Intermediate Clinical Endpoints Research Articles

Intermediate clinical endpoints for surrogacy in localised prostate cancer: an aggregate meta-analysis.

The international Intermediate Clinical Endpoints in Cancer of the Prostate working group has established metastasis-free survival as a surrogate for overall survival in localised prostate cancer based on the findings of 19 predominantly radiotherapy-based trials. We sought to comprehensively assess aggregate trial-level performance of commonly reported intermediate clinical endpoints across all randomised trials in localised prostate cancer. For this meta-analysis, we searched PubMed for all trials in localised or biochemically recurrent prostate cancer published between Jan 1, 1970, and Jan 15, 2020. Eligible trials had to be randomised, therapeutic, reporting overall survival and at least one intermediate clinical endpoint, and with a sample size of at least 70 participants. Trials of metastatic disease were excluded. Intermediate clinical endpoints included biochemical failure, local failure, distant metastases, biochemical failure-free survival, progression-free survival, and metastasis-free survival. Candidacy for surrogacy was assessed using the second condition of the meta-analytical approach (ie, correlation of the treatment effect of the intermediate clinical endpoint and overall survival), using R2 weighted by the inverse variance of the log intermediate clinical endpoint hazard ratio. The intermediate clinical endpoint was deemed to be a surrogate for overall survival if R2 was 0·7 or greater. 75 trials (53 631 patients) were included in our analysis. Median follow-up was 9·1 years (IQR 5·7-10·6). Biochemical failure (R2 0·38 [95% CI 0·11-0·64]), biochemical failure-free survival (R2 0·12 [0·0030-0·33]), biochemical failure and clinical failure (R2 0·28 [0·0045-0·65]), and local failure (R2 0·085 [0·00-0·37]) correlated poorly with overall survival. Progression-free survival (R2 0·46 [95% CI 0·22-0·67]) showed moderate correlation with overall survival, and metastasis-free survival (R2 0·78 [0·59-0·89]) correlated strongly. Intermediate clinical endpoints based on biochemical and local failure did not meet the second condition of the meta-analytical approach and are not surrogate endpoints for overall survival in localised prostate cancer. Our findings validate metastasis-free survival as the only identified surrogate endpoint for overall survival to date. Prostate Cancer Foundation and National Institutes of Health.

Intermediate clinical endpoints in localised prostate cancer.

Intermediate clinical endpoints in localised prostate cancer.

Ultra-processed foods and human health: What do we already know and what will further research tell us?

Ultra-processed foods and human health: What do we already know and what will further research tell us?

Comprehensive Analysis of Candidate Surrogate Endpoints in Localized Prostate Cancer: Analysis of 59 Randomized Trials

The international Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP) working group established metastasis-free survival (MFS) as a surrogate endpoint for overall survival (OS) for men with localized prostate cancer (PCa). ICECaP required individual patient data which limited their analyses to <25% of all eligible randomized controlled trials (RCTs). Since surrogate endpoints are both disease stage and treatment specific, the performance of MFS and other intermediate clinical endpoints (ICEs) across the landscape of localized PCa patients and treatments is unclear. Herein, we comprehensively assess all commonly reported ICEs in localized PCa. A systematic search utilizing Medline to identify RCTs in localized PCa was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Hazard ratios for OS and the ICEs were collected. ICEs included local failure (LF), biochemical failure (BF), distant metastases (DM), BF-free survival (BFS; includes BF, DM, or death), progression-free survival (PFS; LF, DM, or death), and MFS (DM or death) with OS. Candidacy for surrogacy was evaluated using the second condition of the two-stage meta-analytic approach testing whether the treatment effect on the ICE and OS are correlated using R2, weighted by the inverse variance of the log of the ICE hazard ratio. Of 4,217 RCTs screened, 59 trials including 42,272 patients were eligible for analysis. Overall, LF (R2 0.036), BF (R2 0.176), BFS (R2 0.238), and DM (R2 0.364) had poor correlation to the treatment effect on OS. PFS (R2 0.655) had moderate correlation, and MFS (R2 0.781) had the strongest correlation. These trends held true in trials that included or were exclusively in high risk disease. Radiotherapy (RT) RCTs (n = 50, 36,872 patients) showed similar trends with low correlation of LF (R2 0.073), BF (R2 0.334), and BFS (R2 0.229). MFS had stronger correlation to OS (R2 0.777). In RCTs testing use/duration of hormone therapy (n = 26 trials, 24,071 patients), MFS had very strong correlation to OS (R2 0.957). By contrast, in trials evaluating RT dose escalation or fraction size, MFS had lower correlation (R2 0.691). MFS also had strong a correlation to OS (R2 0.947) in patients treated with radical prostatectomy which to date has not been demonstrated. This novel approach corroborates the findings of ICECaP in a substantially larger sampling of RCTs in localized PCa, and supports MFS as the most robust surrogate endpoint for OS across disease stage and treatment type. Importantly, LR and BF have almost no correlation to the treatment effect observed for OS, even in high risk trials, and these ICEs should not be used as surrogate endpoints for phase 3 randomized trials.

