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PURPOSE Docetaxel and abiraterone acetate plus prednisone or prednisolone (AAP) both improve survival when commenced alongside standard of care (SOC) androgen deprivation therapy in locally advanced or metastatic hormone-sensitive prostate cancer. Thus, patient-reported quality of life (QOL) data may guide treatment choices. METHODS A group of patients within the STAMPEDE trial were contemporaneously enrolled with the possibility of being randomly allocated to receive either docetaxel + SOC or AAP + SOC. A mixed-model assessed QOL in those who had completed at least one QLQ-C30 + PR25 questionnaire. The primary outcome measure was difference in global-QOL (QLQ-C30 Q29&30) between patients allocated to docetaxel + SOC or AAP + SOC over the 2 years after random assignment, with a predefined criterion for clinically meaningful difference of > 4.0 points. Secondary outcome measures included longitudinal comparison of functional domains, pain, and fatigue, plus global-QOL at defined timepoints. RESULTS Five hundred fifteen patients (173 docetaxel + SOC and 342 AAP + SOC) were included. Baseline characteristics, proportion of missing data, and mean baseline global-QOL scores (docetaxel + SOC 77.8 and AAP + SOC 78.0) were similar. Over the 2 years following random assignment, the mean modeled global-QOL score was +3.9 points (95% CI, +0.5 to +7.2; P = .022) higher in patients allocated to AAP + SOC. Global-QOL was higher for patients allocated to AAP + SOC over the first year (+5.7 points, 95% CI, +3.0 to +8.5; P < .001), particularly at 12 (+7.0 points, 95% CI, +3.0 to +11.0; P = .001) and 24 weeks (+8.3 points, 95% CI, +4.0 to +12.6; P < .001). CONCLUSION Patient-reported QOL was superior for patients allocated to receive AAP + SOC, compared with docetaxel + SOC over a 2-year period, narrowly missing the predefined value for clinical significance. Patients receiving AAP + SOC reported clinically meaningful higher global-QOL scores throughout the first year following random assignment.

PURPOSE: Abiraterone and enzalutamide are commonly used oral cancer therapies for patients with prostate cancer, both with potentially high out-of-pocket costs for patients. We investigated the prevalence of financial assistance mechanisms used to alleviate out-of-pocket costs and the association of these mechanisms with timing of treatment initiation of abiraterone or enzalutamide. METHODS: Using data from the medical center's specialty pharmacy, we identified first prescriptions for abiraterone or enzalutamide between January 1, 2017, and March 31, 2019. Prescriptions dispensed at an external pharmacy or that were discontinued for reasons unrelated to cost were excluded. Patient demographics, insurance coverage, out-of-pocket cost, and number of days between prescribed date and pill-to-mouth date were collected. RESULTS: Among 220 prescriptions in our final cohort, 185 were filled through our internal specialty pharmacy, 23 through a manufacturer-sponsored patient assistance program (PAP), and 12 were never filled because of cost. One third of the prescriptions in our final cohort (n = 66) were filled with financial assistance: PAP (10%), copay cards (9%), and grants (11%). The median amount of assistance received for the first fill was $2,860 US dollars (USD) (interquartile range $1,856-$10,717 USD). Prescriptions with an out-of-pocket cost < $100 USD were filled in the shortest time (median 5 days), whereas those filled through a PAP had the longest time to initiation (median 30.5 days). CONCLUSION: Among patients prescribed oral therapies for prostate cancer at a single institution, one third of patients received financial assistance. Although receiving assistance is likely to improve financial toxicity, waiting for assistance may lead to longer time to initiation of medication.

Background Real-world evidence suggest that next generation hormonal agents (NHAs) abiraterone and enzalutamide were preferred as first-line (1L) therapies for metastatic castration-resistant prostate cancer (mCRPC) in the United States (US) pre-2020, with chemotherapies, particularly docetaxel, being preferred in subsequent lines (2L+). This real-world study described patient characteristics, treatment patterns, time on treatment (ToT) and overall survival (OS) among patients with mCRPC treated with 2L and 3L docetaxel post-NHAs in the mCRPC setting. Methods Adults with confirmed adenocarcinoma mCRPC diagnosis and ≥1 month of follow-up post-diagnosis were selected from a US electronic health record-derived oncology de-identified database (01/2013–03/2019). Based on the observed line of therapy sequences post-mCRPC diagnosis, patients who received NHA therapy in 1L and docetaxel therapy in 2L were included in the 2L docetaxel cohort, and patients who received NHA therapy in both 1L and 2L and docetaxel therapy in 3L were included in the 3L docetaxel cohort. ToT and OS were evaluated using Kaplan-Meier analysis. Results Among 5,213 patients with mCRPC, 278 and 166 were included in the 2L and the 3L docetaxel cohorts, respectively (median age: 73 years for both cohorts). ADT was the most used class of medication pre-mCRPC (>75%). For the 2L cohort, the most common sequence post-mCRPC was 1L abiraterone → 2L docetaxel (52.5%), while the median ToT and OS post-2L start were 4.1 and 10.5 months, respectively; for the 3L cohort, the most common sequence post-mCRPC was 1L abiraterone → 2L enzalutamide → 3L docetaxel (67.5%), while the median ToT and OS post-3L start were 3.8 and 8.7 months, respectively. Conclusions This real-world study provides novel data on patients treated with docetaxel post-NHAs in a mCRPC setting and highlights the critical unmet need for developing more effective treatment options in this population.

Background: Gallstone disease (GSD) is one of the most common gastroenterological disorders. It is known that drospirenone causes small increased risk of gallbladder diseases. However, the risk may vary between different adverse drug reaction databases. Objective: The purpose of this studty is to examine the safety and risk association between hormonal contraceptive drospirenone and gallbladder diseases using adverse drug reaction database of USFDA’s Federal Adverse Events Reporting System (FAERS), Europe’s Eudravigilance (EV) and Canada’s Canada Vigilance Adverse Reaction Online Database (CVARD). Methods: Individual Case Safety Reports of patients till October 2019 were downloaded from the Federal Adverse Event Reporting System, Eudravigilance, and Canadian database. These reports contained information on adverse events associated with all other drugs inclusive of drospirenone. The disproportionality method of data mining was used to calculate the risk association. Results: The lower limit of 95% CI of PRR was 3.27, 3.47 and 3.76, PRR was 33.08, 41.35 and 115.42, ROR was 37.20, 44.61 and 127.19, Chi-square value was 126572.89, 110392.95 and 362.46, and IC-2SD value was 0.16, 0.17, and 1.21 for FAERS, EU, and CVARD respectively indicating a week signal. Also, all the calculated parameters were above the threshold value. Conclusion: From our study, it was clear that the risk between drospirenone and gallbladder diseases was very low among three databases. There was no harm in prescribing this drug for a contraceptive action.

Purpose Abiraterone acetate, prescribed for metastatic prostate cancer, has enhanced absorption with food. This effect was exploited in a randomized trial which showed noninferiority of PSA decline for 250 mg abiraterone with a low-fat meal (LOW) compared to 1,000 mg abiraterone fasting (STD). Drug was obtained via patient insurance. Patient out-of-pocket costs and adherence were surveyed. Methods Trial participants were randomized to STD or LOW, and surveys of adherence and out-of-pocket costs were administered at baseline and just before coming off study (follow-up). Results Out-of-pocket costs were available from 20 of 36 STD and 21 of 36 LOW patients. Median out-of-pocket costs for a month of drug were $0 (LOW) and $5 (STD); mean costs were $43.61 (LOW) and $393.83 (STD). The two groups did not differ significantly (p = 0.421). Maximum out-of-pocket cost was $1,000 (LOW) and $4,000 (STD). Monthly out-of-pocket costs > $500 were found in 1 LOW and 5 STD patients. For adherence, only 11 STD and 19 LOW patients had questionnaires completed at both baseline and follow-up. STD adherence was 98.18% at baseline and 91.69% at follow-up, differing significantly (p = 0.0078). LOW adherence was 96.52% at baseline and 97.86% at follow-up, not differing significantly (p = 0.3511). Adherence did not correlate with demographics. At follow-up, increasing adherence correlated significantly with decreasing dose (p = 0.013; rho = - 0.458). Conclusions Out-of-pocket costs did not differ significantly in this limited analysis. Adherence was significantly different in STD as the trial progressed, which was not found in LOW. Trial registration ClinicalTrials.gov NCT01543776; registered March 5, 2012.

