Impact of Enzalutamide Administration on Primary Prostate Cancer Volume: A Metabolic Evaluation by Choline Positron Emission Tomography in Castration-Resistant Prostate Cancer Patients

BackgroundEnzalutamide is active in advanced castration-resistant prostate cancer (CRPC) patients, in whom it has shown to be able to increase survival. We report the enzalutamide effect on primary prostate tumors, assessed by changes of metabolic tumor activity detected by ¹⁸F-fluorocholine-positron emission tomography/computerized tomography (¹⁸F-FCH PET/CT).Patients and MethodsWe treated 31 patients with pretreated metastatic CRPC in an enzalutamide named-patient program. All patients were initially evaluated and then followed up by means of repeated ¹⁸F-FCH PET/CT examinations. We identified most radiotracer-avid lesions, which were defined as specific regions of interest (ROIs): for each ROI we defined the maximum radiotracer standardized uptake value (SUV_max) and the threshold-based volume of interest (VOI) with a cutoff SUV value ≥ 2.5. In the 12 patients who did not receive a radical treatment for localized disease, the prostate was also considered an ROI.ResultsThe baseline prostate median SUV_max of 7.25 showed reductions of 25% (P = .012) and 43% (P = .009) after 3 and 7 months of enzalutamide treatment, respectively. The baseline median prostate VOI of 12.73 cm³ showed a reduction of 73% (P = .002) at 3 months and a reduction of 90% (P = .005) at 7 months.ConclusionIn addition to the metabolic changes of metastatic lesions observed with enzalutamide in CRPC patients, our data have shown significant volume reductions of the primary tumors according to ¹⁸F-FCH PET/CT evaluation. These results could suggest the potential of enzalutamide therapy for localized prostate cancer.     

Health-related Quality of Life for Abiraterone Plus Prednisone Versus Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer: Results from a Phase II Randomized Trial

BackgroundAbiraterone and enzalutamide are associated with side effects that may impair health-related quality of life (HRQoL).ObjectiveTo assess patient-reported HRQoL, depression symptoms, and cognitive function for abiraterone versus enzalutamide.Design, setting, and participantsWe randomized 202 patients in a phase II study of abiraterone versus enzalutamide for first-line treatment of metastatic castration-resistant prostate cancer (ClinicalTrials.gov: NCT02125357).InterventionPatients completed Functional Assessment of Cancer Therapy—Prostate (FACT-P) and Patient Health Questionnaire-9 (PHQ-9) questionnaires, and Montreal Cognitive Assessment (MoCA) cognitive assessments at baseline and on treatment.Outcome measurements and statistical analysisTo compare the change in FACT-P scores over time between treatment arms, we used a mixed model for repeated measures (MMRM). For FACT-P domains where there was an interaction between the treatment arm and age, we constructed separate models for patients aged <75 and ≥75 yr. We compared the proportion of patients with clinically meaningful change from baseline for FACT-P, and the proportion of patients with an abnormal score and median change from baseline for PHQ-9 and MoCA using Fisher's exact test and Mann-Whitney U test.Results and limitationsIn the MMRM analysis, there was a positive test for interaction in the treatment arm by age for total FACT-P (p = 0.048). FACT-P change from baseline over time was better for abiraterone than for enzalutamide in the ≥75-yr model (p = 0.003), with no difference in the <75-yr model (p > 0.9). A higher proportion of patients experienced clinically meaningful worsening with enzalutamide for the physical and functional well-being domains (37% vs 21%, p = 0.013; 39% vs 23%, p = 0.015). The distribution of change in PHQ-9 scores from baseline favored abiraterone at weeks 4, 8, and 12. These analyses were not prespecified, and results should be considered to be hypothesis generating.ConclusionsPatient-reported outcomes favored abiraterone compared with enzalutamide with differences in FACT-P HRQoL and PHQ-9 depression scores. Differences in the total FACT-P scores were seen only in the elderly patient subgroup.Patient summaryIn this report, we examined the change in patient-reported quality-of-life scores from the start of treatment over time for patients treated with abiraterone versus enzalutamide for metastatic castration-resistant prostate cancer. We found that elderly patients treated with abiraterone had better quality of life over time, with no difference between treatments for the younger subgroup of patients.     

Battling resistance mechanisms in antihormonal prostate cancer treatment: Novel agents and combinations

Prostate cancer (PCa) is a hormone-sensitive disease. Androgen deprivation therapy lowers serum testosterone levels (castration) or blocks the androgen receptor (AR) ligand-binding domain. Especially in metastatic disease, hormonal therapy has been able to delay disease progression, reduce symptoms, and improve overall survival. Despite subsequent disease progression and development of castration resistance, PCa remains AR driven. Secondary hormonal treatments such as abiraterone acetate or enzalutamide have demonstrated increased overall survival. However, new resistance mechanisms to these agents have been identified, and systemic chemotherapy is still needed especially in fast-progressing castration-resistant PCa. Several promising androgen synthesis inhibitors (orteronel and galeterone), AR inhibitors (ARN-509, EPI-001, AZD3514, and ODM-201), and heat shock protein modulators (AT11387, 17-DMAG, STA-9090, and OGX-427) are currently under investigation. The wide variety in upcoming systemic agents underlines the molecular heterogeneity of castration-resistant PCa. This article reviews antihormonal therapy in PCa and resistance mechanisms and focuses on novel and upcoming agents currently in clinical testing.     