Metastasis-Free Survival, but Not Biochemical Failure, is a Strong Surrogate Endpoint for Overall Survival in Recurrent Prostate Cancer: Analysis of NRG Oncology/RTOG 9601

The Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP) working group identified metastasis-free survival (MFS) as a valid surrogate for overall survival (OS) in men treated for localized prostate cancer. Only 8% of men in the ICECaP MFS analysis were treated with prostatectomy and no salvage radiotherapy (SRT) trials were included. Surrogate endpoints are treatment and disease state specific, thus the performance of intermediate clinical endpoints (ICEs) to function as surrogate endpoints in the SRT setting are unknown. Leveraging NRG/RTOG 9601, we aimed to determine the performance of ICEs as surrogate endpoints for OS in men receiving SRT. Endpoints assessed for surrogacy were biochemical failure (BF), as defined in NRG/RTOG 9601(PSA nadir + 0.3-0.5 ng/mL, or initiation of salvage hormone therapy) and NRG/RTOG 0534 (PSA nadir + 2 ng/mL), distant metastasis (DM), and MFS (DM or all-cause death). Surrogacy was assessed by the Prentice criteria, however given its well-established limitations, the preferred methodology used in ICECaP of a two-stage meta-analytic approach was also utilized. The meta-analytic approach requires two conditions: (1) that the ICE be correlated with OS and (2) that the treatment effect on the ICE and OS be correlated. Condition one was assessed at the patient level with Kendall’s τ and condition two was assessed by randomly dividing the entire trial cohort into 10 pseudo trial centers and calculating the R2 between treatment hazard ratios for ICE and OS. BF defined in NRG/RTOG 9601 and by nadir + 2 ng/mL, DM, and MFS all satisfied each of the four Prentice criteria for surrogacy for OS. However, with the two-condition approach for assessment of surrogacy, there was strong correlation between MFS and OS (τ = 0.86), moderate correlation between DM and OS (τ = 0.66), and weaker correlation between BF (τ = 0.25) or PSA nadir + 2 ng/mL (τ = 0.40) and OS. Similarly, for condition two, the treatment effect of antiandrogen therapy on MFS and OS were correlated (R2 = 0.67), but this was not true for BF and OS (R2 = 0.09), PSA nadir + 2 ng/mL and OS (R2 = 0.12), or DM and OS (R2 = 0.18). We demonstrate that MFS is a strong surrogate for OS in men receiving SRT for recurrent prostate cancer after prostatectomy, consistent with data in the intact primary treatment setting. While BF and PSA nadir + 2 ng/mL both are prognostic, these PSA based ICEs were weakly correlated with OS at the patient level. Similarly, the treatment effect of antiandrogen therapy on these endpoints was only weakly correlated with treatment effect on OS. Thus, caution should be used when inferring clinical benefit from effects on BF as a surrogate for OS.

Partitioned Survival and State Transition Models for Healthcare Decision Making in Oncology: Where Are We Now?