Combining abiraterone (Abi) with androgen deprivation therapy (ADT) improves overall survival, compared to ADT only, in patients with metastatic castration-sensitive prostate cancer (mCSPC). In Japan, bicalutamide (Bica) and ADT (combined androgen blockade: CAB) is frequently provided for mCSPC. Because these two treatments have not been compared, mCSPC patients who received either treatment were retrospectively analyzed. Of 178 patients with LATITUDE high-risk mCSPC, 103 had received ADT plus upfront Abi (Abi group) and 75 had received ADT plus Bica (Bica group) in multiple institutions of the Tokai Urologic Oncology Research Seminar. Kaplan–Meir curves were used to retrospectively analyze survival and cancer recurrence. Univariate and multivariate Cox regression analyses identified potential prognostic factors for progression-free survival (PFS). Significant differences in major clinicopathological characteristics between the two groups were not observed. The rate of castration-resistant development was higher in the Bica compared to Abi group (50.6 vs. 25.2%, p

Most available prognostic nomograms in metastatic castration-resistant prostate cancer (mCRPC) are derived from datasets not representative of the current treatment landscape. A prognostic nomogram for first-line mCRPC treatment was developed from patients treated in the PREVAIL study. To validate the Armstrong model in the COU-AA-302 trial. A post hoc analysis of mCRPC patients treated in the COU-AA-302 trial was carried out (NCT00887198). The Armstrong prognostic model was applied to patients treated in COU-AA-302. A continuous risk score was derived from coefficients from the original model. Time-dependent area under the curve (tAUC) was used to evaluate the overall predictive ability of the model. Patients were categorized according to the number of risk factors present into those at a low (three or fewer risk factors), intermediate (four to six risk factors), and high (seven to ten risk factors) risk. The association with survival was assessed with Cox regression models. Interaction tests were used to assess the impact of treatment arm in each of the prognostic groups. A total of 1088 patients were analyzed. The risk score was associated with overall survival (OS; tAUC 0.733). Most patients were at a low (49%) or intermediate (41%) risk. Risk category was significantly associated with OS (hazard ratio [HR]: 2.3; 95% confidence interval [CI]: 1.9-2.4; p

PURPOSE Androgen receptor (AR) signaling is important in prostate cancer progression, and therapies that target this pathway have been the mainstay of treatment for advanced disease for over 70 years. Tumors eventually progress despite castration through a number of well-characterized mechanisms; however, little is known about what determines the magnitude of response to short-term pathway inhibition. METHODS We evaluated a novel combination of AR-targeting therapies (degarelix, abiraterone, and bicalutamide) and noted that the objective patient response to therapy was highly variable. To investigate what was driving treatment resistance in poorly responding patients, as a secondary outcome we comprehensively characterized pre- and post-treatment samples using both whole-genome and RNA sequencing. RESULTS We find that resistance following short-term treatment differs molecularly from typical progressive castration-resistant disease, associated with transcriptional reprogramming, to a transitional epithelial-to-mesenchymal transition (EMT) phenotype rather than an upregulation of AR signaling. Unexpectedly, tolerance to therapy appears to be the default state, with treatment response correlating with the prevalence of tumor cells deficient for SNAI2, a key regulator of EMT reprogramming. CONCLUSION We show that EMT characterizes acutely resistant prostate tumors and that deletion of SNAI2, a key transcriptional regulator of EMT, correlates with clinical response.

INTRODUCTION: Bone metastases occur frequently in castration-resistant prostate cancer (CRPC) and may lead to skeletal-related events (SREs), including symptomatic skeletal events (SSEs). Bone-modifying agents (BMAs) delay SREs and SSEs. However, the real-world use of BMAs is debated given the absence of demonstrated survival advantage and potential adverse events (AEs). Our retrospective study examined BMA use and SSE rates in Australian patients with CRPC. METHODS: Patients with CRPC and bone metastases were identified from the electronic CRPC Australian Database. Patient characteristics, treatment patterns and AEs were analysed. Descriptive statistics reported baseline characteristics, SSE rates and BMA use. Comparisons between groups used t-tests and Chi-square analyses. Overall survival was calculated by the Kaplan-Meier method. RESULTS: A total of 532 eligible patients were identified with a median age of 73 years (range: 44-97 years). BMAs were prescribed in 232 men (46%), 183 of whom received denosumab. Patients receiving first-line docetaxel for CRPC were more likely to commence BMAs than those receiving abiraterone or enzalutamide (51% vs 31% vs 38%; p = 0.004). SSEs occurred in 148 men (28%), most commonly symptomatic lesions requiring intervention (75%). At the time of initial SSEs, only 28% were receiving BMAs. Patients treated at sites with lower BMA use (

ContextAdrenal-derived 11-oxygenated androgens (11oAs) are known important contributors to human physiology and disease but have not been studied in pregnancy.ObjectiveWe characterize 11oAs in normal human pregnancy and neonatal period and assess the ratios between 11oAs and compare with ratios of other steroids that undergo placental metabolism.DesignProspective cohort study, 2010-2018.SettingAcademic institution.PatientsPairs of pregnant women and newborns (n = 120) were studied. Inclusion criteria were maternal age between 18 and 42 years old, spontaneous singleton pregnancies, and intention to deliver at University of Michigan.InterventionMaternal venous blood was collected during first trimester and at term. Neonatal cord blood was collected following delivery. Steroids were measured via liquid chromatography-tandem mass spectrometry.Main Outcome MeasuresLevels of 11β-hydroxyandrostenedione (11OHA4), 11-ketoandrostenedione (11KA4), 11β-hydroxytestosterone, and 11-ketotestoterone (11KT) in maternal first trimester, maternal term, and neonatal cord blood were compared. 11OHA4-to-11KA4 ratios were correlated with cortisol-to-cortisone ratios.ResultsDominant 11oAs in pregnancy and the cord blood are 11OHA4 and 11KA4, compared to 11OHA4 and 11KT in adult men and nonpregnant women. We found a rise in 11oA concentrations, particularly 11KA4, from first to third trimester. In cord blood, the concentration of 11KA4 exceeded those of both 11OHA4 and 11KT, reflecting placental 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) and 17β-hydroxysteroid dehydrogenase (17βHSD2) activities, respectively. 11OHA4-to-11KA4 ratios are concordant with cortisol-to-cortisone ratios across all maternal and fetal compartments, reflecting placental 11βHSD2 activity.ConclusionsPlacental 17βHSD2 activity defends the fetus against the androgen 11KT. Our normative values may be used in future studies of 11oAs in complicated pregnancies.

BACKGROUND Among men with metastatic prostate cancer, about 10% have germline alterations in DNA damage response genes. Most studies have examined BRCA2 alone or an aggregate of BRCA1/2 and ATM. Emerging data suggest that ATM mutations may have distinct biology and warrant individual evaluation. The objective of this study is to determine whether response to prostate cancer systemic therapies differs between men with germline mutations in ATM (gATM) and BRCA2 (gBRCA2). METHODS This is an international multicenter retrospective matched cohort study of men with prostate cancer harboring gATM or gBRCA2. PSA50 response (≥50% decline in prostate-specific antigen) was compared using Fisher's exact test. RESULTS AND LIMITATIONS The study included 45 gATM and 45 gBRCA2 patients, matched on stage and year of germline testing. Patients with gATM and gBRCA2 had similar age, Gleason grade, and PSA at diagnosis. We did not observe differences in PSA50 responses to abiraterone, enzalutamide, or docetaxel in metastatic castration resistant prostate cancer between the two groups; however, 0/7 with gATM and 12/14 with gBRCA2 achieved PSA50 response to PARPi (p

Objective To assess efficacy, cycle control, and safety of an oral contraceptive containing estetrol (E4) 15 mg and drospirenone (DRSP) 3 mg. Study design Women aged 16 to 50 years with a body mass index ≤35 kg/m2 enrolled in this multicenter, open-label, 13-cycle, phase 3 trial evaluating E4/DRSP in a 24-active/4-placebo regimen. Follow-up was scheduled at Cycles 2, 4, 7, and 10 and within 3 weeks of completing Cycle 13. Participants used daily diaries to record pill use and vaginal bleeding. We evaluated efficacy outcomes in women 16 to 35 years and bleeding patterns and safety (adverse events [AEs]) in all participants. We assessed overall and method-failure pregnancy rates using the Pearl index (PI) and life-table analysis. Scheduled bleeding included spotting or bleeding starting during the 4-day placebo period or first 3 days of the next cycle. Results We enrolled 1864 women of whom 1674 were 16 to 35 years. Women 16 to 35 years had a PI of 2.65 (95% CI 1.73–3.88), method-failure PI of 1.43 (95% CI 0.7–2.39) and 13-cycle life-table pregnancy rate of 2.1%. Scheduled bleeding occurred in 82.9% to 87.0% of women per cycle; median duration was 4.5 days. Unscheduled bleeding decreased from 30.3% in Cycle 1 to 21.3% to 22.1% during Cycles 2 to 4 and remained stable (15.5% to 19.2%) thereafter. The most frequently reported AEs were headache (5.0%) and metrorrhagia (4.6%). One-hundred thirty-two (7.1%) women discontinued the study early for an AE, most commonly for metrorrhagia (0.9%) and menorrhagia (0.8%). No thromboembolic events occurred. Conclusion E4/DRSP is an effective oral contraceptive with a predictable bleeding pattern for most women and low AE rates. Implications statement A new oral contraceptive with a novel estrogen, estetrol, combined with drospirenone has efficacy and safety within the range of other available oral contraceptives. Large phase 4 studies will be needed to confirm if this combination is associated with an improved adverse event profile or lower thrombosis risk.

