Radiographic progression-free survival as a surrogate endpoint of overall survival in men with metastatic castrate-resistant prostate cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5057-5057
Author(s):  
Susan Halabi ◽  
Akash Roy ◽  
Qian Yang ◽  
Wanling Xie ◽  
William Kevin Kelly ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Radiographic Progression ◽  
Progression Free Survival ◽  
Surrogate Endpoint ◽  
Phase Iii ◽  
Random Assignment ◽  
Moderate Correlation ◽  
Free Survival ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

5057 Background: Radiographic progression-free survival (rPFS) is commonly used as a co-primary endpoint in randomized clinical trials in men with metastatic castrate-resistant prostate cancer (mCRPC). However, rPFS has not been established as a valid surrogate endpoint of overall survival (OS) in men with mCRPC. Here, we hypothesized that rPFS is a reliable surrogate for OS in mCRPC. We also explored whether PFS is a valid surrogate endpoint of OS at the aggregate trial level. Methods: We performed a systematic search of the literature encompassing the period January 2004-December 2020 using PubMed and clinical trials.gov to identify completed phase III trials in mCRPC post-docetaxel. Eligible trials had to be randomized phase III therapeutic trials that reported OS, PFS or rPFS. OS was measured from the date of random assignment to date of death from any cause or date of last follow-up. rPFS was defined as the time from random assignment to date of disease progression on CT and/or Tc bone scan per trial definition or death from any cause, whichever occurred first. PFS included PSA progression as a component of the composite endpoint. Trial level surrogacy was evaluated by fitting linear regression on the treatment effect of rPFS (or PFS) and OS (in other words, the weighted linear regression of the log(hazard ratio) of OS on the log(hazard ratio) of rPFS). It was pre-specified that rPFS would be considered a valid surrogate for OS if R² was 0·7 or higher. Results: We identified 33 in men with mCRPC post docetaxel approval. We assessed the association between PFS and OS in 29,456 patients from 30 trials. Overall, a moderate correlation was observed at the trial level between OS and PFS ( R2 = 0.46, 95 %CI = 0.20-0.68) in these trials. In 18 trials with 16,818 mCRPC patients where rPFS was considered as a key endpoint, a moderate correlation between the treatment effects on rPFS and OS was observed at the trial level ( R2= 0.65, 95% CI = 0.23-0.87). Conclusions: This meta-analysis demonstrates moderate correlation between treatment effects of rPFS and OS in patients with mCRPC. However, rPFS did not meet the pre-specified surrogacy threshold of 0.7. Clinical trial information: several.

Postdocetaxel treatment for castrate-resistant prostate cancer: The sequential use of abiraterone and cabazitaxe.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 234-234 ◽  
Author(s):  
David Gareth Fackrell ◽  
Nicholas David James ◽  
Daniel Ford
Keyword(s):  
Prostate Cancer ◽  
Survival Benefit ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Free Survival ◽  
Select Group ◽  
Phase Iii Trials ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant ◽  
The Uk

234 Background: Large phase III trials have shown both abiraterone (Abi) and cabazitaxel (Cbz) to have a survival benefit in patients with metastatic castrate resistant prostate cancer (mCRPC). They are now used routinely throughout the UK in this setting. The mechanisms of resistance of these drugs remain unclear and therefore, their sequential use is less recognised. We present data from patients who have been exposed to both therapies. Methods: In this retrospective study, we searched our own pharmacy databases to identify all patients that had been exposed to both Abi and Cbz. All patients were treated between April 2009 and October 2012. A total of 21 patients were reviewed and clinical data was collected. SPSS software was used to create Kaplan Meier curves. Results: 17 of the 21 patients received Abi before Caz. Median progression free survival for patients on the sequential regimes was 16.9 months (95% Confidence interval: 10.5-23.3). Reviewing the drugs individually found progression free survival was 5.1 months (4.4-6.0 months) with Abi and 7.1 months (5.1-9.1) with Cbz. Conclusions: In a select group of patients who are fit enough to receive both drugs, superior progression free survival is seen than can be expected on one drug alone. The data compares favourably to that seen in the TROPIC study where time to progression on Cbz was 2.8 months. Furthermore, lack of response to one drug did not preclude worthwhile response to the other agent. These findings are consistent with the drugs having separate mechanisms. At this stage the series is not mature enough to draw conclusions on survival benefit. An updated series, involving larger patient numbers, will be presented at the meeting.

scholarly journals Enzalutamide in Metastatic Prostate Cancer Before Chemotherapy

2021 ◽  
pp. 101-106
Author(s):  
Joseph Zabell
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Metastatic Prostate Cancer ◽  
Radiographic Progression ◽  
Progression Free Survival ◽  
Cytotoxic Chemotherapy ◽  
Free Survival ◽  
Prior Chemotherapy ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

This chapter summarizes the findings of the landmark PREVAIL trial conducted in men with castrate-resistant prostate cancer who had received prior chemotherapy comparing enzalutamide to placebo. It demonstrated improved overall survival, radiographic progression-free survival, and time to cytotoxic chemotherapy.