Partitioned survival models (PSMs) are routinely used to inform reimbursement decisions for oncology drugs. We discuss the appropriateness of PSMs compared to the most common alternative, state transition models (STMs). In 2017, we published a National Institute for Health and Care Excellence (NICE) Technical Support Document (TSD 19) describing and critically reviewing PSMs. This article summarizes findings from TSD 19, reviews new evidence comparing PSMs and STMs, and reviews recent NICE appraisals to understand current practice. PSMs evaluate state membership differently from STMs and do not include a structural link between intermediate clinical endpoints (eg, disease progression) and survival. PSMs directly consider clinical trial endpoints and can be developed without access to individual patient data, but limit the scope for sensitivity analyses to explore clinical uncertainties in the extrapolation period. STMs facilitate these sensitivity analyses but require development of robust survival models for individual health-state transitions. Recent work has shown PSMs and STMs can produce substantively different survival extrapolations and that extrapolations from STMs are heavily influenced by specification of the underlying survival models. Recent NICE appraisals have not generally included both model types, reviewed individual clinical event data, or scrutinized life-years accrued in individual health states. The credibility of survival predictions from PSMs and STMs, including life-years accrued in individual health states, should be assessed using trial data on individual clinical events, external data, and expert opinion. STMs should be used alongside PSMs to support assessment of clinical uncertainties in the extrapolation period, such as uncertainty in post-progression survival.

Factors Related to Conversion from Accelerated to Full Approval for Drugs Approved in the United States Between 2000 and 2016.

Accelerated approval (AA) is a program that grants approval to drugs based on clinical trial data for a surrogate endpoint or an intermediate clinical endpoint. Pharmaceutical companies are required to conduct a confirmatory trial to demonstrate true clinical benefit of the drug to obtain full approval (FA) for the AA. This study aimed at clarifying the points that should be considered by examining the characteristics of AA indications in all disease areas and the factors related to the status of conversion from AA to FA. AA indications granted from January 1, 2000, to June 30, 2016, were investigated from the aspects of the characteristics of AAs and the status of conversion from AA to FA. Eighty-nine AAs were examined, of which 65 were converted to FA and 24 were not. A significant association was found between the FA status and period in which AA was granted, disease area, availability of IA data of a confirmatory trial for FA at the time of AA, and sales ranking of the company. To successfully convert from AA to FA, a development plan that focuses not only on AA but also on future FA needs to be considered and implemented from the early stage of development in line with the FDA guidance. In particular, for companies with insufficient experience in the development of AA indications and for products/indications without an established endpoint, more active discussion with the regulatory authorities from an early stage of development should be encouraged.

Event-Free Survival, a Prostate-Specific Antigen-Based Composite End Point, Is Not a Surrogate for Overall Survival in Men With Localized Prostate Cancer Treated With Radiation.

Recently, we have shown that metastasis-free survival is a strong surrogate for overall survival (OS) in men with intermediate- and high-risk localized prostate cancer and can accelerate the evaluation of new (neo)adjuvant therapies. Event-free survival (EFS), an earlier prostate-specific antigen (PSA)-based composite end point, may further expedite trial completion. EFS was defined as the time from random assignment to the date of first evidence of disease recurrence, including biochemical failure, local or regional recurrence, distant metastasis, or death from any cause, or was censored at the date of last PSA assessment. Individual patient data from trials within the Intermediate Clinical Endpoints in Cancer of the Prostate-ICECaP-database with evaluable PSA and disease follow-up data were analyzed. We evaluated the surrogacy of EFS for OS using a 2-stage meta-analytic validation model by determining the correlation of EFS with OS (patient level) and the correlation of treatment effects (hazard ratios [HRs]) on both EFS and OS (trial level). A clinically relevant surrogacy was defined a priori as an R2 ≥ 0.7. Data for 10,350 patients were analyzed from 15 radiation therapy-based trials enrolled from 1987 to 2011 with a median follow-up of 10 years. At the patient level, the correlation of EFS with OS was 0.43 (95% CI, 0.42 to 0.44) as measured by Kendall's tau from a copula model. At the trial level, the R2 was 0.35 (95% CI, 0.01 to 0.60) from the weighted linear regression of log(HR)-OS on log(HR)-EFS. EFS is a weak surrogate for OS and is not suitable for use as an intermediate clinical end point to substitute for OS to accelerate phase III (neo)adjuvant trials of prostate cancer therapies for primary radiation therapy-based trials.

Primary analysis of a phase II study of metastasis-directed ablative therapy to PSMA (18F-DCFPyL) PET-MR/CT defined oligorecurrent prostate cancer.

