Clinical characteristics and outcomes for patients with non‐metastatic castration-resistant prostate cancer
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SUBMITTER: Arnold P
PROVIDER: S-EPMC8589838 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:To review and evaluate current literature on the US Food and Drug Administration (FDA)-approved drug enzalutamide (XTANDI(®)) in metastatic castration-resistant prostate cancer.Literature search was done through PubMed using the terms enzalutamide, MDV3100, abiraterone, and castration-resistant prostate cancer. Data from FDA product labels were also used.Recent and relevant studies were included in the review. Collected clinical trials were screened and evaluated.Enzalutamide is an androgen receptor (AR) inhibitor with high selectivity and affinity to the AR. It was approved by the FDA to treat metastatic castration-resistant prostate cancer in patients previously treated with docetaxel, after a Phase III trial (AFFIRM) that showed a 4.8-month survival benefit in this population. Recently, the FDA expanded the approval of enzalutamide as first-line therapy for metastatic castration-resistant prostate cancer (mCRPC) who did not receive chemotherapy. Moreover, enzalutamide is shown to be associated with an acceptable safety profile.Enzalutamide has been shown to be both safe and effective in improving overall survival in metastatic castration-resistant prostate cancer postchemotherapy with docetaxel and as a first line treatment before initiation of chemotherapy. However, additional studies and head-to-head trials are needed.
| S-EPMC4407758 | biostudies-other
Project description:BackgroundWe have shown previously in multivariable analysis that black men had 19% lower risk of death than white men with metastatic castration-resistant prostate cancer (mCRPC) treated with a docetaxel and prednisone (DP)-based regimen. The primary goal of this analysis was to compare progression-free survival (PFS), biochemical PFS, ≥50% decline in prostate-specific antigen (PSA) from baseline and objective response rate (ORR) in white, black and Asian men with mCRPC treated with a DP-based regimen.Patients and methodsIndividual patient data from 8820 mCRPC men randomized on nine phase III trials to a DP-containing regimen were combined. Race used in the analysis was based on self-report. End points were PFS, biochemical PSA, ≥50% decline in PSA from baseline and ORR. The proportional hazards and the logistic regression models were employed to assess the prognostic importance of race in predicting outcomes adjusting for established prognostic factors.ResultsOf 8820 patients, 7528 (85%) were white, 500 (6%) were black, 424 were Asian (5%) and 368 (4%) had race unspecified. Median PFS were 8.3 [95% confidence interval (CI) 8.2-8.5], 8.2 (95% CI 7.4-8.8) and 8.3 (95% CI 7.6-8.8) months in white, black and Asian men, respectively. Median PSA PFS were 9.9 (95% CI 9.7-10.4), 8.5 (95% CI 8.0-10.3) and 11.1 (95% CI 9.9-12.5) months in white, black and Asian men, respectively.ConclusionsWe observed no differences in clinical outcomes by race and ethnic groups in men with mCRPC enrolled on these phase III clinical trials with DP.
| S-EPMC7580036 | biostudies-literature
Project description:BackgroundRecent approvals of second-generation androgen receptor inhibitors (SGARIs) have changed the treatment landscape for non-metastatic castration-resistant prostate cancer (nmCRPC). These SGARIs have similar efficacy but differ in safety profiles. We used a discrete choice experiment to explore how United States physicians make treatment decisions between adverse events (AEs) and survival gains in nmCRPC, a largely asymptomatic disease.MethodsTreating physicians (n = 149) participated in an online survey that included 14 treatment choice questions, each comparing 2 hypothetical treatment profiles, which varied in terms of 5 safety and 2 efficacy attributes. We described safety attributes (fatigue, skin rash, cognitive problems, falls, and fractures) in terms of severity and frequency, and efficacy attributes (overall survival [OS] and time to pain progression) in terms of duration of effect. We used a random parameters logit model to estimate preference weights and importance scores for each attribute. We also estimated the amount of survival gain physicians were willing to trade for a reduction in specific AEs between treatment options.ResultsPhysicians placed more importance on survival than on time to pain progression, and viewed a reduction in cognitive problems from severe to none, a reduction in risk of a serious fracture from 8% to none, and a reduction in fatigue from severe to none as the most important safety attributes. Physicians were willing to forego 9.1 and 6.6 months of OS, respectively, to reduce cognitive problems and fatigue from severe to mild-to-moderate. To reduce the risk of a serious fracture from 8 to 5% and 5% to none, physicians were willing to trade 3.9 and 5.3 months of OS, respectively.ConclusionsPhysicians were willing to trade substantial amounts of survival to avoid AEs between hypothetical treatments. These results emphasize the importance of carefully balancing therapies' benefits and risks to ultimately optimize the overall quality of nmCRPC patients' survival. Nonetheless, it is noted that the results from the study sample of 149 physicans may not be representative of the viewpoints of all nmCRPC-treating physicians.