Clinical outcomes in a contemporary series of “young” patients with castration-resistant prostate cancer who were 60 years and younger

BackgroundThe prognosis of younger patients with prostate cancer is unclear, and the very few studies assessing those with metastatic castration-resistant prostate cancer (mCRPC) have mainly involved patients treated with older therapies. The aim of this observational study was to evaluate the clinical outcomes of a contemporary series of docetaxel-treated patients with mCRPC who were 60 years and younger.Patients and methodsWe retrospectively identified 134 patients who were 60 years and younger who were treated with docetaxel in 25 Italian hospitals and recorded their predocetaxel history of prostate cancer, their characteristics at the start of chemotherapy, and their postdocetaxel treatment history and outcomes.ResultsMost of the 134 consecutive patients with mCRPC received the standard 3-week docetaxel schedule; median progression-free survival (PFS) was 7 months, and 90 patients underwent further therapies after progression. The median overall survival (OS) from the start of docetaxel treatment was 21 months, but OS was significantly prolonged by the postprogression treatments, particularly those based on the new agents such as cabazitaxel, abiraterone acetate, or enzalutamide. OS was significantly shorter in the patients with a shorter interval between the diagnosis of prostate cancer and the start of docetaxel treatment; those who received hormonal treatment for a shorter period; those with shorter prostate-specific antigen doubling times; and those with lower hemoglobin levels, a worse performance status, and higher lactate dehydrogenase levels before starting treatment with docetaxel.ConclusionsThe findings of this first study of clinical outcomes in a contemporary series of younger patients with mCRPC showed that their survival is similar to that expected in unselected patients with mCRPC who were of any age.     

Impact of Abiraterone Acetate plus Prednisone or Enzalutamide on Patient-reported Outcomes in Patients with Metastatic Castration-resistant Prostate Cancer: Final 12-mo Analysis from the Observational AQUARiUS Study

BackgroundFew studies have examined patient-reported outcomes (PROs) with abiraterone acetate plus prednisone (abiraterone) versus enzalutamide in metastatic castration-resistant prostate cancer (mCRPC).ObjectiveTo determine the impact of abiraterone and enzalutamide on PROs.Design, setting, and participantsAQUARiUS (NCT02813408) was a prospective, 12-mo, observational study in patients with mCRPC from Denmark, France, and the UK.InterventionAbiraterone or enzalutamide treatment according to routine practise.Outcome measurements and statistical analysisPROs were collected over 12 mo using Functional Assessment of Cancer Therapy—Cognitive Function (FACT-Cog), Brief Fatigue Inventory—Short Form (BFI-SF), Brief Pain Inventory—Short Form, and European Organisation for Research and Treatment of Cancer—Quality of Life Questionnaire (QLQ-C30) at baseline and routine visits. Outcomes included mean change in PROs, patients with clinically meaningful worsening (CMW) in PROs, and safety. Data were analysed using repeated measures linear and logistic models adjusted for baseline characteristics.Results and limitationsAbiraterone-treated (N = 105) and enzalutamide-treated (N = 106) patients were included. Key PRO items (cognitive impairments and fatigue) were significantly (p < 0.05) in favour of abiraterone versus enzalutamide during the study. “Perceived cognitive impairment” and “comments from others” (FACT-Cog); “fatigue right now”, “usual level of fatigue”, and “worst level of fatigue” (BFI-SF); and “cognitive functioning” and “fatigue” (QLQ-C30) were significantly in favour of abiraterone over enzalutamide for three or more consecutive periods up to month 12. From study initiation, significantly fewer patients receiving abiraterone experienced one or more CMW episode in cognition and fatigue. Fatigue and asthenia (adverse events) were lower with abiraterone than with enzalutamide (5% vs 15% and 10% vs 11%, respectively). There were no treatment-related deaths. Limitations included lack of randomisation.ConclusionsIn a real-world setting, this 12-mo analysis suggests an advantage of abiraterone acetate plus prednisone over enzalutamide on fatigue and cognitive function; this finding occurred early after treatment initiation. This difference should be considered when choosing treatment.Patient summaryThis study looked at the effect of two treatments (abiraterone acetate plus prednisone and enzalutamide) for metastatic castration-resistant prostate cancer on patient quality of life over 12 mo. Using established questionnaires, patients reported that they experienced less fatigue and cognitive impairments (including memory loss and reduced thinking abilities) with abiraterone acetate plus prednisone than with enzalutamide.     

Synaptophysin expression on circulating tumor cells in patients with castration resistant prostate cancer undergoing treatment with abiraterone acetate or enzalutamide

Background

With the advent of secondary androgen receptor (AR)-targeted therapies in metastatic castration resistant prostate cancer (PC), nonadenocarcinoma PCs are becoming more prevalent. Many of these cancers express neuroendocrine markers, which may provide biomarkers for emergence of this disease state. We aimed to quantify the expression of synaptophysin (Syp) on circulating tumor cells (CTCs) from serial samples of patients being treated with abiraterone acetate or enzalutamide.

