cancer after combined androgen blockade for recurrence following radical treatment.Trial registration UMIN000018964, CRB6180007.

Project description:Enzalutamide is a novel antiandrogen with proven efficacy in metastatic castration-resistant prostate cancer (mCRPC).To evaluate enzalutamide's effects on cancer and on androgens in blood and bone marrow, and associate these with clinical observations.In this prospective phase 2 study, 60 patients with bone mCRPC received enzalutamide 160mg orally daily and had transilial bone marrow biopsies before treatment and at 8 wk of treatment.Androgen signaling components (androgen receptor [AR], AR splice variant 7 (ARV7), v-ets avian erythroblastosis virus E26 oncogene homolog [ERG], cytochrome P450, family 17, subfamily A, polypeptide 1 [CYP17]) and molecules implicated in mCRPC progression (phospho-Met, phospho-Src, glucocorticoid receptor, Ki67) were assessed by immunohistochemistry; testosterone, cortisol, and androstenedione concentrations were assessed by liquid chromatography-tandem mass spectrometry; AR copy number was assessed by real-time polymerase chain reaction. Descriptive statistics were applied.Median time to treatment discontinuation was 22 wk (95% confidence interval, 19.9-29.6). Twenty-two (37%) patients exhibited primary resistance to enzalutamide, discontinuing treatment within 4 mo. Maximal prostate-specific antigen (PSA) decline ? 50% and ? 90% occurred in 27 (45%) and 13 (22%) patients, respectively. Following 8 wk of treatment, bone marrow and circulating testosterone levels increased. Pretreatment tumor nuclear AR overexpression (> 75%) and CYP17 (> 10%) expression were associated with benefit (p = 0.018). AR subcellular localization shift from the nucleus was confirmed in eight paired samples (with PSA decline) of 23 evaluable paired samples. Presence of an ARV7 variant was associated with primary resistance to enzalutamide (p = 0.018). Limited patient numbers warrant further validation.The observed subcellular shift of AR from the nucleus and increased testosterone concentration provide the first evidence in humans that enzalutamide suppresses AR signaling while inducing an adaptive feedback. Persistent androgen signaling in mCRPC was predictive of benefit and ARV7 was associated with primary resistance.We report a first bone biopsy study in metastatic prostate cancer in humans that searched for predictors of outcome of enzalutamide therapy. Benefit is linked to a pretreatment androgen-signaling signature.ClinicalTrials.gov identifier NCT01091103.

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Dataset Information

Dual Blockade of c-MET and the Androgen Receptor in Metastatic Castration-resistant Prostate Cancer: A Phase I Study of Concurrent Enzalutamide and Crizotinib.

Purpose

Patients and methods

Results

Conclusions

Publications

Dual Blockade of c-MET and the Androgen Receptor in Metastatic Castration-resistant Prostate Cancer: A Phase I Study of Concurrent Enzalutamide and Crizotinib.

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