Purpose: In metastatic castration-resistant prostate cancer (mCRPC) low serum androgens prior to starting abiraterone acetate (AA) is associated with more rapid progression. We evaluated the effect of AA on androgens in castration-resistant prostate cancer (CRPC) metastases and associations of intratumoral androgens with response. Experimental Design: We performed a phase II study of AA plus prednisone in mCRPC. The primary outcome was tissue testosterone at 4 weeks. Exploratory outcomes were association of steroid levels and genomic alterations with response, and escalating AA to 2,000 mg at progression. Results: Twenty-nine of 30 men were evaluable. Testosterone in metastatic biopsies became undetectable at 4 weeks (P < 0.001). Serum and tissue dehydroepiandrosterone sulfate (DHEAS) remained detectable in many patients and was not increased at progression. Serum and tissue DHEAS in the lowest quartile (pretreatment), serum DHEAS in the lowest quartile (4 weeks), and undetectable tissue DHEAS (on-therapy) associated with rapid progression (20 vs. 48 weeks, P = 0.0018; 20 vs. 52 weeks, P = 0.0003; 14 vs. 40 weeks, P = 0.0001; 20 vs. 56 weeks, P = 0.02, respectively). One of 16 men escalating to 2,000 mg had a 30% PSA decline; 13 developed radiographic progression by 12 weeks. Among patients with high serum DHEAS at baseline, wild-type (WT) PTEN status associated with longer response (61 vs. 33 weeks, P = 0.02). Conclusions: Low-circulating adrenal androgen levels are strongly associated with an androgen-poor tumor microenvironment and with poor response to AA. Patients with CRPC with higher serum DHEAS levels may benefit from dual androgen receptor (AR)-pathway inhibition, while those in the lowest quartile may require combinations with non–AR-directed therapy.

Purpose: Steroid hormones in hormonal contraceptives influence a variety of metabolic parameters. Mainly, ethinyloestradiol (EE) in combined hormonal contraceptives (CHC) is a potent inducer of hep...

For patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after an androgen receptor axis-targeted therapy and docetaxel, poly (ADP-ribose) polymerase (PARP) inhibitors and chemotherapy with cabazitaxel have shown promise. We address the trials for the two approaches and consider possible sequencing of these drugs. We suggest that only patients with a BRCA2 mutation should receive a PARP inhibitor, and docetaxel or cabazitaxel should be favored in the absence of BRCA2 alterations, provided the patient is naïve to these drugs.

Background To use ddPCR to quantify plasma exosomal class III β‐tubulin (βIII‐tubulin, TUBB3, encoded by the TUBB3 gene) mRNA expression in metastatic castration‐resistant prostate cancer (mCRPC) patients, and study the association of this expression with abiraterone efficacy. Methods Blood samples were prospectively collected from 52 mCRPC patients using abiraterone as first‐line therapy to measure plasma exosomal TUBB3 mRNA expression value before the initiation of abiraterone. Study endpoints were PSA response rate, PSA‐progression‐free survival (PSA‐PFS), and overall survival (OS, from CRPC to death). Results Patients with positive exosomal TUBB3 expression showed shorter PSA‐PFS (negative TUBB3 vs. positive TUBB3: 11.0 vs. 7.9 months; p = 0.014). Further analysis demonstrated that patients with strongly positive exosomal TUBB3 (>20 copies/20 µl) was associated with even shorter PSA‐PFS (negative TUBB3 vs. positive TUBB3 [20 copies/20 µl]: 11.0 vs. 8.3 vs. 3.6 months, p = 0.005). In multivariate analyzes, TUBB3 (+) (HR: 2.114, p = 0.033) and ECOG score >2 (HR: 3.039, p = 0.006) were independent prognosticators of poor PSA‐PFS. PSA response and OS did not present significant differences. Conclusion The exosomal TUBB3 mRNA expression level is associated with poor PSA‐PFS of abiraterone in mCRPC patients. The detection of exosomal TUBB3 can be valuable in their management., In this study, we presented this novel, non‐invasive biomarker for abiraterone resistance in mCRPC patients using a ddPCR approach to quantificationally measure the exosomal TUBB3 mRNA expression. We found that a higher TUBB3 level is correlated with shorter progression time after first‐line abiraterone treatment in mCRPC patients.

Metastatic castration-resistant prostate cancer (mCRPC) disproportionately affects the elderly. There is limited data assessing the efficacy and tolerability of abiraterone acetate (AA) versus enzalutamide in this population.To compare the clinical efficacy and tolerability of AA versus enzalutamide in patients ≥ 80 years with mCRPC.A retrospective propensity-weighted comparative cohort study of first-line AA versus enzalutamide among patients with mCRPC aged ≥80 years.Inverse probability treatment weights based on propensity scores were generated to assess the treatment effect of AA versus enzalutamide on time to PSA progression (TTPP), time to progression (TTP) (first of PSA/radiographic/clinical progression) and overall survival using a weighted Cox proportional hazards model. PSA response rate (PSA RR) was compared between groups using ΧOne hundred fifty-three patients received AA, and 125 received enzalutamide. Enzalutamide was associated with higher PSA RR (61.6% vs 43.8%, P 0.004), and TTP (hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.50-0.88, P = 0.01) but not TTPP (HR 0.73, 95% CI 0.53-1.01, P = 0.06). There were significantly more dose reductions with enzalutamide (22.9% vs 44.8%, P 0.001) but there was no interaction between median proportion of full dose received and TTPP or TTP for either drug. Rates of treatment discontinuation (for reasons other than progression) were also significantly different between AA and enzalutamide (28.8% vs 40.8%, respectively, P = 0.04). The most common reason for dose reductions and discontinuation of enzalutamide was fatigue (30.4% and 5.6%, respectively).Despite more dose reductions and a higher treatment discontinuation rate, enzalutamide was associated with a higher PSA RR and longer time to progression, than AA. Given that clinical outcomes were not adversely impacted by decreased treatment exposure, dose modification may be a useful treatment strategy to balance toxicity and tolerance.

Background Docetaxel (DOC) and abiraterone (ABI) in the upfront setting have separately improved clinical outcomes for metastatic hormone-sensitive prostate cancer (mHSPC), but there are no studies comparing drug efficacies or the influence of racial disparities. Materials and Methods We performed a retrospective multicenter review from Winship Cancer Institute at Emory University and Georgia Cancer Center for Excellence at Grady Memorial Hospital (2014–2020) for patients with mHSPC treated with either upfront DOC or ABI. Outcomes evaluated were overall survival (OS), progression-free survival (PFS), and prostate-specific antigen complete response (PSA CR). Results A total of 168 patients were included, consisting of 92 (54.8%) Black patients and 76 (45.2%) non-Black patients (69 White and 7 Asian or Hispanic). Ninety-four (56%) received DOC and 74 (44%) received ABI. Median follow-up time was 22.8 months with data last reviewed June 2020. For OS, there was no significant difference between ABI versus DOC and Black versus non-Black patients. For PFS, DOC was associated with hazard ratio (HR) 1.7 compared with ABI for all patients based on univariate association and HR 2.27 compared with ABI for Black patients on multivariable analysis. For PSA CR, Black patients were less likely to have a CR (odds ratio [OR] = 0.27). Conclusion ABI and DOC have similar OS with a trend toward better PFS for ABI in a cohort composed of 54% Black patients. Racial disparities were observed as prolonged PFS for Black patients treated with ABI, more so compared with all patients, and less PSA CR for Black patients. A prospective trial comparing available upfront therapies in a diverse racial population is needed to help guide clinical decision-making in the era of novel treatment options. Implications for Practice Overall survival is similar for abiraterone and docetaxel when used as upfront therapy in metastatic hormone-sensitive prostate cancer in a cohort composed of 54% Black patients. There is a trend towards improved progression-free survival for abiraterone in all patients and Black patients. Non-Black patients were more likely to achieve prostate-specific antigen (PSA) complete response regardless of upfront therapy.

Purpose:Cross-resistance renders multiple lines of androgen receptor (AR) signaling inhibitors increasingly futile in metastatic castration-resistant prostate cancer (mCRPC). We sought to determine acquired genomic contributors to cross-resistance.Experimental Design:We collected 458 serial plasma cell-free DNA samples at baseline and progression timepoints from 202 patients with mCRPC receiving sequential AR signaling inhibitors (abiraterone and enzalutamide) in a randomized phase II clinical trial (NCT02125357). We utilized deep targeted and whole-exome sequencing to compare baseline and posttreatment somatic genomic profiles in circulating tumor DNA (ctDNA).Results:Patient ctDNA abundance was correlated across plasma collections and independently prognostic for sequential therapy response and overall survival. Most driver alterations in established prostate cancer genes were consistently detected in ctDNA over time. However, shifts in somatic populations after treatment were identified in 53% of patients, particularly after strong treatment responses. Treatment-associated changes converged upon the AR gene, with an average 50% increase in AR copy number, changes in AR mutation frequencies, and a 2.5-fold increase in the proportion of patients carrying AR ligand binding domain truncating rearrangements.Conclusions:Our data show that the dominant AR genotype continues to evolve during sequential lines of AR inhibition and drives acquired resistance in patients with mCRPC.

