Prostate cancer: Intermediate efficacy end points to assess modern therapies.
Ontology highlight
ABSTRACT:
SUBMITTER: Madan RA
PROVIDER: S-EPMC6594368 | biostudies-literature | 2013 Dec
REPOSITORIES: biostudies-literature
Publications
Prostate cancer: Intermediate efficacy end points to assess modern therapies.
Madan Ravi A RA Gulley James L JL
Nature reviews. Urology 20131126 12
Similar Datasets
Project description: Not available
| S-EPMC5750273 | biostudies-literature
Project description:ImportanceThe US Food and Drug Administration (FDA) awards the breakthrough therapy designation to expedite development and review of therapeutics intended to treat serious conditions when preliminary clinical evidence demonstrates potential substantial improvement over existing therapies on clinically significant end points. Under the 21st Century Cures Act of 2016, the FDA is required to publish and routinely update a list of surrogate markers to provide industry sponsors with indication-specific information about end points that were or may be considered for approval. Therapeutics that are granted breakthrough therapy designation can receive accelerated or traditional approval; however, little is known about those approved through the latter pathway, where postmarketing confirmatory studies are typically not required, regardless of the end point used.ObjectiveTo evaluate the primary end points used in premarket pivotal trials supporting FDA breakthrough therapy-designated approvals and to determine whether postmarketing studies confirming efficacy were required for approvals based on pivotal trials using surrogate markers as primary end points.Design, setting, and participantsThis cross-sectional study used data from the Drugs@FDA database for all original breakthrough therapy-designated approvals from inception to December 31, 2023, in the US. The first designation was approved on November 1, 2013. Data analysis was performed in January 2024.Main outcomes and measuresDescriptive analyses were used to characterize the breakthrough therapy-designated indication approval pathways, the primary end points of pivotal efficacy trials, and their postmarketing requirements or commitments.ResultsFrom 2013 to 2023, the FDA approved 157 original indications with breakthrough therapy designation. Of these, 52 (33%) were granted accelerated approval and 105 (67%) were granted traditional approval. All accelerated approvals were based on pivotal trials using surrogate markers as primary end points and had FDA-required postmarketing studies to confirm efficacy. Of these 52 indications, 51 (98%) were approved based on surrogate end points listed in the FDA table of surrogate end points for the same indication. Among traditional approvals, 61 (58%) were based on pivotal trials using surrogate markers as primary end points, of which 4 (7%) had FDA-required postmarketing studies to confirm efficacy and 39 (64%) were approved based on surrogate end points listed in the FDA table for the same indication.Conclusions and relevanceIn this cross-sectional study of original FDA breakthrough therapy-designated approvals from 2013 to 2023, trials supporting these approvals often used surrogate markers as primary end points (even when not approved via accelerated approval) and lacked FDA-required postmarketing studies to verify clinical benefit. These findings suggest that requiring postmarketing studies for breakthrough therapy-designated indications approved based on surrogate markers, regardless of approval pathway, may increase patient and clinician certainty of the expected clinical benefit.
| S-EPMC11350476 | biostudies-literature
Project description:New therapeutic approaches for castration-resistant prostate cancer (CRPC) introduce new treatment dilemmas: how best to sequence these options to maximally benefit patients, what tests to perform before and after treatment to assess disease status, and how to interpret the test results and use them to guide treatment. New and specific end points for different classes of drugs are needed to provide the information to guide these treatment decisions. In 2008, the Prostate Cancer Working Group 2 consensus criteria for early-phase clinical trials redefined clinical trial end points as first, to control, relieve, or eliminate disease manifestations present when treatment is started and second, to prevent or delay future disease manifestations. Disease manifestations include prostate-specific antigen (PSA), soft-tissue disease (nodes and/or viscera), bone disease (most common site of spread), and symptoms. Recent US Food and Drug Administration (FDA) approvals for CRPC therapies have been based on the prevent/delay end points that reflect unequivocal benefit to a patient: prolongation of life or reduction in skeletal-related events (SREs). For the practicing oncologist, the control/relieve/eliminate outcomes should serve primarily to inform the decision of whether to continue therapy. In this review, we consider individual end points such as PSA, imaging, and patient-reported outcomes in the context of the control/relieve/eliminate and prevent/delay framework. We address the time-to-event end points of metastasis prevention, SRE, time to progression, and overall survival in the context of regulatory approvals. We also discuss circulating tumor cells measured with the CellSearch assay, recently cleared by the FDA for monitoring CRPC.
| S-EPMC3675708 | biostudies-literature
Project description:People living with cancer should have access to clear and comprehensible treatment information to empower informed decision-making. With the increasing adoption of open access publishing and plain-language summaries, clinical trial findings in journals are becoming more accessible. However, this will only help patients if they are equipped with the relevant knowledge and understanding to make sense of these findings. This podcast highlights the need to support this aspect of health literacy by bringing together the perspectives of a patient, a patient advocate and a medical oncologist. It is accompanied by two visual, plain-language guides designed to help general audiences understand the key efficacy end points that are commonly used in trials of solid tumor treatments.
