The Cardiovascular Toxicity of Abiraterone and Enzalutamide in Prostate Cancer

Introduction

The cardiovascular toxicity related to abiraterone and enzalutamide has been previously studied by our group. In this analysis, we aim to update our previous findings related to abiraterone and enzalutamide, including the new available evidence, both in castration-resistant and hormone-sensitive prostate cancer.

TP53 Gain-of-Function Mutations in Circulating Tumor DNA in Men With Metastatic Castration-Resistant Prostate Cancer

BackgroundCirculating tumor DNA (ctDNA), which can be assessed by liquid biopsy, can provide valuable genomic information that may affect treatment response in prostate cancer. The aim of this study was to characterize TP53 mutations and treatment history in prostate cancer.Patients and MethodsThis study included 143 patients with metastatic castration-resistant prostate cancer who had undergone ctDNA sequencing via Guardant360 testing. The presence or absence of TP53 mutations was analyzed along with treatment history for this group. TP53 mutations were further classified as gain of function (GOF) or not GOF, and analyzed with prior therapies.ResultsChi-square analysis was performed for treatment history and TP53 status (further specified as all TP53 mutations or only TP53 GOF mutations). There were no associations between prior receipt of abiraterone/enzalutamide therapy and all TP53 mutations, or between docetaxel therapy and all TP53 mutations. However, TP53 GOF mutations had a positive association with prior abiraterone/enzalutamide therapy (P = .047). There was no association of TP53 GOF mutations with prior docetaxel therapy. The most frequent alterations co-occurring with all TP53 mutations were in AR, BRAF, EGFR, MYC, and PIK3CA. Common coalterations with TP53 GOF mutations included AR, BRAF, EGFR, RB1, NF1, and PIK3CA. There was an association of RB1 mutations with TP53 GOF mutations, versus RB1 mutations and no TP53 GOF mutations (P = .0036).ConclusionTP53 GOF mutations may provide a valuable pathway to delineate metastatic castration-resistant prostate cancer TP53 mutations into therapeutic categories. Association with disease progression while receiving abiraterone/enzalutamide therapy was apparent in this study; however, further studies are needed to elaborate the therapeutic and prognostic implications.     

Evaluation of Response to Enzalutamide Consecutively After Abiraterone Acetate/Prednisone Failure in Patients With Metastatic Castration-resistant Prostate Cancer

Introduction

Treatment of metastatic castration-resistant prostate cancer (mCRPC) has evolved significantly during the past decade, and the preferred combination and/or sequence of these treatments remains controversial. In this retrospective study, we explored clinical and pathologic factors that could predict response to consecutive treatment with enzalutamide (ENZA) after disease progression (PD) on abiraterone acetate and prednisone (AA/P).

Abiraterone for Treatment of Metastatic Castration-resistant Prostate Cancer: a Systematic Review and Meta-analysis

Introduction: Although most prostate cancers initially respond to castration with luteinizing hormonereleasinganalogues or bilateral orchiectomy, progression eventually occurs. Based on the exciting results ofseveral randomized controlled trials (RCTs), it seems that patients with metastatic castration-resistant prostatecancer (mCRPC) might benefit more from treatment withabiraterone. Therefore we conducted a systematicreview to evaluate the efficacy and toxicity of abiraterone in the treatment of mCRPC. Methods: Literaturewas searched from Embase, PubMed, Web of Science, and Cochrane Library up to July, 2013. Quality of thestudy was evaluated according to the Cochrane’s risk of bias of randomized controlled trial (RCT) tool, then theGrading of Recommendations Assessment, Development and Evaluation (GRADE) System was used to rate thelevel of evidence. Stata 12.0 was used for statistical analysis. Summary data from RCTs comparing abirateroneplus prednisone versus placebo plus prednisone for mCRPC were meta-analyzed. Pooled hazard ratios (HRs)for overall survival (OS), radiographic progression-free survival (RPFS) and time to PSA progression (TTPP);Pooled risk ratios (RR) for PSA response rate, objective response rate and adverse event were calculated. Results:Ten trials were included in the systematic review; Data of 2,283 patients (1,343 abiraterone; 940 placebo) fromtwo phase 3 trials: COU-AA-301 and COU-AA-302 were meta-analyzed. Compared with placebo, abirateronesignificantly prolonged OS (HR, 0.74; 95% confidence interval [CI], 0.66 to 0.84), RPFS (HR, 0.59; 95% CI,0.48 to 0.74) and time to PSA progression (HR, 0.55; 95% CI, 0.43 to 0.70); it also significantly increased PSAresponse rate (RR, 3.63; 95% CI, 1.72 to 7.65) and objective response rate (RR, 3.05; 95% CI, 1.51 to 6.15). Thismeta-analysis suggested that the adverse events caused by abiraterone are acceptable and can be controlled.Conclutios: Abiraterone significantly prolonged OS, RPFS and time to progression patients with mCRPC,regardless of prior chemotherapy or whether chemotherapy-naïve, and no unexpected toxicity was evident.Abiraterone can serve as a new standard therapy for mCRPC.     