Purpose/objective(s) Metastasis- directed therapy (MDT) utilizing stereotactic body radiotherapy (SBRT) for oligoprogressive lesions could provide a delay in next-line systemic treatment (NEST) change while undergoing androgen receptor-targeted agents (ARTA) treatment. We evaluated prognostic factors for prostate cancer-specific survival (PCSS) and progression-free survival (PFS) to characterize patients receiving treatment with ARTA who may benefit from MDT for oligoprogressive lesions. The impact of MDT on delaying NEST and the predictive factors for NEST-free survival (NEST-FS) were also assessed. Materials/methods The clinical data of 54 metastatic castration-resistant prostate cancer patients with 126 oligoprogressive lesions receiving abiraterone (1 g/day) or enzalutamide (160 mg/day) before or after systemic chemotherapy were analyzed. A median of three lesions (range: 1-5) were treated with MDT. The primary end points were PCSS and PFS. The secondary end points were time to switch to NEST and NEST-FS. Results The median follow-up time was 19.1 months. Univariate analysis showed that the number of oligoprogressive lesions treated with SBRT and the time between the start of ARTA treatment and oligoprogression were significant prognostic factors for PCSS, and the timing of ARTA treatment (before or after chemotherapy) and the PSA response after MDT were significant prognostic factors for PFS. Multivariate analysis showed that early MDT for oligoprogressive lesions delivered less than six months after beginning of ARTA [HR = 3.20 (95% CI, 1.12-9.15); P = 0.03] and higher PSA levels after MDT [HR = 1.01 (95% CI 1.00-1.01), P = 0.02] were significant predictors of worse PCSS and PFS. The median total duration of ARTA treatment was 13.8 months. The median time between the start of ARTA treatment and the start of MDT for oligoprogressive lesions was 5.2 months, and MDT extended the ARTA treatment by 8.6 months on average. Thirty-two (59.3%) patients continued ARTA treatment after MDT. ARTA treatment after chemotherapy, early oligoprogression requiring MDT, and lower radiation doses for MDT were independent predictors of NEST-FS in multivariate analysis. Conclusion MDT for oligoprogressive lesions is effective and may provide several benefits compared to switching from ARTA treatment to NEST. Patients with early progression while on ARTAs and inadequate PSA responses after MDT have a greater risk of rapid disease progression and poor survival, which necessitates intensified treatment.

Objectives To evaluate the effect on endocrine and metabolic parameters of a new combined oral contraceptive (COC) containing estetrol (E4) and drospirenone (DRSP). Study design Randomized, open-label, controlled, 3-arm, parallel study. Healthy subjects received either E4 15 mg/DRSP 3 mg (E4/DRSP) (n = 38), or ethinylestradiol (EE) 30 µg/levonorgestrel (LNG) 150 µg (n = 29), or EE 20 µg/DRSP 3 mg (n = 31) for 6 treatment cycles. Median percentage change from baseline to cycle 3 and to cycle 6 were evaluated for endocrine parameters, liver proteins, lipid profile, and carbohydrate metabolism. Results At cycle 6, E4/DRSP treatment had less effect on gonadotropins (follicle stimulating hormone [FSH] +30.5%, luteinizing hormone [LH] −7.5%) compared to EE/LNG (FSH −84.0%, LH −92.0%) and EE/DRSP (FSH −64.0%, LH −90.0%). With E4/DRSP increases in total cortisol (+26.0%) and cortisol binding globulin ([CBG] (+40.0%) were less compared to EE/LNG (cortisol +109.0%, CBG +152.0%) and EE/DRSP (cortisol +107.0%, CBG +140.0%). Liver proteins, except CRP, increased, but the effect was less pronounced with E4/DRSP for angiotensinogen (+75.0%) compared to EE/LNG (+170.0%) and EE/DRSP (+206.5%) and for sex hormone binding globulin ([SHBG] +55.0%), compared to EE/LNG (+74.0%) and EE/DRSP (+251.0%). E4/DRSP had minimal impact on lipid parameters; the largest effect was observed for triglycerides (+24.0%), which was less compared to EE/LNG (+28.0%) and EE/DRSP (+65.5%). E4/DRSP had no effect on carbohydrate metabolism. Conclusions E4/DRSP treatment has limited effects on endocrine and metabolic parameters. The effects on gonadotropins, cortisol, CBG, angiotensinogen, SHBG and triglycerides were less pronounced compared to EE-containing products. Implications statement Combining E4 15 mg with DRSP 3 mg resulted in a COC with a different metabolic profile in comparison to EE-containing products. The clinical relevance of these findings needs to be further assessed, using clinical endpoints to establish the safety profile of this new COC.

Background Real-world utilization and outcomes of combination therapy for men with metastatic castrate-resistant prostate cancer (mCRPC) are largely unknown. We evaluated the overall survival (OS) and skeletal-related events (SREs) among men who received radium-223 with or without concomitant abiraterone or enzalutamide in the Veterans Affairs (VA) Health System. Methods We reviewed charts of all mCRPC patients who received radium-223 in the VA from January 2013 to September 2017. We used Cox models to test the association between concomitant therapy versus radium-223 alone on OS and SRE. Sensitivity analyses were performed for concomitant use of denosumab/bisphosphonates. Results Three hundred and eighteen patients treated with radium-223 were identified; 116/318 (37%) received concomitant abiraterone/enzalutamide. Two hundred and seventy-seven (87%) patients died during follow-up. Patients who received concomitant therapy were younger at radium-223 initiation (median age 68 vs. 70, p = .027) and had a longer follow-up (median 29.5 vs. 17.9 months, p = .030). There was no OS benefit for those on concomitant therapy (hazard ratio [HR]: 0.87, 95% confidence interval [CI]: 0.67-1.12, p = .28). There was a trend for an increased SRE risk for patients on concomitant therapy (HR: 1.87, 95% CI: 0.96-3.61, p = .066), but this was not significant. When analyses were limited to men using bone heath agents, similar results were seen for OS (HR: 0.86, 95% CI 0.64-1.15, p = .30) and SRE (HR: 2.36, 95% CI: 0.94-5.94, p = .068). Conclusions Despite the common use of concomitant therapy in this real-world study, there was no difference in OS among mCRPC patients. A nonsignificant increased SRE risk was observed. Further work needs to evaluate the optimal sequence, timing, and safety of combination therapies.

The treatment of advanced prostate cancer has evolved due to recent advances in molecular research and new drug development. Dynamic aberrations in the androgen receptor, DNA repair genes, PTEN-PI3K, and other pathways drive the behavior of advanced prostate cancer allowing a better selection of therapies in each patient. Tumor testing for BRCA1 and BRCA2 is recommended for patients with metastatic prostate cancer, also considering a broad panel to guide decisions and genetic counseling. In symptomatic metastatic patients, castration should be stared to palliate symptoms and prolong survival. In high-risk or high-volume metastatic hormone-naïve patients, castration should be combined with docetaxel, abiraterone, enzalutamide or apalutamide. Radiotherapy to the primary tumor combined with systemic therapy is recommended in low-volume mHNPC patients. In patients with non-metastatic castration-resistant tumors, risk stratification can define the frequency of imaging. Adding enzalutamide, darolutamide or apalutamide to these patients prolongs metastasis-free and overall survival, but potential adverse events need to be taken into consideration. The choice of docetaxel, abiraterone or enzalutamide for treating metastatic castration-resistant patients depends on previous therapies, with cabazitaxel being also recommended after docetaxel. Olaparib is recommended in BRCA1/BRCA2 mutated castration-resistant patients after progression on at least one new hormonal therapy. Aggressive variants of prostate cancer respond to platinum-based chemotherapy. To optimize treatment efficiency, oncologists should incorporate all of these advances into an overall therapeutic strategy.

Background The aim of our study was to evaluate the cost-effectiveness of cabazitaxel versus abiraterone or enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel who had progression within 12 months while receiving an alternative inhibitor (abiraterone or enzalutamide) from a US payer’s perspective. Methods To conduct the cost-effectiveness analysis, a Markov decision model was established. Three health states (progression-free survival (PFS), progressive disease (PD) and death) were included, and the incremental cost-effectiveness ratio (ICER) was regarded as the primary endpoint. The willingness-to-pay (WTP) threshold was set at $100,000.00/quality-adjusted life year (QALY), and discounted rates were set at 3% annually. Efficacy data were derived from the CARD trial and Weibull distribution curves were modeled to fit the survival curves. The robustness of the analysis was tested with a series of one-way sensitivity analyses and probabilistic sensitivity analyses. Results Overall, the incremental effectiveness and cost of cabazitaxel versus androgen-signaling-targeted inhibitors (ASTIs) were 0.16 QALYs and $49,487.03, respectively, which yielded an ICER of $309,293.94/QALY. Our model was mostly sensitive to the duration of PFS in the cabazitaxel group, cost of cabazitaxel and utility of the PFS state. At a WTP threshold of $100,000.00/QALY, cabazitaxel was the dominant strategy in 0% of the simulations. Conclusions Cabazitaxel is unlikely to be a cost-effective treatment option compared with ASTIs in patients with mCRPC previously treated with docetaxel who had progression within 12 months while receiving ASTIs.

Background Androgen receptor (AR) signaling inhibitors represent the standard treatment in metastatic castration resistance prostate cancer (mCRPC) patients. However, some patients display a primary resistance, and several studies investigated the role of the AR as a predictive biomarker of response to treatment. This study is aimed to evaluate the role of AR in liquid biopsy to predict clinical outcome to AR signaling inhibitors in mCRPC patients. Methods Six milliliters of plasma samples were collected before first-line treatment with abiraterone or enzalutamide. Circulating free DNA (cfDNA) and exosome-RNA were isolated for analysis of AR gain and AR splice variant 7 (AR-V7), respectively, by digital droplet PCR. Results Eighty-four mCRPC patients received abiraterone (n = 40) or enzalutamide (n = 44) as first-line therapy. Twelve patients (14.3%) presented AR gain and 30 (35.7%) AR-V7+ at baseline. Median progression-free survival (PFS) and overall survival (OS) were significantly longer in AR-V7− vs AR-V7+ patients (24.3 vs 5.4 months, p p = 0.0001, respectively). Patients carrying the AR gain had a median PFS of 4.8 vs 24.3 months for AR normal patients (p AR normal vs patients with AR gain (not reached vs 8.17 months, p AR gain was observed (r = 0.28; p = 0.01). The AR gain/AR-V7 combined analysis confirmed a strong predictive effect for biomarkers combination vs patients without any AR aberration (PFS 3.8 vs 28 month, respectively; OS 6.1 vs not reached, respectively; p Conclusions The present study demonstrates that cfDNA and exosome-RNA are both a reliable source of AR variants and their combined detection in liquid biopsy predicts resistance to AR signaling inhibitors.