| S-EPMC11789468 | biostudies-literature
Project description:Treatment of malignant tumors, such as rhabdomyosarcoma (RMS), can improve overall survival (OS). It is time-consuming and expensive for patients to obtain benefits from randomized controlled trials (RCTs) with OS as the primary end-point. Therefore, another surrogate end-point is necessary; however, there is no report on the surrogacy analysis of RMS. In this study, we performed a systematic review of RCTs, involving patients with newly diagnosed RMS, and 11 RCTs were identified. We performed a meta-analysis to assess the surrogacy of intermediate end-points for OS. The correlations between surrogate end-points and OS were investigated using Spearman's rank correlation coefficient (ρ). The coefficient of determination (R2) was employed to measure the strength of the association. A total of 5183 patients were randomly allocated to 34 treatment groups. A marginal correlation (R2 = 0.281, ρ = 0.445) between the hazard ratios (HRs) for event-free survival (EFS) and OS was observed. In patients with localized RMS, the EFS HR had a weaker correlation with OS HR in the sensitivity analysis than that in the primary analysis. Overall, the surrogacy of EFS for OS cannot be confirmed.
| S-EPMC9653385 | biostudies-literature
Project description:While androgen ablation remains a mainstay for advanced prostate cancer therapy, nearly all patients will inevitably develop disease escape with time. Upon the development of castration-resistant prostate cancer, other androgen-axis-targeted treatments may be added in an effort to starve the disease of its androgen signaling. Nevertheless, additional androgen-pathway resistance usually develops to these novel hormonal therapies. In this review, we will discuss the resistance mechanisms to modern androgen-axis modulators and how these alterations can influence a patient's response to novel hormonal therapy. We conceptualize these resistance pathways as three broad categories: (1) reactivation of androgen/AR-signaling, (2) AR bypass pathways, and (3) androgen/AR-independent mechanisms. We highlight examples of each, as well as potential therapeutic approaches to overcome these resistance mechanisms.
| S-EPMC4888068 | biostudies-literature
Project description:Genomic classifiers such as the Genomic Prostate Score (GPS) could help to personalize treatment for men with intermediate-risk prostate cancer (I-PCa). In this study, we aimed to evaluate the ability of the GPS to change therapeutic decision making in I-PCa. Only patients in the intermediate NCCN risk group with Gleason score 3 + 4 were considered. The primary objective was to assess the impact of the GPS on risk stratification: NCCN clinical and genomic risk versus NCCN clinical risk stratification alone. We also analyzed the predictive role of the GPS for locally advanced disease (≥pT3+) and the potential change in treatment strategy. Thirty patients were tested for their GPS between November 2018 and March 2020, with the median age being 70 (45-79). Twenty-three patients had a clinical T1 stage. Eighteen patients were classified as favorable intermediate risk (FIR) based on the NCCN criteria. The median GPS score was 39 (17-70). Among the 23 patients who underwent a radical prostatectomy, Gleason score 3 + 4 was found in 18 patients. There was a significant correlation between the GPS and the percentage of a Gleason grade 4 or higher pattern in the surgical sample: correlation coefficient r = 0.56; 95% CI = 0.2-0.8; p = 0.005. In this study, the GPS combined with NCCN clinical risk factors resulted in significant changes in risk group.
| S-EPMC9913491 | biostudies-literature
Project description: Not available
| S-EPMC3950277 | biostudies-literature
Project description:Advanced prostate cancer is the second leading cause of death from cancer in the United States. In the era of cancer immunotherapy, it was the first malignancy to demonstrate improved survival with a cancer-specific vaccine, thus proving that prostate cancer is an immune-responsive disease. However, the success with immune checkpoint therapies in metastatic prostate cancer has been limited to date with only a subset of patients experiencing clinical benefit. The relative lack of response could be attributed to patient selection based on clinical attributes and the tumor microenvironment. Here, we review the current data on immune checkpoint therapies in prostate cancer and propose future directions.
| S-EPMC4847149 | biostudies-literature
Project description:BackgroundEnd points used to detect influenza in vaccine efficacy trials have varied. Both the inactivated and live attenuated influenza vaccines are efficacious; however, failure to protect occurs.MethodsWe compared characteristics of influenza A (H3N2) and B cases from 3 years of a comparative placebo-controlled trial of inactivated and live attenuated vaccines, and we evaluated the laboratory end points used to determine efficacy.ResultsAlthough illness duration and reported symptoms did not differ by intervention, subjects with influenza in the inactivated vaccine group were less likely than those in the placebo group to report medically attended illnesses. All influenza type A (H3N2) and B cases isolated in cell culture were also identified by real-time polymerase chain reaction (rtPCR). However, only 69% of type A (H3N2) cases identified by rtPCR also were isolated in cell culture. Isolation frequency was lowest among live attenuated vaccine failures, a reflection of lower specimen viral loads. Among cases of rtPCR identified influenza A (H3N2), 90% of placebo and 87% of live attenuated vaccine recipients but only 23% of inactivated vaccine recipients demonstrated serologic confirmation of infection.ConclusionsIn influenza vaccine efficacy studies, virus identification using rtPCR is the ideal end point. Isolation in cell culture will miss cases, and a serologic end point alone will overestimate inactivated vaccine efficacy.
| S-EPMC3069734 | biostudies-literature