5553 Background: Despite maximal local therapies (MLT) (radical prostatectomy followed by radiotherapy [RT]), 20-30% of men will progress to incurable prostate cancer (PCa). Most recurrences in this scenario are characterized by rise in PSA with negative bone scan (BS) and computed tomography (CT). We conducted a phase II trial for men with rising PSA after MLT using 18F-DCFPyL (PSMA) PET-MR/CT followed by metastasis-directed therapy (MDT) to PET positive foci. We report the results of our primary analysis. Methods: Patients with rising PSA (0.4-3.0 ng/mL) after MLT, negative BS/CT and no prior salvage ADT were eligible. All patients underwent PSMA PET-MR and PET-CT. Those with limited disease burden amenable to MDT underwent either stereotactic ablative RT (SABR) or surgery (lymph node dissection). No ADT was used. The primary endpoint was biochemical response rate (complete [undetectable PSA] or partial [PSA decline ≥50% from baseline]) following MDT. A Simon’s two-stage study design was employed. Estimated time of delay in salvage ADT was calculated using the Kaplan-Meier method. Toxicity was prospectively recorded (CTCAE v4.0). Results: After a median of 63 months (range 3-180) post MLT, 72 patients underwent PSMA PET-MR/CT with median PSA 0.98 ng/mL (range 0.4-3.1). Sixteen patients had negative and 56 had positive PET-MR/CT scans, of which 37 (51%) were amenable to MDT. The median number of treated lesions was 2 (range 1-5). Of the treated patients, 30 (81%) had miT0N1M0 disease, 2 (5.5%) had miT0N1M1a, 2 (5.5%) had miT0N0M1a and 3 (8%) had miT0N0M1b. Twenty-seven patients underwent SABR (median 30 Gy in 3 fractions) and 10 had surgery. At a median of 11 months (range 1-29) post MDT, 8 patients (22%) had complete (CR) and 14 (38%) had partial (PR) responses. Among the 8 CRs, 5 had surgery and 3 had SABR; of the 14 PRs, 2 had surgery and 12 had SABR. The estimated median delay in salvage ADT for the entire cohort, PR and CR subgroups was 13 months (IQR 8-20), 16 months (IQR 13-20) and 30 months (IQR not reached), respectively. Two grade 2+ toxicities were observed, both in surgical patients: deep venous thrombosis and ureteric injury requiring stent placement. Conclusions: 18F-DCFPyL PET-MR/CT has high detection rates (78%) in men with rising PSA after MLT. We observed a favorable therapeutic index with MDT (60% response rate) for patients with metachronous PSMA-unveiled oligometastatic PCa following MLT. Phase III studies using validated intermediate clinical endpoints are needed before integration into routine practice. Clinical trial information: NCT03160794 .

Surrogate endpoints for overall survival for patients with metastatic hormone-sensitive prostate cancer in the CHAARTED trial.

Metastasis-free survival has been shown to be a robust surrogate for overall survival (OS) in men with nonmetastatic prostate cancer (PC). However, this surrogate only holds true for a select subset of patients, and leaves those trials analyzing metastatic disease at a disadvantage. We aimed to identify the best surrogate for predicting OS in patients with metastatic hormone-sensitive PC. We analyzed data from the Chemohormonal Therapy versus Androgen Ablation Randomized Trial for Extensive Disease trial in which patients were randomly assigned to receive either androgen deprivation therapy (ADT) or ADT plus docetaxel. PSA response, progression and development of castration-resistant PC (CRPC) within 6 and 12 months were investigated as potential OS surrogates, in accordance with the Prentice Criteria. The proportion the of treatment effect (PTE) was calculated for each surrogate and used to identify the best one. Data from 790 patients were considered: 393 (49.7%) men received ADT alone, while 397 (50.3%) received combination therapy. Four intermediate clinical endpoints met the criteria for surrogacy: progression within 6 months (HR: 5.70; 95%CI: 4.26, 7.64; p < 0.001) and 12 months (HR: 7.09; 95%CI: 5.16, 9.76; p < 0.001) as well as development of CRPC within 6 (HR: 5.11; 95%CI: 3.81, 6.85; p < 0.001) and 12 months (HR: 6.24; 95%CI: 4.58, 8.51; p < 0.001). The PTE for the four surrogates were 88%, 52%, 80%, and 46%, respectively. The 2-year OS rates for patients who progressed within 6 months of randomization were 42 versus 89% for the patient population that did not progress that quickly. Progression within 6 months following combination therapy emerged as the best surrogate for OS.