Comparison of Alternative Androgen Receptor-axis-targeted Agent (ARATA) and Docetaxel as Second-line Therapy for Patients With Metastatic Castration-resistant Prostate Cancer With Progression After Initial ARATA in Real-world Clinical Practice in Japan

Background

The objective of the present study was to assess the oncologic outcomes of patients receiving second-line therapy against metastatic castration-resistant prostate cancer (mCRPC).

Treating De Novo Metastatic Castration-Sensitive Prostate Cancer With Visceral Metastases: An Evolving Issue

Visceral metastasis is widely considered a prognostic factor for overall survival of men with metastatic castration-sensitive prostate cancer (mCSPC) and has been historically managed with androgen deprivation therapy (ADT). More recently, this therapeutic scenario has been enriched by the possibility to integrate ADT with chemotherapy or novel androgen-signaling–targeted inhibitors. In order to define the effect of chemotherapy/androgen-signaling–targeted inhibitors plus ADT, we performed a pooled analysis on patients with mCSPC and visceral metastases, revealing that survival was significantly improved in patients without visceral metastasis (hazard ratio, 0.64; 95% confidence interval, 0.56-0.74; P < .01) compared to men with visceral metastases (hazard ratio, 0.68; 95% confidence interval, 0.51-0.91; P < .01). Although several limitations do not allow us to draw definitive conclusions, our analysis confirms the efficacy of chemotherapy/androgen-signaling–targeted inhibitors in combination with ADT in mCSPC with visceral metastases as well. In the absence of specific randomized controlled trials, symptoms, toxicity, cost, patient preference, and clinical experience should guide the decision to add chemotherapy or androgen receptor–targeted therapy to ADT in patients with visceral metastases from mCSPC.     

Pharmacokinetic/Pharmacodynamic Relationship of Enzalutamide and Its Active Metabolite N-Desmethyl Enzalutamide in Metastatic Castration-Resistant Prostate Cancer Patients

IntroductionEnzalutamide (ENZA) is an oral androgen receptor inhibitor approved by the Food and Drug Administration and the European Medicines Agency for the treatment of metastatic and nonmetastatic castration-resistant prostate cancer (CRPC). ENZA is extensively metabolized by cytochrome P450 3A4 into N-desmethyl ENZA (NDE), an active metabolite. We aimed to explore the pharmacokinetic/pharmacodynamic relationship for ENZA and NDE in metastatic CRPC patients from a real-world setting.Patients and MethodsTrough plasma concentration (C_trough) of ENZA and NDE were assayed using liquid chromatography coupled with UV detection. The relationship between ENZA, NDE, and composite (ENZA with NDE) plasma concentration and requirement of ENZA dose reduction was investigated using the Mann–Whitney test. A survival univariate analysis was conducted to explore association between progression-free survival (PFS), overall survival (OS), and plasma C_trough (ENZA, NDE, and composite).ResultsTwenty-two metastatic CRPC patients treated with ENZA (median age, 75.5 years; 13 patients (59%) with Eastern Cooperative Oncology Group status 0-1) were prospectively included. Mean plasma C_trough of ENZA and NDE were 12.4 ± 3.0 μg/mL and 8.8 ± 2.1 μg/mL, respectively. Neither PFS nor OS were statistically associated with ENZA, NDE, or composite plasma C_trough. In 4 patients (18%) who required ENZA dose reduction because of severe clinical toxicity, an increased ENZA plasma C_trough was observed compared with 18 remaining patients (16.1 ± 2.4 μg/mL vs. 11.6 ± 2.6 μg/mL, respectively; P = .027).ConclusionThe low interindividual variability in ENZA and NDE C_trough and the lack of relationship with survival do not support the need for plasma drug monitoring. Severe asthenia might be related to higher exposure and could be improved by decreasing ENZA dosing.     