| S-EPMC7310549 | biostudies-literature
Project description:ObjectiveThe study objectives were to understand how patients view the quality of life in non-metastatic castration-resistant prostate cancer (nmCRPC), including unmet needs and what patients consider most important in treatment outcomes. A gap analysis was conducted on existing patient-reported outcomes (PROs) measures versus what is missing from the patient perspective, to guide future development of PRO-based real-world evidence for nmCRPC in Japan. A conceptual model for nmCRPC Japanese patients' HRQOL was also created.MethodsThis non-interventional, qualitative study consisted of a targeted literature review, PRO instrument review, and interviews with 20 nmCRPC patients and five treating physicians. Triangulation of the gap analysis, evidence from the targeted review of the literature, and qualitative interview findings were employed to assess the comprehensiveness of current nmCRPC and HRQOL measures.ResultsSymptoms most reported by patients were frequent urination (70%), nocturia (65%), and general pain (65%). Others reported included lack of strength (30%). HRQOL impacts most reported were anxiety (45%) and worry (50%) about their diagnosis. Additional impacts mentioned were weight changes, loss of sleep, difficulty walking, loss of appetite, and difficulty traveling and seeking toilets in public. The gap analysis revealed 31 symptoms and 33 impacts not covered in existing prostate cancer-specific PRO instruments. Patients mentioned musculoskeletal symptoms such as fractures, leg pain, cramps, numbness, and loss of leg bone strength. Impacts not previously discussed in the literature or in outcome measures were feelings of self-consciousness around diagnosis, stigma around illness, and the impact on mobility including traveling.ConclusionKey results reveal pain and urinary symptoms are the most experienced by Japanese nmCRPC patients. The diagnosis and treatment of disease leads to significant impacts in patient lives. Analysis revealed that symptoms and life impacts are missing in the current literature and outcome measures. Testing and debriefing of specific items could further substantiate these dimensions.
| S-EPMC9883429 | biostudies-literature
Project description:BACKGROUND:In the SPARTAN study, compared with placebo, apalutamide added to ongoing androgen deprivation therapy significantly prolonged metastasis-free survival (MFS) and time to symptomatic progression in patients with high-risk non-metastatic castration-resistant prostate cancer (nmCRPC). Overall survival (OS) results at the first interim analysis (IA1) were immature, with 104 of 427 (24%) events required for planned final OS analysis. Here, we report the results of a second pre-specified interim analysis (IA2). METHODS:One thousand two hundred and seven patients with nmCRPC were randomized 2?:?1 to apalutamide (240?mg daily) or placebo. The primary end point of the study was MFS. Subsequent therapy for metastatic CRPC was permitted. When the primary end point was met, the study was unblinded. Patients receiving placebo who had not yet developed metastases were offered open-label apalutamide. At IA2, pre-specified analysis of OS was undertaken, using a group-sequential testing procedure with O'Brien-Fleming-type alpha spending function. Safety and second progression-free survival (PFS2) were assessed. RESULTS:Median follow-up was 41?months. With 285 (67% of required) OS events, apalutamide was associated with an improved OS compared with placebo (HR 0.75; 95% CI 0.59-0.96; P?=?0.0197), although the P-value did not cross the pre-specified O'Brien-Fleming boundary of 0.0121. Apalutamide improved PFS2 (HR 0.55; 95% CI 0.45-0.68). At IA2, 69% of placebo-treated and 40% of apalutamide-treated patients had received subsequent life-prolonging therapy for metastatic CRPC. No new safety signals were observed. CONCLUSION:In patients with nmCRPC, apalutamide was associated with a 25% reduction in risk of death compared with placebo. This OS benefit was observed despite crossover of placebo-treated patients and higher rates of subsequent life-prolonging therapy for the placebo group.