PD16-06 SURROGATE ENDPOINTS FOR OVERALL SURVIVAL FOR PATIENTS WITH METASTATIC HORMONE-SENSITIVE PROSTATE CANCER IN THE CHAARTED TRIAL

INTRODUCTION AND OBJECTIVE:Given the long natural history of prostate cancer (PC), intermediate clinical endpoints (ICEs) might aid in study design and expedite drug approvals, if surrogacy is met....

New drug approvals in oncology.

The traditional regulatory drug approval paradigm comprising discrete phases of clinical testing that culminate in a large randomized superiority trial has historically been predominant in oncology. However, this approach has evolved in the current era of drug development, with multiple other development pathways now being utilized. Indeed, treatment approaches designed on the basis of an improved understanding of cancer biology have led to unprecedented responses in early phase trials, sometimes resulting in drug approvals in the absence of large-scale trials. At the same time, improved molecular diagnostic technologies have led to the identification of ever-smaller patient subgroups for molecularly targeted therapy. Moreover, new FDA regulatory paradigms have enabled the rapid review and accelerated approval of certain drugs in the absence of survival data. Regulatory approvals based on large-cohort trials with surrogate or intermediate clinical end points or on non-inferiority trials, as well as new tumour-agnostic indications, also set important precedents in the field. In this Viewpoint, we asked two leading oncologists involved in clinical drug development, an expert in regulatory science and prescription drug policy and a prominent patient advocate, to provide their opinions on the implications of these changes in regulatory practices for patient care.

Surrogate Endpoints in Localized Prostate Cancer.

Randomized clinical trials assessing novel therapies in men with localized prostate cancer frequently require large patient numbers and more than a decade of follow-up to demonstrate improvements in overall survival. As the landscape of treatment options for prostate cancer is rapidly changing, clinical trials requiring long follow-up threaten to impede treatment improvements and run the risk of results being obsolete by the time that they are reported in publication. To address these issues, there has been tremendous interest in identifying an intermediate clinical endpoint that can be assessed earlier in the disease course to serve as a robust surrogate for overall survival in men with localized prostate cancer. Herein we review the relevant data for surrogate endpoints in localized prostate cancer, highlighting the work performed by the Intermediate Clinical Endpoints in Cancer of the Prostate Working Group identifying metastasis-free survival as a valid surrogate for men treated for localized prostate cancer.

The association between preconception fruit and vegetable intake in relation to in-vitro fertilization treatment outcome among women attempting fertility

AbstractIntroductionAdequate intake of fruits and vegetables (F&amp;V) has been long promoted as a public health priority based on the evidence supporting various health benefits attributed to these food groups. Their effects on reproductive outcomes, however, remain poorly explored. F&amp;V intake has been positively associated with embryo quality in women undergoing in-vitro fertilization (IVF) but there is lack of data regarding potential associations with IVF final outcomes (clinical pregnancy and live birth). Thus, the aim of this study was to evaluate habitual F&amp;V intake in relation to clinical pregnancy and live birth among women undergoing infertility treatment.Materials and MethodsNulliparous non-obese women [n = 244, 22–41 years old, body mass index (BMI) &lt; 30 kg/m2] undergoing their first IVF cycle were recruited from an Assisted Conception Unit in Athens, Greece, between November 2013 and September 2016. Habitual F&amp;V intake was estimated via a validated for the Greek population semi-quantitative food-frequency questionnaire and expressed in servings/day. Intermediate outcomes (i.e. oocyte yield and embryo quality measures) and clinical endpoints (implantation, clinical pregnancy and live birth) were prospectively recorded. Generalized linear models adjusting for age, ovarian stimulation protocol, BMI, physical activity, anxiety levels, infertility diagnosis, caloric intake and supplements use were used to test associations between F&amp;V intake and IVF outcomes.ResultsOverall, 229 women (93.9%) had an embryo transfer, 104 (42.6%) achieved a clinical pregnancy and 99 (40.5%) had a live birth. Women with a clinical pregnancy and live birth did not differ in age, BMI, smoking habits, physical activity or stress levels, compared to those who did not achieve pregnancy (all P &gt; 0.05). Compared to women with IVF failure, those achieving clinical pregnancy and live birth reported consuming more fruits (median values: 1.77 vs. 1.49 servings/day and 1.77 vs. 1.41 servings/day, respectively) and more vegetables (1.79 vs. 1.37 servings/day and 1.89 vs. 1.36 servings/day, respectively), all P &lt; 0.05. No significant association between F&amp;V intake and IVF intermediate outcomes was recorded. The multivariable-adjusted relative risk (95% confidence interval) for clinical pregnancy for increasing intake of fruit and vegetable (servings/day, continuous) was 1.23 (1.06–1.44) and 1.25 (1.02–1.57), respectively, and for live birth it was 1.29 (1.10–1.51) and 1.36 (1.10–1.71), respectively.DiscussionHigher pre-treatment F&amp;V was related to higher probability of clinical pregnancy and live birth among women undergoing IVF. These results highlight the importance of dietary influences on fertility and suggest the need for additional research on the effects of F&amp;V intake on reproductive endpoints in women conceiving through infertility treatments.