Activity of Cabazitaxel After Docetaxel and Abiraterone Acetate Therapy in Patients With Castration-Resistant Prostate Cancer

BackgroundCabazitaxel and AA have been approved by the US Food and Drug Administration for use after docetaxel in mCRPC. Recently, CAB appeared to be active when given after AA. AA is capable of inducing AR splice variants that confer ligand-independent AR transactivation. Because microtubule-targeting agents impair AR nuclear transport and activity, we raised concerns about CAB efficacy after AA failure in mCRPC.Patients and MethodsOne hundred thirty mCRPC patients received AA after docetaxel treatment in compassionate programs. Of them, 24 (18.4%) subsequently received CAB. We retrospectively reviewed their data using conventional methods.ResultsTwenty-four patients received a median of 4 (range, 1-13) CAB cycles. Nineteen (79.1%) of them received primary prophylaxis with growth factors. Median patient characteristics were: age 65 (range, 57-85) years; Gleason score: 8 (range, 6-10); and PSA: 128.1 (range, 0.01-1700) ng/mL. A PSA response (≥ 50% decrease from baseline) occurred in 6 (31.5%) of 19 evaluable patients (95% confidence interval [CI], 11.8-54.2%). CAB therapy obtained a partial response in 2 of the 13 (15.3%) evaluable patients (95% CI, 2.9-45.4%). Median survival from initiation of CAB was 8.2 (95% CI, 3.34-13.05) months, from AA 16.1 (95% CI, 11.56-20.64) and from docetaxel 32.0 (95% CI, 11.56-39.69).ConclusionA limited number of patients with mCRPC received CAB after docetaxel and AA treatment. In this selected population, CAB was active.     

Phase 2 Study of Seviteronel (INO-464) in Patients With Metastatic Castration-Resistant Prostate Cancer After Enzalutamide Treatment

BackgroundSeviteronel was being developed by Innocrin Pharmaceuticals as a selective cytochrome P450c17a (CYP17) 17,20-lyase (lyase) inhibitor and androgen receptor antagonist with activity against prostate cancer cells in vitro and in vivo. This open-label phase 2 clinical study evaluated the tolerability and efficacy of seviteronel in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with enzalutamide.Patients and MethodsPatients with mCRPC whose disease previously progressed while receiving enzalutamide therapy were divided into 2 cohorts on the basis of prior exposure to docetaxel. Seviteronel was administered without routine oral steroids either twice daily with dose titration (450 mg) or once daily without dose titration (600 or 750 mg). The primary objective was to determine the rate of significant prostate-specific antigen response (ie, decline of ≥ 50%) after 12 weeks of seviteronel therapy.ResultsSeventeen patients, with a median (range) age of 71 (60-92) years, were enrolled, with 8 patients having received prior docetaxel. Patients received a median of 2 cycles of treatment, with most patients discontinuing treatment because of toxicity related to the study drug. The most common adverse events included concentration impairment, fatigue, tremor, and nausea. Despite changes in dosing, the study was closed prematurely because of the high magnitude of toxicity. One (6%) of 17 patients experienced a significant decline in prostate-specific antigen.ConclusionSeviteronel was not generally well tolerated nor associated with significant clinical responses in patients with mCRPC who had previously received enzalutamide. Further investigation of single-agent seviteronel in this patient population is not warranted; however, studies investigating seviteronel with low-dose dexamethasone are ongoing in patients with androgen receptor–positive tumors.     