Objective: To assess the effect on hemostasis parameters of a new combined oral contraceptive (COC). Study design: In this randomized, single centre, open-label, exploratory study, healthy women received either 15 mg estetrol/3 mg drospirenone (E4/DRSP) (n = 39), 30 mcg ethinylestradiol/150 mcg levonorgestrel (EE/LNG) (n = 30), or 20 mcg ethinylestradiol/3 mg drospirenone (EE/DRSP) (n = 32) for six 28day cycles. Blood was collected at baseline, cycle 3, and cycle 6. Median change from baseline was evaluated for procoagulant, anticoagulant, and fibrinolytic parameters, and for sex hormone-binding globulin (SHBG).Results: Median change of endogenous thrombin potential (ETP) based activated protein C sensitivity resistance (APCr) at cycle 6 was +30% for E4/DRSP, +165% for EE/LNG (p-value

Combined hormonal contraceptives, despite their high efficacy, are associated with an increased relative risk of cardiovascular events. The contraceptive mechanism of action of combined pills depends fundamentally on their progestin component.A narrative review was performed.The drospirenone-only pill, including this synthetic progestogen with antimineralocorticoid and antiandrogenic activity, has high contraceptive efficacy that has been demonstrated with a 24-day schedule of 4-day administration of hormone-free pills. Due to its safety profile, the drospirenone-only pill is suitable even in high-risk populations, such as women with high blood pressure, thromboembolism, smoking or dyslipidemia.Considering the increasing prevalence of these comorbidities in Latin America, the 4 mg drospirenone-only pill is suggested as one of the strategies of choice in the region for those women who choose oral contraceptives.

Purpose Oligorecurrent prostate cancer has historically been treated with indefinite androgen deprivation therapy (ADT), although many patients and providers opt to defer this treatment at the time of recurrence given quality-of-life and/or comorbidity considerations. Recently, metastasis-directed therapy (MDT) has emerged as a potential intermediary between surveillance and immediate continuous ADT. Simultaneously, advanced systemic therapy in addition to ADT has also been shown to improve survival in metastatic hormone-sensitive disease. This study aimed to compare the cost-effectiveness of treating oligorecurrent patients with upfront MDT before standard-of-care systemic therapy. Methods and Materials A Markov-based cost-effectiveness analysis was constructed comparing 3 strategies: (1) upfront MDT → salvage abiraterone acetate plus prednisone (AAP) + ADT → salvage docetaxel + ADT; (2) upfront AAP + ADT → salvage docetaxel + ADT; and (3) upfront docetaxel + ADT → salvage AAP + ADT. Transition probabilities and utilities were derived from the literature. Using a 10-year time horizon and willingness-to-pay threshold of $100,000/quality-adjusted life year (QALY), net monetary benefit values were subsequently calculated for each treatment strategy. Results At 10 years, the base case revealed a total cost of $141,148, $166,807, and $136,154 with QALYs of 4.63, 4.89, and 4.00, respectively, reflecting a net monetary benefit of $322,240, $322,018, and $263,407 for upfront MDT, upfront AAP + ADT, and upfront docetaxel + ADT, respectively. In the probabilistic sensitivity analysis using a Monte Carlo simulation (1,000,000 simulations), upfront MDT was the cost-effective strategy in 53.6% of simulations. The probabilistic sensitivity analysis revealed 95% confidence intervals for cost ($75,914-$179,862, $124,431-$223,892, and $103,298-$180,617) and utility in QALYs (3.85-6.12, 3.91-5.86, and 3.02-5.22) for upfront MDT, upfront AAP + ADT, and upfront docetaxel + ADT, respectively. Conclusions At 10 years, upfront MDT followed by salvage AAP + ADT, is comparably cost-effective compared with upfront standard-of-care systemic therapy and may be considered a viable treatment strategy, especially in patients wishing to defer systemic therapy for quality-of-life or comorbidity concerns. Additional studies are needed to determine whether MDT causes a sustained meaningful delay in disease natural history and whether any benefit exists in combining MDT with upfront advanced systemic therapy.

Purpose:ZEN-3694 is a bromodomain extraterminal inhibitor (BETi) with activity in androgen-signaling inhibitor (ASI)-resistant models. The safety and efficacy of ZEN-3694 plus enzalutamide was evaluated in a phase Ib/IIa study in metastatic castration-resistant prostate cancer (mCRPC).Patients and Methods:Patients had progressive mCRPC with prior resistance to abiraterone and/or enzalutamide. 3+3 dose escalation was followed by dose expansion in parallel cohorts (ZEN-3694 at 48 and 96 mg orally once daily, respectively).Results:Seventy-five patients were enrolled (N = 26 and 14 in dose expansion at low- and high-dose ZEN-3694, respectively). Thirty (40.0%) patients were resistant to abiraterone, 34 (45.3%) to enzalutamide, and 11 (14.7%) to both. ZEN-3694 dosing ranged from 36 to 144 mg daily without reaching an MTD. Fourteen patients (18.7%) experienced grade ≥3 toxicities, including three patients with grade 3 thrombocytopenia (4%). An exposure-dependent decrease in whole-blood RNA expression of BETi targets was observed (up to fourfold mean difference at 4 hours post–ZEN-3694 dose; P ≤ 0.0001). The median radiographic progression-free survival (rPFS) was 9.0 months [95% confidence interval (CI), 4.6–12.9] and composite median radiographic or clinical progression-free survival (PFS) was 5.5 months (95% CI, 4.0–7.8). Median duration of treatment was 3.5 months (range, 0–34.7+). Lower androgen receptor (AR) transcriptional activity in baseline tumor biopsies was associated with longer rPFS (median rPFS 10.4 vs. 4.3 months).Conclusions:ZEN-3694 plus enzalutamide demonstrated acceptable tolerability and potential efficacy in patients with ASI-resistant mCRPC. Further prospective study is warranted including in mCRPC harboring low AR transcriptional activity.

Background Visceral metastasis (VM), an important poor prognostic factor of prostate cancer (PC), is not commonly observed in castration sensitive status but is often observed after castration-resistant progression. However, the site, timing of emergence, and incidence of VM in castration-resistant patients have not yet been fully elucidated. Methods Demographic, surgical, pathological, and follow-up data of PC patients treated at Kanazawa University Hospital between January 2000 and December 2016 were retrospectively analyzed using their medical charts. From this data, risk factors of VM and survival of patients with VM were elucidated. Results Of 1364 patients, 21 (1.5%) had VM at diagnosis. Of 179 (13.1%) castration-resistant patients, 55 experienced emergence of new VM during treatment course. Incidence of new VM, especially nonlung, such as liver and adrenal metastases, increased significantly in proportion with the number of prescribed treatments. Multivariate analysis revealed that T stage, M stage, age, and treatment history with androgen receptor (AR) signaling-targeted agents and/or taxanes significantly increased the risk of VM. Compared with the group with VM at diagnosis, survival after diagnosis of VM following treatment was significantly shorter. Conclusion Although sequential use of new AR signaling-targeted agents and taxanes for castration-resistant PC (CRPC) is a standard treatment strategy, it often results in development of VM. Elucidating the mechanisms of VM are essential to improve survival in patients with CRPC.

Precision medicine approaches for managing patients with metastatic castrate-resistant prostate cancer (mCRPC) are lacking. Non-invasive approaches for molecular monitoring of disease are urgently needed, especially for patients suffering from bone metastases for whom tissue biopsy is challenging. Here we utilized baseline blood samples to identify mCRPC patients most likely to benefit from abiraterone plus prednisone (AAP) or enzalutamide. Baseline blood samples were collected for circulating tumor cell (CTC) enumeration and qPCR-based gene expression analysis from 51 men with mCRPC beginning treatment with abiraterone or enzalutamide. Of 51 patients (median age 68 years [51–82]), 22 received AAP (abiraterone 1000 mg/day plus prednisone 10 mg/day) and 29 received enzalutamide (160 mg/day). The cohort was randomly divided into training (n = 37) and test (n = 14) sets. Baseline clinical variables (Gleason score, PSA, testosterone, and hemoglobin), CTC count, and qPCR-based gene expression data for 141 genes/isoforms in CTC-enriched blood were analyzed with respect to overall survival (OS). Genes with expression most associated with OS included MSLN, ARG2, FGF8, KLK3, ESRP2, NPR3, CCND1, and WNT5A. Using a Cox-elastic net model for our test set, the 8-gene expression signature had a c-index of 0.87 (95% CI [0.80, 0.94]) and was more strongly associated with OS than clinical variables or CTC count alone, or a combination of the three variables. For patients with a low-risk vs. high-risk gene expression signature, median OS was not reached vs. 18 months, respectively (HR 5.32 [1.91–14.80], p = 0.001). For the subset of 41 patients for whom progression-free survival (PFS) data was available, the median PFS for patients with a low-risk vs high-risk gene expression signature was 20 vs. 5 months, respectively (HR 2.95 [1.46–5.98], p = 0.003). If validated in a larger prospective study, this test may predict patients most likely to benefit from second-generation antiandrogen therapy.