Defining the Most Informative Intermediate Clinical Endpoints for Patients Treated with Salvage Radiotherapy for Prostate-specific Antigen Rise After Radical Prostatectomy

Intermediate clinical endpoints (ICEs) might aid in trial design and potentially expedite study results. However, little is known about the most informative ICE for patients receiving salvage radiation therapy (sRT) after radical prostatectomy. To investigate the most informative ICE for patients receiving sRT, we used a multi-institutional database encompassing patients treated at eight tertiary centers. Overall, 1301 men with node-negative disease who had not received any form of androgen deprivation therapy were identified. Associations of biochemical (BCR) and clinical recurrence (CR) within 1, 3, 5, and 7yr after surgery with the risk of overall mortality were evaluated using multivariable Cox regression analyses fitted at the landmark points of 1, 3, 5, and 7yr after sRT. The discriminative ability of each model for predicting overall survival (OS) was assessed using Harrell’s c index. Median follow-up for survivors was 5.6yr (interquartile range 2.0–8.8). On multivariable analysis, progression to CR within 3yr from sRT (hazard ratio 4.19, 95% confidence interval 1.44–11.2; p= 0.008) was the most informative ICE for predicting OS (c index 0.78) compared to CR within 1, 5, and 7yr (c index 0.72, 0.75, and 0.71). In conclusion, progression to CR within 3yr after sRT, irrespective of the time of surgery, was the most informative ICE for prediction of OS. Our study is hypothesis-generating. If these results are confirmed in future prospective studies and surrogacy is met, this information could be applied for study design and could potentially expedite earlier release of results from ongoing randomized controlled trials. Patient summaryClinical recurrence of prostate cancer within 3yr after salvage radiation therapy, irrespective of the time of radical prostatectomy, represents the most informative intermediate clinical endpoint for the prediction of overall survival. This information could be applied in the design of future studies and could potentially expedite earlier release of results from ongoing randomized controlled trials.

Defining the Most Informative Intermediate Clinical Endpoints for Predicting Overall Survival in Patients Treated with Radical Prostatectomy for High-risk Prostate Cancer