Real-world Characteristics and Outcomes of Patients With Metastatic Castration-resistant Prostate Cancer Receiving Chemotherapy Versus Androgen Receptor-targeted Therapy After Failure of First-line Androgen Receptor-targeted Therapy in the Community Setting

Background

In metastatic castration-resistant prostate cancer (mCRPC), optimal treatment sequences are unknown. We assessed second-line taxane (TT) versus androgen receptor-targeted therapy (ART), after initial ART failure, in United States oncology community practices.

Sequential Use of Androgen Receptor Axis-targeted Agents in Chemotherapy-naive Castration-resistant Prostate Cancer: A Multicenter Retrospective Analysis With 3-Year Follow-up

BackgroundThere has been no established clinical evidence for using sequential treatment in castration-resistant prostate cancer (CRPC). Despite evident cross-resistance, androgen receptor axis-targeted agents (ARTAs), namely abiraterone (ABI) and enzalutamide (ENZ), are often used sequentially owing to less toxicity compared with chemotherapy.Patients and MethodsA multicenter retrospective review of chemotherapy-naive patients with CRPC who had received ABI followed by ENZ (ABI-to-ENZ) or ENZ followed by ABI (ENZ-to-ABI) was conducted. Combined progression-free survival (PFS), overall survival (OS), and prostate-specific antigen (PSA) response (≥ 50% PSA decline) to each drug were compared between the 2 groups at the median follow-up of 36.0 months.ResultsThere were no significant differences in combined PFS (12.4 vs. 10.9 months; hazard ratio [HR], 0.94; 95% confidence interval [CI], 0.72-1.23; P = .6594) or OS (28.3 vs 29.3 months; HR, 0.96; 95% CI, 0.66-1.38; P = .8314) between the ABI-to-ENZ and ENZ-to-ABI groups. PSA response rate was not significantly different in first-line ARTAs (48.9% vs. 58.4%; P = .153) but significantly higher in ENZ as a second-line ARTA (40.4% vs. 13.7%; P < .0001). Although multivariate analysis revealed that the ABI-to-ENZ sequence was associated with favorable PFS on second-line ARTA (HR, 0.65; 95% CI, 0.49-0.85; P = .0019), it was not associated with an increased combined PFS or OS.ConclusionWith relatively longer follow-up, ARTA sequence did not affect clinical outcomes of CRPC treatment except for PSA response and PFS on a second-line ARTA. These findings will be useful information in clinical decision-making, particularly in chemotherapy-unfit patients with CRPC.     

A Single-arm Phase II Study Combining NLG207, a Nanoparticle Camptothecin,with Enzalutamide in Advanced Metastatic Castration-resistant Prostate Cancer Post-Enzalutamide

BackgroundDespite the clinical efficacy of enzalutamide monotherapy in patients with advanced prostate cancer, therapeutic resistance and disease progression are inevitable. We proposed a study to evaluate NLG207, a nanoparticle-drug conjugate (NDC) of the potent topoisomerase I inhibitor camptothecin, in combination with enzalutamide, in patients with metastatic castration-resistant prostate cancer (mCRPC) following progression on enzalutamide.MethodsThis was a single-arm, optimal two-stage, phase II study to evaluate the efficacy of NLG207 in combination with enzalutamide in patients with mCRPC who received prior enzalutamide. A lead-in dose escalation evaluated the recommended phase 2 dose of NLG207 in combination with enzalutamide. Patients received NLG207 via IV infusion every 2 weeks and enzalutamide 160 mg orally once daily.ResultsBetween March 2019 and June 2021, four patients were accrued to the lead-in dose escalation. Two of the four patients were evaluable and both experienced DLTs at the NLG207 12 mg/m² dose level; one DLT was related to a dose delay for noninfective cystitis and myelosuppression, the other a grade 3 noninfective cystitis. Further evaluation of NLG207 in combination with enzalutamide was halted and the study was ultimately terminated. PSA declines from baseline were observed in two patients.ConclusionNLG207 12 mg/m² in combination with enzalutamide was not well tolerated in patients with mCRPC following several lines of the standard of care therapy.ClinicalTrials.gov Identifier{"type":"clinical-trial","attrs":{"text":"NCT03531827","term_id":"NCT03531827"}}NCT03531827.     