| S-EPMC6927320 | biostudies-literature
Project description:Androgen deprivation therapy (ADT) is an important component of systemic therapy in advanced prostate cancer; however, resistance to ADT is inevitable. Three large studies demonstrated the efficacy of novel androgen receptor (AR)-targeted therapies in prolonging metastasis-free survival and time to symptomatic progression in patients with non-metastatic castration-resistant prostate cancer (nmCRPC). Enzalutamide and apalutamide have been approved by the FDA in the nmCRPC setting. This review discusses the role of AR and ADT in prostate cancer, mechanism of ADT resistance and the nmCRPC stage. In addition, pharmacologic characteristics and clinical development of apalutamide, role of apalutamide in nmCRPC, and ongoing clinical studies of apalutamide in different stages of prostate cancer are discussed.
| S-EPMC6682169 | biostudies-literature
Project description:BackgroundTo evaluate PSA levels and kinetic cutoffs to predict positive bone scans for men with non-metastatic castration-resistant prostate cancer (CRPC) from the Shared Equal Access Regional Cancer Hospital (SEARCH) cohort.MethodsRetrospective analysis of 531 bone scans of 312 clinically CRPC patients with no known metastases at baseline treated with a variety of primary treatment types in the SEARCH database. The association of patients' demographics, pathological features, PSA levels and kinetics with risk of a positive scan was tested using generalized estimating equations.ResultsA total of 149 (28%) scans were positive. Positive scans were associated with younger age (odds ratio (OR)=0.98; P=0.014), higher Gleason scores (relative to Gleason 2-6, Gleason 3+4: OR=2.03, P=0.035; Gleason 4+3 and 8-10: OR=1.76, P=0.059), higher prescan PSA (OR=2.11; P<0.001), shorter prescan PSA doubling time (PSADT; OR=0.53; P<0.001), higher PSA velocity (OR=1.74; P<0.001) and more remote scan year (OR=0.92; P=0.004). Scan positivity was 6, 14, 29 and 57% for men with PSA<5, 5-14.9, 15-49.9 and ⩾ 50 ng ml(-1), respectively (P-trend <0.001). Men with PSADT ⩾ 15, 9-14.9, 3-8.9 and <3 months had a scan positivity of 11, 22, 34 and 47%, correspondingly (P-trend <0.001). Tables were constructed using PSA and PSADT to predict the likelihood of a positive bone scan.ConclusionsPSA levels and kinetics were associated with positive bone scans. We developed tables to predict the risk of positive bone scans by PSA and PSADT. Combining PSA levels and kinetics may help select patients with CRPC for bone scans.
| S-EPMC4640947 | biostudies-literature
Project description:ObjectiveTo assess the efficacy and toxicity of cediranib, a highly potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, in patients with metastatic castration-resistant prostate cancer (CRPC) previously treated with docetaxel-based therapy.Patients and methodsThe study used a Simon two-stage trial design, which required at least two of 12 patients in the first cohort to be progression-free at 6 months. We enrolled a total of 35 evaluable patients who all received cediranib 20 mg orally daily. In a second cohort, 23 additional patients received prednisone 10 mg daily with cediranib. Endpoints included tumour response, progression-free survival (PFS), overall survival (OS), vascular permeability via dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and toxicity.ResultsA total of 59 patients were enrolled, of whom 67% had received two or more previous chemotherapy regimens. Six of 39 patients with measurable disease had confirmed partial responses and one had an unconfirmed partial response. At 6 months, 43.9% of patients were progression-free; the median PFS and OS periods for all patients were 3.7 months and 10.1 months, respectively. We found that the DCE-MRI variables baseline transport constant (Ktrans ) and rate constant at day 28 were significantly associated with PFS in univariate analyses, but only baseline Ktrans remained significant when considered jointly. The most frequent toxicities were hypertension, fatigue, anorexia and weight loss; the addition of prednisone reduced the incidence of constitutional toxicities.ConclusionThis study demonstrated that cediranib was generally well tolerated with some anti-tumour activity in highly pretreated patients with metastatic CRPC who had progressive disease after docetaxel-based therapy.