BackgroundGiven the prolonged natural history of clinically localized, high-risk prostate cancer, there is a need for the identification of intermediate clinical endpoints (ICEs) to predict long-term overall survival (OS). ObjectiveTo explore the role of novel potential ICEs based on clinical follow-up to predict long-term survival in patients with high-risk prostate cancer. Design, setting, and participantsOverall, 3507 patients treated at 12 tertiary referral centers between 1988 and 2016 were evaluated. InterventionRadical prostatectomy (RP) with extended pelvic lymph node dissection. Outcome measurements and statistical analysisThe impact of biochemical recurrence (BCR) and clinical recurrence (CR) within 1, 3, 5, and 7yr after surgery on the risk of OS was evaluated in multivariable Cox regression analyses. In patients with BCR, the impact of progression to CR within 6mo and 1, 3, and 5yr on long-term OS was investigated. Discrimination was assessed using Harrell's c index. Results and limitationsMedian follow-up for survivors was 76mo. The 5- and 10-yr OS and cancer-specific survival rates were 94% and 81% versus 98% and 95%, respectively. On a time-varying multivariable analysis, BCR (hazard ratio [HR]: 1.02; 95% confidence interval [CI]: 1.00, 1.04) and CR (HR: 1.05; 95% CI: 1.03–1.07) emerged as predictors of OS (p<0.001). The development of CR within 5yr after surgery was the most informative ICE for predicting OS (c index: 0.74). In patients with BCR, progression to CR within 12mo represented the most informative predictor for the subsequent risk of dying from all causes. Patients who developed BCR within 5yr after RP and progressed to CR within 12mo had a 10-yr OS rate of 47%. These results require prospective validation. ConclusionsWhen predicting long-term survival in surgically treated high-risk patients, progression to CR within 5yr of RP confers the highest discrimination with respect to other landmark points. In men experiencing BCR, progression to CR within the subsequent 12mo achieved the highest discrimination. Further studies are needed to validate our findings. Patient summaryWe investigated the most informative intermediate clinical endpoints for predicting overall survival (OS). Occurrence of clinical recurrence within 5yr after radical prostatectomy confers the highest discrimination to a model predicting OS.

Association of metastasis-free survival (MFS) and overall survival (OS) in nonmetastatic castration-resistant prostate cancer (nmCRPC).

5032Background: Intermediate clinical end points are needed for prostate cancer to inform clinical decisions and facilitate drug development. The international Intermediate Clinical Endpoints in Ca...

Adherence to the Mediterranean diet and IVF success rate among non-obese women attempting fertility.

Is adherence to the Mediterranean diet (MedDiet) associated with better IVF performance in women attempting fertility? Greater adherence to the MedDiet, defined using the validated Mediterranean diet score (MedDietScore), was associated with a higher likelihood of achieving clinical pregnancy and live birth among non-obese women <35 years of age. Diet impacts fertility and certain nutrients and food groups appear to have a greater effect on reproductive health, but there are relatively few published data on the role of dietary patterns, and the MedDiet in particular, on assisted reproductive performance. This prospective cohort study included 244 non-obese women (22-41 years of age; BMI < 30 kg/m2) who underwent a first IVF treatment in an Assisted Conception Unit in Athens, Greece, between November 2013 and September 2016. The study was designed to evaluate the influence of habitual dietary intake and lifestyle on fertility outcomes. Diet was assessed before the IVF treatment via a validated food-frequency questionnaire. Adherence to the MedDiet was assessed through the MedDietScore (range: 0-55), with higher scores indicating greater adherence. Intermediate outcomes (oocyte yield, fertilization rate and embryo quality measures) and clinical endpoints (implantation, clinical pregnancy and live birth) were abstracted from electronic medical records. Associations between MedDietScore and IVF outcomes were analysed using generalized linear models adjusting for age, ovarian stimulation protocol, BMI, physical activity, anxiety levels, infertility diagnosis, caloric intake and supplements use. No association of MedDietScore with any of the intermediate outcomes or with implantation was found. However, compared with women in the highest tertile of the MedDietScore (≥36, n = 86), women in the lowest tertile (≤30, n = 79) had significantly lower rates of clinical pregnancy (29.1 vs 50.0%, P = 0.01) and live birth (26.6 vs 48.8%, P = 0.01). The multivariable-adjusted relative risk (95% CI) for clinical pregnancy comparing women in the lowest with women in the highest tertile of the MedDietScore was 0.35 (0.16-0.78; P-trend=0.01), and for live birth it was 0.32 (0.14-0.71; P-trend = 0.01). These associations were significantly modified by women's age (P-interaction <0.01 for both outcomes). MedDietScore was positively related to clinical pregnancy and live birth among women <35 years old (P ≤ 0.01) but not among women ≥35 years. Among women <35 years, a beneficial 5-point increase in the MedDietScore was associated with ~2.7 times higher likelihood of achieving clinical pregnancy and live birth. Our finding cannot be generalized to the whole reproductive population nor to obese women nor to women attending infertility clinics around the world. In addition, due to the observational study design, causal inference is limited. The results suggest that diet modifications and greater compliance to the Mediterranean diet may help increase the chances of a successful pregnancy and delivering a live baby for women undergoing IVF treatment. This work was partially supported by a grand from Harokopio University (KE321). All authors declare no conflicts of interest. NCT03050944.