Metastatic hormone-sensitive prostate cancer: How should it be treated?

The number of treatment options for metastatic hormone-sensitive prostate cancer has increased substantially in recent years. The classic treatment approach for these patients—androgen-deprivation therapy alone—is now considered suboptimal. Several randomized phase III clinical trials have demonstrated significant clinical benefits—including significantly better overall survival and quality of life—for treatments that combine androgen-deprivation therapy with docetaxel, abiraterone acetate, enzalutamide, apalutamide, and/or radiotherapy to the primary tumour. As a result, these approaches are now included in treatment guidelines and considered standard of care. However, the different treatment strategies have not been directly compared, and thus treatment selection remains at the discretion of the individual physician or, ideally, a multidisciplinary team. Given the range of available treatment approaches with varying toxicity profiles, treatment selection should be individualized based on the patient’s clinical characteristics and preferences, which implies active patient participation in the decision-making process. In the present document, we discuss the changing landscape of the management of patients with metastatic hormone-sensitive prostate cancer in the context of several recently-published landmark randomized trials. In addition, we discuss several unresolved issues, including the optimal sequencing of systemic treatments and the incorporation of local treatment of the primary tumour and metastases.     

U.S. Food and Drug Administration Approval Summary: Enzalutamide for the Treatment of Patients With Chemotherapy‐Naïve Metastatic Castration‐Resistant Prostate Cancer

The U.S. Food and Drug Administration approved enzalutamide for the treatment of patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC). At the prespecified interim analysis, a statistically significant improvement in overall survival was demonstrated for patients in the enzalutamide arm compared with patients in the placebo arm. The overall benefit-risk profile supports the expanded indication for enzalutamide. On September 10, 2014, the U.S. Food and Drug Administration approved enzalutamide for the treatment of patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC). Enzalutamide was initially approved in 2012 for use in patients with mCRPC who had previously received docetaxel. The current approval was based on the results of a randomized, placebo-controlled, double-blind trial conducted in 1,717 asymptomatic or minimally symptomatic patients with chemotherapy-naïve mCRPC. Patients were assigned to receive either enzalutamide 160 mg or placebo orally once daily. The coprimary endpoints were overall survival (OS) and radiographic progression-free survival (rPFS), which was assessed by independent central radiology review. At the prespecified interim analysis, a statistically significant improvement in OS was demonstrated for patients in the enzalutamide arm compared with patients in the placebo arm (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.60–0.84). The median OS was 32.4 and 30.2 months in the enzalutamide and placebo arms, respectively. A statistically significant prolongation of rPFS was observed in patients in the enzalutamide arm (HR, 0.17; 95% CI, 0.14–0.21). In addition, the time to initiation of cytotoxic chemotherapy was prolonged in the enzalutamide arm (HR, 0.35; 95% CI, 0.30–0.40), with median times of 28.0 and 10.8 months in the enzalutamide and placebo arms, respectively. The safety profile was similar to that previously reported for enzalutamide. Adverse reactions of interest included seizure, hypertension, and falls. Enzalutamide should be discontinued if a seizure occurs during treatment. The overall benefit-risk profile supports the expanded indication for enzalutamide.

Implications for Practice:

This new approval expands the enzalutamide indication, allowing health care providers and patients to use enzalutamide for the treatment of metastatic castration-resistant prostate cancer either before or after cytotoxic chemotherapy.     

Choix des nouveaux traitements médicaux dans le cancer de la prostate résistant à la castration: marqueurs prédictifs et évaluation de l’effi cacité

IntroductionDocetaxel has been the cornerstone in the treatment of castration- resistant prostate cancer (CRPC) since 2004. The recent and almost simultaneous arrival of new and effective molecules – several of which are already available on the market – has added to the CRPC treatment arsenal. Several studies have explored the optimal order in which these new treatments should be administered. The aim of this review was to present their respective predictive and evaluative factors and suggest potential administration sequences.MethodsThe PubMed medical literature citations database was searched using the following key words: prostate cancer, castration resistant, metastatic, targeted therapy, treatment sequence, immunotherapy and clinical trials. The reports of the most recent European and North American congresses were also included.ResultsWhile no predictive factors have been clearly identified for these new therapies to date, a Gleason score of not less than 8 and one or more chemotherapy sessions seemed to be predictive of lower efficacy for abiraterone. Promising elements for further investigation include the circulating tumour cell count and variation in this count per treatment, ERG mutation status or the intratumoural androgen status. Substitution criteria have not yet been reported but, as is the case with all hormone therapies, changes in PSA levels emerge as a valuable indicator of the efficacy of abiraterone. The best treatment sequence for patients who develop castration-resistance remains to be defined.ConclusionAlthough new molecules have recently become available, the experience with their use is limited. Thus, no predictive markers of response rates and treatment outcomes or data concerning the best treatment sequence to use in patients with CRPC are as yet available.     

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.