Objectives To assess the impact of antiandrogen withdrawal syndrome after bicalutamide withdrawal in castration-resistant prostate cancer patients treated with androgen receptor-axis targeted agents. Methods The study cohort comprised 94 patients treated with abiraterone (n = 34) or enzalutamide (n = 60) as a first-line androgen receptor-axis targeted agent for castration-resistant prostate cancer despite combined androgen blockade by castration with bicalutamide as the first-line therapy. The association between clinicopathological factors (including antiandrogen withdrawal syndrome) and therapeutic outcome after using abiraterone and enzalutamide was investigated. Results The decline in the prostate-specific antigen level after use of abiraterone or enzalutamide was comparable between patients with and without antiandrogen withdrawal syndrome. Antiandrogen withdrawal syndrome (hazard ratio 3.84, 95% confidence interval 1.29-11.45; P = 0.016) was associated with a higher risk of progression on multivariate analysis, but not all-cause death after abiraterone use. Progression-free survival and overall survival after enzalutamide use did not differ between patients with and without antiandrogen withdrawal syndrome. Conclusions The present data suggest a modest therapeutic efficacy of abiraterone in castration-resistant prostate cancer patients with anti-androgen withdrawal syndrome after bicalutamide withdrawal.

BACKGROUND Abiraterone and enzalutamide are high-cost oral therapies that increasingly are used to treat patients with advanced prostate cancer; these agents carry the potential for significant financial consequences to patients. In the current study, the authors investigated coping and material measures of the financial hardship of these therapies among patients with Medicare Part D coverage. METHODS The authors performed a retrospective cohort study on a 20% sample of Medicare Part D enrollees who underwent treatment with abiraterone or enzalutamide between July 2013 and June 2015. The authors described the variability in adherence rates and out-of-pocket payments among hospital referral regions in the first 6 months of therapy and determined whether adherence and out-of-pocket payments were associated with patient factors and the socioeconomic characteristics of where a patient was treated. RESULTS There were 4153 patients who filled abiraterone or enzalutamide prescriptions through Medicare Part D in 228 hospital referral regions. The mean adherence rate was 75%. The median monthly out-of-pocket payment for abiraterone and enzalutamide was $706 (range, $0-$3505). After multilevel, multivariable adjustment for patient and regional factors, adherence was found to be lower in patients who were older (69% for patients aged ≥85 years vs 76% for patients aged

Prostate cancer (PC) is a potentially high-risk disease and the most common cancer in American men. It is a leading cause of cancer-related deaths in men in the US, second only to lung and bronchus cancer. Advanced and metastatic PC is initially treated with androgen deprivation therapy (ADT), but nearly all cases eventually progress to castrate-resistant prostate cancer (CRPC). CRPC is incurable in the metastatic stage but can be slowed by some conventional chemotherapeutics and second-generation ADT, such as enzalutamide and abiraterone. Therefore, novel therapeutic strategies are urgently needed. Prostate-specific membrane antigen (PSMA) is overexpressed in almost all aggressive PCs. PSMA is widely used as a target for PC imaging and drug delivery. Anti-PSMA monoclonal antibodies (mAbs) have been developed as bioligands for diagnostic imaging and targeted PC therapy. However, these mAbs are successfully used in PC imaging and only a few have gone beyond phase-I for targeted therapy. The 5D3 mAb is a novel, high-affinity, and fast-internalizing anti-PSMA antibody. Importantly, 5D3 mAb demonstrates a unique pattern of cellular localization to the centrosome after internalization in PSMA(+) PC3-PIP cells. These characteristics make 5D3 mAb an ideal bioligand to deliver tubulin inhibitors, such as mertansine, to the cell centrosome, leading to mitotic arrest and elimination of dividing PC cells. We have successfully developed a 5D3 mAb- and mertansine (DM1)-based antibody-drug conjugate (ADC) and evaluated it in vitro for binding affinity, internalization, and cytotoxicity. The in vivo therapeutic efficacy of 5D3-DM1 ADC was evaluated in PSMA(+) PC3-PIP and PSMA(–) PC3-Flu mouse models of human PC. This therapeutic study has revealed that this new anti-PSMA ADC can successfully control the growth of PSMA(+) tumors without inducing systemic toxicity.

To examine whether there is a positive association between sexual dysfunction (SD) and different types of progestin-based contraceptives. Nested case-control study in women of child-bearing age (15–45 years) from the IQVIA® Ambulatory electronic medical record database from 2008 to 2018. Cases defined by diagnosis of sexual dysfunction identified by international classification for disease clinical modification code 9th and 10th. Each case was matched to four controls and rates of prescriptions of the following were compared: levonorgestrel intra-uterine device (IUD), progestin, and ethinyl estradiol (EE) combined oral contraceptive (COC) formulations including levonorgestrel, norgestimate, drospirenone, desogestrel, norethindrone, and norgestrel; etonogestrel vaginal ring; and medroxyprogesterone injection. Overall, 6689 cases of patients with SD were matched to 26,756 matched controls. Compared with matched controls, more subjects with SD used levonorgestrel IUD (OR 1.24, 95% CI 1.08–1.44), EE-levonorgestrel COC (OR 1.18, 95% CI 1.00–1.41), EE-drospirenone (OR 1.28, 95% CI 1.00–1.67), and medroxyprogesterone (OR 1.38, 95% CI 1.12–1.70). The use of norgestrel exhibited a protective effect (OR 0.83, 95% CI 0.73–0.95). When using the EE-levonorgestrel COC as a comparator, norgestrel users exhibited a protective effect (OR 0.70, 95% CI 0.57–0.87) while no other contraceptives showed a statistically significant difference in association with SD. Our study found an increase in the use of levonorgestrel (COC and IUD), drospirenone, and medroxyprogesterone in subjects with SD. The risk of contraceptives did not differ when compared with oral levonorgestrel. The small association size and lack of difference between drug formulations suggest a minimal impact of progestin-based contraceptives on sexual dysfunction.

Background: Menopause is often associated with a central accumulation of body fat. This provokes insulin resistance. The resulting hyperinsulinemia may increase the risk of diabetes, cardiovascular disease and breast cancer. Long-term studies indicate that menopausal hormone therapy (MHT) reduces insulin resistance. To broaden knowledge of the mechanisms behind the influence of MHT on glucose homeostasis we focused on the direct short-term effects of MHT with oral combined estradiol and drospirenone on glucose and insulin metabolism in healthy postmenopausal women. Methods: This randomized, placebo-controlled study recruited 80 healthy postmenopausal women. Women were randomized to treatment with estradiol 1 mg continuously combined with drospirenone 2 mg or placebo for 6-8 weeks. All participants underwent an oral glucose tolerance test (OGTT) before and after the treatment period. Glucose, insulin, fructosamine and C-peptide levels were measured in serum before and 30, 60, 90, 120 and 150 min after a 75-gram oral glucose challenge. Results: After intervention, significantly higher glucose levels at 120 min (p < 0.024) and 150 min (p < 0.030) were observed in the MHT group compared with the placebo group. These glucose levels remained within the normal range. A significantly lower insulin peak serum level (p < 0.040) and a non-significantly smaller area under the curve (AUC) for insulin levels (p = 0.192) was observed in the MHT group at the end of the study period relative to baseline. No significant change in the insulin AUC in the placebo group was observed. There were no significant differences in fructosamine, HOMA-IR and C-peptide levels between the MHT group and the placebo group. Conclusion: This double-blind randomized study (EC/2008/694) indicates that treating healthy, postmenopausal women with 1 mg estradiol continuously combined with 2 mg drospirenone significantly decreases peak insulin levels and increases peak glucose levels during an OGTT compared to placebo. These glucose levels remained within the normal range.

Aim: To evaluate the influence of YB-1 rs10493112 variant as a genetic marker for response to second-generation androgen receptor axis-target agents. Methods: A hospital-based cohort study of 78 patients with metastatic castration-resistant prostate cancer was conducted. Genotyping was performed by TaqMan®allelic discrimination technology. Main results: In abiraterone-treated and high-risk patients, YB-1 rs10493112 AA genotype carriers showed lower progression-free survival than C allele genotype patients (4 vs 17 months; p = 0.009). For carriers of AA genotype, multivariate Cox regression analysis revealed a fivefold increased risk of progression (p = 0.035). Conclusion: The study findings suggest that, for metastatic and castration-resistant prostate cancer patients, this polymorphism might be a putative marker for the clinical outcome.