Racial disparities in utilization and effectiveness of first-line therapies in metastatic castrate-resistant prostate cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e17541-e17541
Author(s):  
Mallika Marar ◽  
Ronac Mamtani ◽  
Vivek Narayan ◽  
Neha Vapiwala ◽  
Ravi Bharat Parikh
Keyword(s):  
Prostate Cancer ◽  
Racial Disparities ◽  
Real World ◽  
Progression Free Survival ◽  
White Men ◽  
First Line ◽  
Free Survival ◽  
All Cause Mortality ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

e17541 Background: Prospective evidence suggests that abiraterone use is associated with improved progression-free survival in African-American (AA) men with metastatic castrate-resistant prostate cancer (mCRPC) compared to white men. It is unclear whether race-based differences in treatment utilization and effectiveness exist for men with newly diagnosed mCRPC treated in real-world clinical practice. Methods: In this retrospective cohort study, we used the Flatiron Health electronic health record-derived de-identified database to identify patients with mCRPC who received first-line (1L) systemic therapy between 2012 and 2018. We used multivariable logistic regression analysis to examine differences in utilization of abiraterone, enzalutamide, and docetaxel between AA and white men. We then used Fine-Gray models with death as a competing risk to assess treatment-specific associations between race and time to next therapy (TTNT) – a proxy for progression-free survival. Finally, we used multivariable Cox proportional hazards analyses to assess for treatment-specific racial disparities in all-cause mortality. All analyses were adjusted for age, Elixhauser comorbidity index, baseline steroid or opioid use (a proxy for disease aggressiveness), performance status, insurance status, and (if significant) an interaction term for race and age. Results: Of 3,808 mCRPC patients in the cohort, 2,165 (68.7%) were white and 404 (10.6%) were AA. At time of metastatic diagnosis, AA men were younger (69 vs. 75, p < 0.001) and more likely to have PSA value greater than 50 (57.9% vs. 42.6%, p < 0.001) compared to white men. Median follow up was 15 months. There were no significant racial differences in 1L utilization, TTNT, or all-cause mortality associated with abiraterone, enzalutamide, or docetaxel use (Table). Conclusions: In this large real-world analysis of men with mCRPC who received 1L therapy, we found no significant treatment-specific differences in utilization, TTNT, or all-cause mortality between AA and white men. Long-term prospective evidence is needed to justify differential treatment selection for AA men with mCRPC. [Table: see text]

Prevalence of ARV7 in Asian metastatic castrate-resistant prostate cancer (mCRPC) patients using multiple detection platforms.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 245-245
Author(s):  
Johan Chan ◽  
Whee Sze Ong ◽  
Quan Sing Ng ◽  
Chee-Keong Toh ◽  
Tanujaa Rajasekaran ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Lower Risk ◽  
Progression Free Survival ◽  
Detection Methods ◽  
Free Survival ◽  
Blood Samples ◽  
Psa Response ◽  
Castrate Resistant Prostate Cancer ◽  
Psa Progression ◽  
Castrate Resistant

245 Background: The presence of AR-V7 in metastatic castrate resistant prostate cancer (mCRPC) men has been associated with worse outcome in men initiated on 2nd generation androgen receptor signalling inhibitors (ARSI) in the Caucasian population. A multinational study was conducted to investigate this in the Asian population. Methods: mCRPC patients were recruited prospectively across 5 countries. Blood samples were collected and processed from patients with progressive disease immediately before the initiation of a new treatment and at progression. AR-V7 detection were performed using 3 methods: CTC enrichment followed by automated immunofluorescent staining (Clearbridge [CB]), CTC enrichment followed by reverse-transcription PCR analysis (IBN), and the AdnaTest Prostate Cancer(Adna) platform for CTC analysis and detection. Only blood samples collected in Singapore underwent all 3 methods of detecting AR-V7. Comparison of AR-V7 prevalence using the 3 detection methods were done on patients with the AdnaTest platform as gold standard. We examined associations between AR-V7 status and PSA response rates, PSA progression free survival and overall survival(OS). Results: 102 patients were recruited. 72 patients had ARSi while 30 patients had chemotherapy. 66 patients were included for the comparison of AR-V7 detection methods. AR-V7 prevalence rate was 14.3% (95% CI 4.8-30.3), 21.6% (95% CI 12.9-32.7) and 33.7% (95% CI 24.6-43.8) based on Adna, CB and IBN respectively. Concordance between Adna and CB was 75% while Adna and IBN was 68%. AR-V7- patients had a trend towards higher PSA response, lower risk of PSA progression as compared to AR-V7+ patients. AR-V7- patients had a significantly lower risk of death as compared to AR-V7+ patients detected by Adna and IBN platforms but not the CB platform. The association between ARV7 status and outcomes did not vary when compared across treatment groups. Conclusions: AR-V7 positivity in Asian mCRPC patients is consistent with the data reported in Western populations with lower PSA response rates, PSA progression free survival and OS. This data suggest that ARV7 is more likely a prognostic than a predictive biomarker. Clinical trial information: 2015/2797.