A Phase II Study of PX-866 in Patients With Recurrent or Metastatic Castration-resistant Prostate Cancer: Canadian Cancer Trials Group Study IND205

BackgroundIn PTEN-loss models, the phosphatidylinositol 3-kinase (PI3K)/AKT and androgen receptor signaling pathways cross-regulate by reciprocal feedback whereby inhibition of one activates the other, creating a rationale for co-targeting. We studied the irreversible, pan-isoform inhibitor of Class I PI-3K PX-866 singly (part A) and with abiraterone acetate (AA) in patients on AA with rising prostate-specific antigen (PSA) (part B).Patients and MethodsThe primary endpoint was lack of progression at 12 weeks. Exploratory endpoints included changes in circulating tumor cells (CTC), pharmacodynamic studies on platelets (part A), and archival tumor exploration of PTEN as predictor of response (part B).ResultsA total of 43 and 25 patients accrued to parts A and B, respectively. In part A, 14 (33%) patients were progression-free at 12 weeks, with 2 partial objective responses and 1 confirmed PSA response. Favorable CTC conversion (< 5 CTC/7.5 mL) occurred in 6 (24%) of 25 evaluable patients. In part B, 11 of 25 patients had measurable disease. Six (24%) patients were progression-free at 12 weeks. No objective or PSA responses were observed. For all 68 patients, the most common toxicities were diarrhea (53 patients), nausea (36), anorexia (24), fatigue (22), and vomiting (20). Among 17 patients for whom PTEN testing was possible, 3 had PTEN homozygous deletion and 14 had no change. No correlation between PTEN status and response was seen.ConclusionsPX-866 had modest single agent activity. Adding AA to PX-866 showed no evidence of resistance reversal. Strategies to combine PI3K inhibition with androgen receptor-targeted therapies could consider initiation earlier, combination with other agents, and/or recruiting a selected population.     

Androgens and Overall Survival in Patients With Metastatic Castration-resistant Prostate Cancer Treated With Docetaxel

BackgroundPre-treatment androgen levels are associated with overall survival (OS) in patients with metastatic castration-resistant prostate cancer (CRPC) treated with androgen synthesis inhibitors. The current study sought to determine whether pre-treatment serum androgens predict clinical outcome among patients with metastatic CRPC treated with docetaxel chemotherapy.Materials and MethodsData were obtained from 1050 men who were chemotherapy-naive prior to treatment with docetaxel, prednisone, and either bevacizumab or placebo (CALGB 90401). Pretreatment serum assays for testosterone, androstenedione, and dehydroepiandrosterone (DHEA) were performed with tandem liquid chromatography-mass spectrometry.ResultsMedian values for testosterone, androstenedione, and DHEA were 1.00, 13.50, and 8.12 ng/dL, respectively. The median was used to define the midpoint between low and high values. In univariate analysis, median OS for low versus high levels was 21.4 and 24.2 months for testosterone, 23.8 and 21.9 months for androstenedione, and 20.2 and 25.2 months for DHEA (P = NS). In multivariable analysis of all androgens, baseline DHEA was prognostic of ≥ 50% PSA decline from baseline (P = .008). In multivariable analysis adjusting for 10 known prognostic values and prior ketoconazole use for metastatic CRPC, a 10-unit increase in baseline testosterone increased risk of death (hazard ratio, 1.11; 95% confidence interval, 1.01-1.23; P = .039), whereas a 10-unit increase in androstenedione lowered risk of death (hazard ratio, 0.92; 95% confidence interval, 0.88-0.97; P = .001).ConclusionConsistent with prior studies, higher androstenedione levels in patients with metastatic CRPC treated with docetaxel are associated with improved survival. However pretreatment levels of other androgen levels are associated with varied effects on clinical outcome in chemotherapy-treated patients.     

Impact of Addition of Metformin to Abiraterone in Metastatic Castration-Resistant Prostate Cancer Patients With Disease Progressing While Receiving Abiraterone Treatment (MetAb-Pro): Phase 2 Pilot Study

Background

There is evidence linking metformin to improved prostate cancer–related outcomes.