Background Clinical trials have demonstrated the efficacy of several life-prolonging therapies for metastatic castration-resistant prostate cancer (mCRPC); however, real-world data on their use, survival effect, and safety are limited. Using electronic health record data from the Flatiron Health database, we studied real-world treatment patterns and health outcomes in patients with mCRPC. Patients and Methods We conducted a retrospective, non-interventional cohort analysis of electronic health record data of patients with confirmed mCRPC between January 2013 and September 2017. The primary objective was to describe real-world treatment patterns, including treatment type, duration, and sequencing. Secondary objectives included describing patient characteristics and clinical outcomes. Results Of 2559 patients with mCRPC, 1980 (77%) received at least 1 line of life-prolonging therapy (abiraterone, enzalutamide, docetaxel, cabazitaxel, sipuleucel-T, or radium-223). Of patients receiving first-line therapy, 49% received second-line therapy, and of these, 43% received third-line therapy. Abiraterone/prednisone and enzalutamide accounted for 65% of first-line therapies and 54% of second-line therapies. Docetaxel was the most common third-line therapy (24%). Back-to-back use of abiraterone/prednisone and enzalutamide was common. Radium-223 monotherapy use was 2% in the first-line setting, 3% in the second-line setting, and 8% in the third-line setting. The median overall survival was longer in patients who received life-prolonging therapies (23.7 months; 95% confidence interval: 22.3-25.1 months) than in those who did not (10.1 months; 95% confidence interval: 9.1-11.5 months). Conclusion These real-world insights on over 2500 patients with mCRPC supplement findings from randomized controlled trials and may help to inform clinical trial design, treatment guidelines, and clinical decision-making.

Background The clinical course in metastatic castrate-resistant prostate cancer (mCRPC) can be complicated when patients have disease progression after prior treatment with second generation hormone therapy (second HT), such as enzalutamide or abiraterone. Currently, limited data exist regarding the optimal choice of chemotherapy for mCRPC after failing second generation hormone therapy. We sought to evaluate three common chemotherapy regimens in this setting. Methods We retrospectively identified 150 mCRPC patients with disease progression on enzalutamide or abiraterone. Of these 150 patients, 92 patients were chemo-naive while 58 patients had previously received docetaxel chemotherapy before being started on second HT. After failing second HT, 90 patients were assigned for docetaxel-alone (group A), 33 patients received carboplatin plus docetaxel (group B), while 27 patients received cabazitaxel-alone (Group C). A favorable response was defined by more than or equal to 50% reduction in prostate-specific antigen from the baseline level after a complete course of chemotherapy. Survival outcomes were assessed for 30-month overall survival. Results Patients in group (B) were 2.6 times as likely to have a favorable response compared to patients in group (A) (OR = 2.625, 95%CI: 1.15-5.99) and almost three times compared to patients in group (C) (OR = 2.975, 95%CI: 1.04-8.54) (P = .0442). 30-month overall survival was 70.7%, 38.9% and 30.3% for group (B), (A), and (C), respectively (P = .008). We report a Hazard Ratio of 3.1 (95% CI, 1.31-7.35; P = .0037) between patients in group (A) versus those in group (B) and a Hazard Ratio of 4.18 (95% CI, 1.58-11.06; P = .0037) between patients in group (C) compared to those in group (B) CONCLUSION: This data demonstrates improved response and overall survival in treatment-refractory mCRPC with a chemotherapy regimen of docetaxel plus carboplatin when compared to docetaxel alone or cabazitaxel alone. Further investigations are required.

Despite treatment with abiraterone acetate and prednisone (AA/P), most patients with metastatic hormone sensitive prostate cancer (mHSPC) will develop castration-resistant disease (metastatic castration-resistant prostate cancer [mCRPC]). The early identification of who will progress on AA/P is limited. This study investigates the role of prostate surface antigen (PSA) kinetics as a predictor of progression in mHSPC patients treated with AA/P. All patients with mHSPC who initiated androgen deprivation therapy (ADT) and AA/P from June 2017 to February 2019 at the Cleveland Clinic were eligible. PSA-mCRPC was defined as a PSA rise at two consecutive time points. Patients were followed until first mCRPC or last contact after AA/P. Patterns of PSA change were evaluated using a longitudinal mixed model at time 0, 3, 6, 9, and 12 months from AA/P initiation. The association between PSA profile at 3 months and PSA-mCRPC was examined using survival analysis. Radiographic progression (Rad-mCRPC) was also analyzed. A total of 130 men with follow-up were included. The median (interquartile range [IQR]) follow-up time was 15.3 (10.5, 22.5) months. Eighty-two percent were Caucasian (median age 68.5 years); participants had a median (IQR) PSA of 16.8 (5.3, 48.0) ng/mL. Half of the patients had de novo disease, and 46.2% had high-risk disease (61% had a Gleason score ≥ 8, 16% had visceral disease, and 54% had three or more bony lesions). The greatest PSA percentage reduction from baseline after AA/P initiation occurred at the first 3 months (median 98.3%). The reduction at 6–12 months from baseline was small (99.7–100%). Patients without PSA-mCRPC had a significantly greater 3-month reduction of PSA values compared to patients who developed PSA-mCRPC (p interaction = 0.0002). 50.8% of patients were able to achieve a non-detectable PSA (median 13.1 months). PSA-mCRPC (n = 20) was observed from 4 to 24 months after AA/P, with the majority of events occurring within the first 12 months. Patients with PSA

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus (SARS-CoV)-2 has resulted in the death of more than 328,000 persons worldwide in the first 5 months of 2020. Herculean efforts to rapidly design and produce vaccines and other antiviral interventions are ongoing. However, newly evolving viral mutations, the prospect of only temporary immunity, and a long path to regulatory approval pose significant challenges and call for a common, readily available, and inexpensive treatment. Strategic drug repurposing combined with rapid testing of established molecular targets could provide a pause in disease progression. SARS-CoV-2 shares extensive structural and functional conservation with SARS-CoV-1, including engagement of the same host cell receptor (angiotensin-converting enzyme 2) localized in cholesterol-rich microdomains. These lipid-enveloped viruses encounter the endosomal/lysosomal host compartment in a critical step of infection and maturation. Niemann-Pick type C (NP-C) disease is a rare monogenic neurodegenerative disease caused by deficient efflux of lipids from the late endosome/lysosome (LE/L). The NP-C disease-causing gene (NPC1) has been strongly associated with viral infection, both as a filovirus receptor (e.g., Ebola) and through LE/L lipid trafficking. This suggests that NPC1 inhibitors or NP-C disease mimetics could serve as anti-SARS-CoV-2 agents. Fortunately, there are such clinically approved molecules that elicit antiviral activity in preclinical studies, without causing NP-C disease. Inhibition of NPC1 may impair viral SARS-CoV-2 infectivity via several lipid-dependent mechanisms, which disturb the microenvironment optimum for viral infectivity. We suggest that known mechanistic information on NPC1 could be utilized to identify existing and future drugs to treat COVID-19.

Background Two new drugs, abiraterone and enzalutamide, had recently shown beneficial effects on survival in patients with metastatic castration-resistant prostate cancer. We systematically reviewed the efficacy and safety of abiraterone and enzalutamide in metastatic castration-resistant prostate cancer in real-world practice. Methods A search from PubMed, Web of Science, Cochrane, Embase was conducted up to 6 March 2019. Available articles from conferences were searched. The endpoint was prostate-specific antigen response, overall survival, progression-free survival, number of patients with any adverse event. Results Fourteen cohort studies involving 3469 participants were included. Pooled result showed that prostate-specific antigen response was higher for patients receiving enzalutamide than abiraterone (790 patients, odds ratio (OR) 0.47, 95% confidence interval (CI) 0.29–0.77, P = 0.003, I2=59%). Enzalutamide was significantly associated with increased adverse events rate in comparison with abiraterone (730 patients, OR 0.35, 95%CI 0.13–0.92, P = 0.03, I2=65%). There was no statistical difference between abiraterone and enzalutamide with respect to perceived cognitive impairments (1856 patients, OR 0.90, 95%CI 0.29–2.76, P = 0.85, I2=5%). Enzalutamide was significantly associated with increased fatigue risk in comparison with abiraterone (2477 patients, OR 0.46, 95%CI 0.34–0.63, P＜0.00001, I2=0%). Conclusions Our results demonstrated that enzalutamide was more efficacious than abiraterone for patients with metastatic castration-resistant prostate cancer, but was associated with a significantly elevated risk of side effects, particularly fatigue.

In the present guidelines for the management of metastatic castration-resistant prostate cancer (mCRPC), it is unclear who benefits most from androgen receptor axis-targeted agents (ARATs) or docetaxel as the first-line treatment. We conducted a retrospective study to explore new treatment-specific biomarkers in mCRPC. A total of 211 patients with mCRPC who received either ARAT or docetaxel as first-line treatment were included. Patients were compared for radiographic progression and prostate-specific antigen (PSA) progression. Multivariable Cox regression models were used to assess the association between pretreatment biomarkers and risk of events. The statistical interaction between biomarkers and clinical outcomes was also evaluated. Of all analyzed biomarkers, multivariable Cox regression models identified MPV [≤ median (9.7 fL)] as an independent prognostic factor of radiographic progression [hazard ratio (HR), 2.35; 95% confidence interval (CI), 1.15–4.80; P = 0.019] and PSA progression (HR, 1.96; 95% CI, 1.01–3.95; P = 0.048) in patients treated with ARAT, whereas such associations were not observed in those treated with docetaxel. Interaction analyses showed that those initially treated with docetaxel have lower risk of radiographic progression (HR, 0.33; 95% CI, 0.13–0.79; P = 0.014) and PSA progression (HR, 0.48; 95% CI, 0.23–0.98; P = 0.044) than ARAT when MPV was small. The present study identified pretreatment MPV as a significant treatment-specific prognostic factor of PSA and radiographic progression in patients with mCRPC who received first-line treatment. Furthermore, our results suggested that those with small MPV may better be treated initially with docetaxel than ARAT.