Intermediate Endpoints After Postprostatectomy Radiotherapy: 5-Year Distant Metastasis to Predict Overall Survival

BackgroundIntermediate clinical endpoints (ICEs) prognostic for overall survival (OS) are needed for men receiving postprostatectomy radiation therapy (PORT) to improve clinical trial design. ObjectiveTo identify a potential ICE for men receiving PORT. Design, setting, and participantsWe performed an institutional review board–approved multi-institutional retrospective study of 566 men consecutively treated with PORT at tertiary care centers from 1986 to 2013. The median follow-up was 8.2 yr. Outcome measurements and statistical analysisBiochemical failure (BF), distant metastases (DM), and castrate-resistant prostate cancer (CRPC) were evaluated for correlation with OS and assessed as time-dependent variables in a multivariable Cox proportional hazards model and in landmark analyses at 1, 3, 5, and 7 yr after PORT. Cross-validated concordance (c) indices were used to assess model discrimination. Results and limitationsOS at 1, 3, 5, and 7 yr after PORT was 98%, 95%, 90%, and 82%, respectively. In a time-varying model controlling for clinical and pathologic variables, BF (hazard ratio [HR] 2.32, 95% confidence interval [CI] 1.45–3.71; p<0.001), DM (HR 6.52, 95% CI 4.20–10.1; p<0.001), and CRPC (HR 2.47, 95% CI 1.56–3.92; p<0.001) were associated with OS. In landmark analyses, 5-yr DM had the highest c index when adjusting for baseline covariates (0.78), with 5-yr DM also providing the greatest increase in discriminatory power over a model only including baseline covariates. These findings require validation in prospective randomized data. ConclusionsWhile limited by the retrospective nature of the data, 5-yr DM is associated with lower OS following PORT, outperforming the prognostic capability of BF and CRPC at 1, 3, 5, or 7 yr after treatment. Confirmation of this ICE as a surrogate for OS is needed from randomized trial data so that it can be incorporated into future clinical trial design. Patient summaryWe assessed potential intermediate clinical endpoints prognostic for overall survival in a cohort of men receiving radiotherapy after prostatectomy. We identified the development of metastatic disease within 5 yr after treatment as the strongest predictor of overall survival.

Metastasis-Free Survival Is a Strong Surrogate of Overall Survival in Localized Prostate Cancer

Purpose Adjuvant therapy for intermediate-risk and high-risk localized prostate cancer decreases the number of deaths from this disease. Surrogates for overall survival (OS) could expedite the evaluation of new adjuvant therapies. Methods By June 2013, 102 completed or ongoing randomized trials were identified and individual patient data were collected from 28 trials with 28,905 patients. Disease-free survival (DFS) and metastasis-free survival (MFS) were determined for 21,140 patients from 24 trials and 12,712 patients from 19 trials, respectively. We evaluated the surrogacy of DFS and MFS for OS by using a two-stage meta-analytic validation model by determining the correlation of an intermediate clinical end point with OS and the correlation of treatment effects on both the intermediate clinical end point and OS. Results Trials enrolled patients from 1987 to 2011. After a median follow-up of 10 years, 45% of 21,140 men and 45% of 12,712 men experienced a DFS and MFS event, respectively. For DFS and MFS, 61% and 90% of the patients, respectively, were from radiation trials, and 63% and 66%, respectively, had high-risk disease. At the patient level, Kendall's τ correlation with OS was 0.85 and 0.91 for DFS and MFS, respectively. At the trial level, R2 was 0.86 (95% CI, 0.78 to 0.90) and 0.83 (95% CI, 0.71 to 0.88) from weighted linear regression of 8-year OS rates versus 5-year DFS and MFS rates, respectively. Treatment effects-measured by log hazard ratios-for the surrogates and OS were well correlated ( R2, 0.73 [95% CI, 0.53 to 0.82] for DFS and 0.92 [95% CI, 0.81 to 0.95] for MFS). Conclusion MFS is a strong surrogate for OS for localized prostate cancer that is associated with a significant risk of death from prostate cancer.