scholarly journals Identification of subgroups of metastatic castrate-resistant prostate cancer (mCRPC) patients treated with abiraterone plus prednisone at low- vs. high-risk of radiographic progression: An analysis of COU-AA-302

2018 ◽  
Vol 13 (6) ◽  
Author(s):  
Lisa J. Martin ◽  
Shabbir M.H. Alibhai ◽  
Maria Komisarenko ◽  
Narhari Timilshina ◽  
Antonio Finelli
Keyword(s):  
Prostate Cancer ◽  
Radiographic Progression ◽  
Proportional Hazards ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
Limited Resource ◽  
Abiraterone Acetate ◽  
Cox Proportional Hazards ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

Introduction: Radiographic imaging is used to monitor disease progression for men with metastatic castrate-resistant prostate cancer (mCRPC). The optimal frequency of imaging, a costly and limited resource, is not known. Our objective was to identify predictors of radiographic progression to inform the frequency of imaging for men with mCRPC. Methods: We accessed data for men with chemotherapy-naive mCRPC in the abiraterone acetate plus prednisone (AA-P) group of a randomized trial (COU-AA-302) (n=546). We used Cox proportional hazards modelling to identify predictors of time to progression. We divided patients into groups based on the most important predictors and estimated the probability of radiographic progression-free survival (RPFS) at six and 12 months. Results: Baseline disease and change in prostate-specific antigen (PSA) at eight weeks were the strongest determinants of RPFS. The probability of RPFS for men with bone-only disease and a ≥50% fall in PSA was 93% (95% confidence interval [CI] 87–96) at six months and 80% (95% CI 72–86) at 12 months. In contrast, the probability of RPFS for men with bone and soft tissue metastasis and <50% fall in PSA was 55% (95% CI 41–67) at six months and 34% (95% CI 22–47) at 12 months. These findings should be externally validated. Conclusions: Patients with chemotherapy-naive mCRPC treated with first-line AA-P can be divided into groups with significantly different risks of radiographic progression based on a few clinically available variables, suggesting that imaging schedules could be individualized.

scholarly journals Apalutamide in the treatment of castrate-resistant prostate cancer: evidence from clinical trials

2018 ◽  
Vol 10 (12) ◽  
pp. 445-454 ◽  
Author(s):  
Vadim S. Koshkin ◽  
Eric J. Small
Keyword(s):  
Prostate Cancer ◽  
Clinical Trials ◽  
Specific Antigen ◽  
The United States ◽  
Phase Iii ◽  
Metastatic Progression ◽  
Free Survival ◽  
Phase Iii Trials ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

Apalutamide (ARN-509) is a second-generation androgen receptor (AR) antagonist that was developed to inhibit AR-mediated prostate cancer cell proliferation. Following the initial promising clinical efficacy results in phase I and II clinical trials of patients with metastatic castrate-resistant prostate cancer (CRPC), apalutamide has been investigated in several phase III trials. Particular interest has focused on the development of effective therapy for the prevention of disease progression in patients with nonmetastatic (nm or M0) CRPC, especially patients who have a rapid prostate-specific antigen (PSA) doubling time that is indicative of shorter bone metastasis-free survival and associated with significant morbidity and mortality. The results from the phase III SPARTAN trial were recently published and reported a significant benefit of apalutamide relative to placebo in patients with nmCRPC and a high risk of metastatic progression. The study noted marked improvement in the primary endpoint of metastasis-free survival as well as several relevant secondary clinical endpoints, including time to symptomatic progression. These results led to the United States Food and Drug Administration (US FDA) approval of apalutamide in the nmCRPC setting in February 2018. This review summarizes the clinical development of apalutamide, culminating with the pivotal SPARTAN trial as well as other phase III trials which may further expand potential indications for this agent in the near future.

Progression free survival in patients with castrate resistant metastatic prostate cancer: Does sequence matter?