Metastatic castration-resistant prostate cancer (CRPC) is a potentially symptomatic disease with an eventual lethal outcome. Novel pharmaceutical agents are continuously studied with encouraging results in CRPC.In this perspective, the authors present established and promising pharmacotherapeutic strategies for the management of CRPC; both with and without metastases. Apart from the different treatment strategies, the authors present the relevant sequence of treatment through disease progression.Usually, docetaxel should be considered the first line treatment in mCRPC. Abiraterone acetate (AA) plus prednisone or enzalutamide (ENZ) could be alternative treatments in chemotherapy naïve patients. Sipuleucel-T has been approved for the treatment of asymptomatic or minimally symptomatic mCRPC. Ra-223 has been approved for patients with mCRPC with symptomatic bone metastases (not visceral metastases). Cabazitaxel has been approved as the second line treatment to docetaxel in mCRPC. No differences in the overall survival has been observed between sequences starting with docetaxel versus AA/ENZ. Between AA-to-ENZ and ENZ-to-AA sequence, the AA-to-ENZ sequence appeared to be more favorable than the ENZ-to-AA regarding progression-free survival but not overall survival. Carbazitaxel seemed to retain its activity regardless of the treatment sequence. Of note, ENZ and apalutamide have been approved in non-metastatic CRPC.

Background In this study, we evaluated real-world data on radium-223 plus abiraterone/prednisone or enzalutamide. Previously, the ERA 223 trial (NCT02043678) demonstrated increased fracture risk with concurrent treatment with radium-223 and abiraterone plus prednisone/prednisolone in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods We used the Flatiron Health database to perform a retrospective study of patients with mCRPC treated with radium-223. Treatment with radium-223 plus abiraterone/prednisone or enzalutamide was defined as concurrent if both drugs started within 30 days of one another, or layered when the second drug started ≥30 days after the first. The index date was defined as the day of the first radium-223 dose. Outcome measures included symptomatic skeletal events (SSEs), overall survival (OS), and patterns of treatments received. Results Of the 625 patients treated with radium-223, 22% received it together with abiraterone/prednisone and 27% with enzalutamide. When these agents were combined, they were often initiated in a layered fashion (73% layered, 23% concurrent). Prior or concomitant bone health agents (BHAs) were received by 67% and 55% of patients, respectively. Median follow-up was 9 months. Overall, incidence rates for SSEs and pathologic fractures were 0.35 and 0.11 patients per person-year, respectively. Median OS from mCRPC diagnosis was 28.1 months. Conclusions In this real-world setting, combination treatments with radium-223 and abiraterone/prednisone or enzalutamide were common. These agents were more commonly given in a layered than a concurrent fashion. Incidence rates for SSEs were reduced when BHAs were used; however, BHAs were underutilized.

Context The human adrenal is the dominant source of androgens in castration-resistant prostate cancer (CRPC) and classic 21-hydroxylase deficiency (21OHD). Abiraterone, derived from the prodrug abiraterone acetate (AA), inhibits the activity of cytochrome P450 17-hydroxylase/17,20-lyase (CYP17A1), the enzyme required for all androgen biosynthesis. AA treatment effectively lowers testosterone and androstenedione in 21OHD and CRPC patients. The 11-oxygenated androgens are major adrenal-derived androgens, yet little is known regarding the effects of AA administration on 11-oxygenated androgens. Objective To test the hypothesis that AA therapy decreases 11-oxygenated androgens. Design Samples were obtained from 21OHD or CRPC participants in AA or AA plus prednisone (AAP)-treatment studies, respectively. Methods We employed liquid chromatography-tandem mass spectrometry (LC-MS/MS) to measure the 11-oxygenated androgens, 11β-hydroxyandrostenedione, 11-ketoandrostenedione, 11β-hydroxytestosterone, and 11-ketotestosterone, in plasma or serum samples from six 21OHD and six CRPC patients before and after treatment with AA or AAP, respectively. Results In CRPC patients, administration of AAP (1000 mg/day AA with prednisone and medical castration) lowered all four 11-oxygenated androgens to below the lower limits of quantitation ( Conclusions We conclude that AA and AAP therapies markedly reduce the production of the adrenal-derived 11-oxygenated androgens, both in patients with high (21OHD) or normal (CRPC) 11-oxygenated androgens at baseline, respectively. Reduction of 11-oxygenated androgens is an important aspect of AA and AAP pharmacology.

To investigate the feasibility and effectiveness of prostate‐specific membrane antigen (PSMA) imaging to make response assessment regarding novel hormone treatment and to predict the outcomes for metastatic castration‐resistant prostate cancer (mCRPC) patients. This retrospective study enrolled 68 mCRPC patients who had daily received a novel hormone agent named abiraterone. Tc‐99m PSMA single‐photon emission computed tomography (SPECT/CT) was performed at the baseline (SPECT/CT1) and after 3‐6 months of treatment (SPECT/CT2). The treatment response was determined by visual analysis based on molecular imaging PSMA (miPSMA) scores framework and was compared with conventional biochemical analysis. We chose either the hottest lesion (target A) or five of the hottest lesions (target B) to calculate the tumor/background ratio (TBR) and the maximum standardized uptake value (SUVmax) and compared their performances in predicting progression‐free survival (PFS). Changes in PSMA expression between SPECT/CT1 and SPECT/CT2 were well associated with the results of the visual analysis. The TBR and the SUVmax of both targets were significantly associated with the baseline serum PSA level (P, We found it very accurate to evaluate the effect of abiraterone on prostate cancer using PSMA molecular imaging. PSMA imaging is expected to replace traditional imaging in prostate diagnosis and treatment

The neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR), as markers of systematic inflammation response, have been reported to be indicators in metastatic castration-resistant prostate cancer (mCRPC), whereas their prognostic values remain conflict. This study was to assess the prognostic value of NLR and PLR in mCRPC patients and to assess the response of abiraterone or enzalutamide through using NLR and PLR. Databases searching was conducted in the PubMed, EMBASE, Google Scholar, and the Cochrane Library for relevant published literature up to October 2019. Data extraction and quality evaluation were performed on the eligible studies. STATA 14.0 software was used to pooled hazard ratios (HRs) and their 95% confidence intervals (CIs) for overall survival (OS) and progression-free survival (PFS). A total of 3144 mCRPC patients were enrolled from 15 cohort studies in this meta-analysis. The pooled results demonstrated that elevated NLR had a significant association with inferior OS in mCRPC patients treated with abiraterone (HR = 1.63, 95% CI: 1.43–1.85, P

PURPOSE: As novel hormonal therapies, such as abiraterone and enzalutamide, move into earlier stages of treatment of advanced prostate cancer, there are significant cost implications. We used the ASCO Value Framework (AVF) and European Society of Medical Oncology (ESMO) Magnitude of Clinical Benefit Scale (MCBS) to quantify and compare the incremental clinical benefit and costs of these agents in the metastatic castration-resistant prostate cancer (mCRPC) and metastatic castration-sensitive prostate cancer (mCSPC) settings. METHODS: We searched PubMed for randomized phase III trials of abiraterone and enzalutamide in mCRPC and mCSPC. Incremental clinical benefit was quantified using the AVF and ESMO-MCBS by 2 independent assessors. Incremental drug costs were calculated using average wholesale prices (AWPs) from the RED BOOK Online. RESULTS: In mCRPC, 2 abiraterone trials (COU-AA-301 and COU-AA-302) and 2 enzalutamide trials (AFFIRM and PREVAIL) met search criteria. AVF scores ranged from 46.3 to 66.6, suggesting clinical benefit; ESMO-MCBS scores ranged from 3 to 5, with lower clinical benefit in the mCRPC predocetaxel setting. The overall incremental AWP ranged from $83,460.94 to $205,128.85. In mCSPC, 4 trials met criteria (LATITUDE, STAMPEDE, ENZAMET, and ARCHES; AVF scores were 79.8, 33.3, 59, and 17, respectively). All of the studies showed benefit except ARCHES. By ESMO-MCBS, both LATITUDE and STAMPEDE showed benefit (score for 4 for both studies); ENZAMET and ARCHES were not evaluable. The overall cost of treatment was significantly higher in the mCSPC setting. CONCLUSION: The AVF and ESMO-MCBS frameworks generated slightly different results but suggested that abiraterone and enzalutamide show clinical benefit in both mCRPC and mCSPC but trended to lower clinical benefit and increased costs in earlier disease stages. Further refinement of the AVF and ESMO-MCBS is needed to facilitate their use and their ability to inform clinical practice in a rapidly changing treatment landscape.

Purpose In recent years, the treatment options for metastatic hormone-sensitive prostate cancer (mHSPC) have expanded significantly. In addition to androgen deprivation therapy, the systemic treatments now include docetaxel, abiraterone, enzalutamide, and apalutamide. Radiation to the primary is also an option for select low-volume patients. Methods We conducted a review of the pivotal trials that have changed the practice of mHSPC. Results We describe an overview of the trials that investigated docetaxel (CHAARTED and STAMPEDE-Docetaxel), abiraterone (LATTITUDE and STAMPEDE-Abiraterone), enzalutamide (ARCHES, ENZAMET), apalutamide (TITAN), and radiation to the primary (STAMPEDE-Radiation). Discussion The treatment of mHSPC is a complex topic, and treatment choice should be individualized. Patient preferences, cost, volume of disease, and side effect profiles are important in determining which option is the best for an individual patient.