| S-EPMC3660464 | biostudies-literature
Project description:Altered metabolism is a hallmark of cancer. Malignant cells metabolise glutamine to fulfil their metabolic needs. In prostate cancer, androgen receptor signalling promotes glutamine metabolism, which is also involved in cholesterol homeostasis. We aimed to determine whether the plasma glutamine levels correlate with the blood lipid profile, clinical characteristics and outcomes in patients with metastatic castration resistance prostate cancer (mCRPC) undergoing taxanes. We retrospectively assessed the glutamine and glutamate levels in plasma samples by a bioluminescent assay. Pre-treatment glutamine, glutamate, cholesterol and triglycerides levels were correlated with patients' clinical characteristics, taxanes response and clinical outcomes. Seventy-five patients with mCRPC treated with taxanes were included. The plasma glutamine levels were significantly higher in patients that received abiraterone or enzalutamide prior to taxanes (p = 0.003). Besides, patients with low glutamine levels were more likely to present a PSA response to taxanes (p = 0.048). Higher glutamine levels were significantly correlated with shorter biochemical/clinical progression-free survival (PSA/RX-PFS) (median 2.5 vs. 4.2 months; p = 0.048) and overall survival (OS) (median 12.6 vs. 20.3; p = 0.008). High cholesterol levels independently predicted early PSA/RX-PFS (p = 0.034). High glutamine and cholesterol in the plasma from patients with mCRPC were associated with adverse clinical outcomes, supporting the relevance of further research on metabolism in prostate cancer progression.
| S-EPMC8507765 | biostudies-literature
Project description:BackgroundBoth changes in circulating lipids represented by a validated poor prognostic 3-lipid signature (3LS) and somatic tumour genetic aberrations are individually associated with worse clinical outcomes in men with metastatic castration-resistant prostate cancer (mCRPC). A key question is how the lipid environment and the cancer genome are interrelated in order to exploit this therapeutically. We assessed the association between the poor prognostic 3-lipid signature (3LS), somatic genetic aberrations and clinical outcomes in mCRPC.MethodsWe performed plasma lipidomic analysis and cell-free DNA (cfDNA) sequencing on 106 men with mCRPC commencing docetaxel, cabazitaxel, abiraterone or enzalutamide (discovery cohort) and 94 men with mCRPC commencing docetaxel (validation cohort). Differences in lipid levels between men ± somatic genetic aberrations were assessed with t-tests. Associations between the 3LS and genetic aberrations with overall survival (OS) were examined using Kaplan-Meier methods and Cox proportional hazard models.ResultsThe 3LS was associated with shorter OS in the discovery (hazard ratio [HR] 2.15, 95% confidence interval [CI] 1.4-3.3, p < 0.001) and validation cohorts (HR 2.32, 95% CI 1.59-3.38, p < 0.001). Elevated plasma sphingolipids were associated with AR, TP53, RB1 and PI3K aberrations (p < 0.05). Men with both the 3LS and aberrations in AR, TP53, RB1 or PI3K had shorter OS than men with neither in both cohorts (p ≤ 0.001). The presence of 3LS and/or genetic aberration was independently associated with shorter OS for men with AR, TP53, RB1 and PI3K aberrations (p < 0.02). Furthermore, aggressive-variant prostate cancer (AVPC), defined as 2 or more aberrations in TP53, RB1 and/or PTEN, was associated with elevated sphingolipids. The combination of AVPC and 3LS predicted for a median survival of ~12 months. The relatively small sample size of the cohorts limits clinical applicability and warrants future studies.ConclusionsElevated circulating sphingolipids were associated with AR, TP53, RB1, PI3K and AVPC aberrations in mCRPC, and the combination of lipid and genetic abnormalities conferred a worse prognosis. These findings suggest that certain genotypes in mCRPC may benefit from metabolic therapies.
| S-EPMC8953070 | biostudies-literature