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 356-356
Author(s):  
Adam McLain Kase ◽  
Cheryl Cook ◽  
Winston Tan
Keyword(s):  
Prostate Cancer ◽  
Chart Review ◽  
Progression Free Survival ◽  
Second Line ◽  
First Line ◽  
Free Survival ◽  
First Line Therapy ◽  
Line Therapy ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

356 Background: Approval of multiple therapeutic agents for castrate resistant prostate cancer (CPRPC) has improved survival and also quality of life. However, how to optimize sequencing is still an ongoing challenge for most clinicians. Methods: A retrospective chart review of patients treated with FDA approved regimens for castrate resistant prostate cancer from 2002 to 2017 at Mayo Clinical Florida was completed. Data on progression free survival of the various treatment sequences including abiraterone, docetaxel, and enzalutamide were reviewed. Results: One hundred patients were included in the study. Those on clinical trial were excluded. All patients were on LHRH agonist /antagonist and were continued while on the subsequent treatments. The first line therapy progression free survival (PFS) was 245 days with abiraterone acetate (AA), 307 days with enzalutamide (E) and docetaxel 285 days, respectively. The second line therapy PFS was 201 days with AA and 166 days with E. When AA was given after E PFS was 97 days and when E was given after AA the PFS was 68 days. E given after docetaxel resulted in a PFS of 390 days for one patient. Conclusions: In this chart review, enzalutamide had the longest PFS when used as the first line therapy and the PFS was improved when used as a second line after docetaxel. This retrospective review suggests therapy sequencing may be optimized to increase progressive free survival in patients with metastatic castrate resistant prostate cancer.

scholarly journals Progression-Free Survival as a Predictor of Overall Survival in Men With Castrate-Resistant Prostate Cancer

2009 ◽  
Vol 27 (17) ◽  
pp. 2766-2771 ◽  
Author(s):  
Susan Halabi ◽  
Nicholas J. Vogelzang ◽  
San-San Ou ◽  
Kouros Owzar ◽  
Laura Archer ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Proportional Hazards ◽  
Proportional Hazards Model ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
Free Survival ◽  
Castrate Resistant Prostate Cancer ◽  
Biochemical Progression ◽  
Castrate Resistant

Purpose To explore whether progression-free survival (PFS) or biochemical PFS can be used as a predictor of overall survival (OS) and to investigate the dependence between PFS and OS in men with castrate-resistant prostate cancer. Patients and Methods Data from nine Cancer and Leukemia Group B trials that enrolled 1,296 men from 1991 to 2004 were pooled. Men were eligible if they had prostate cancer that had progressed during androgen deprivation therapy and did not receive prior treatment with chemotherapy, immunotherapy, or other nonhormonal therapy. Landmark analyses of PFS at 3 and 6 months from randomization/registration were performed to minimize lead time bias. The proportional hazards model was used to assess the significance effect of PFS rate at 3 and at 6 months in predicting OS. In addition, biochemical progression using the definitions of Prostate-Specific Antigen Working Group (PSAW) Criteria PSAWG1 and PSAWG2 were analyzed as time-dependent covariates in predicting OS. Results The median survival time among men who experienced progression at 3 months was 9.2 months (95% CI, 8.0 to 10.0 months) compared with 17.8 months in men who did not experience progression at 3 months (95% CI, 16.2 to 20.4 months; P < .0001). Compared with men who did not progress at 3 and at 6 months, the adjusted hazard ratios for death were 2.0 (95% CI, 1.7 to 2.4; P < .001) and 1.9 (95% CI, 1.6 to 2.4; P < .001) for men who experienced progression at 3 and 6 months, respectively. In addition, biochemical progression at 3 months predicted OS. The association between PFS and OS was 0.30 (95% confidence limits = 0.26, 0.32). Conclusion PFS at 3 and 6 months and biochemical progression at 3 months predict OS. These observations require prospective validation.

SWOG S0421: Phase III study of docetaxel (D) and atrasentan (A) versus docetaxel and placebo (P) for men with advanced castrate resistant prostate cancer (CRPC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4511-4511 ◽  
Author(s):  
David I. Quinn ◽  
Catherine M. Tangen ◽  
Maha Hussain ◽  
Primo Lara ◽  
Amir Goldkorn ◽  
...  
Keyword(s):  
Bone Markers ◽  
Progression Free Survival ◽  
Circulating Tumor Cell ◽  
Phase Iii ◽  
Endothelin Receptor ◽  
Free Survival ◽  
Primary Endpoints ◽  
Phase Iii Study ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

4511 Background: The endothelin pathway has a mechanistic role in bone metastases (mets). Atrasentan (A), an endothelin receptor antagonist, has reported activity in CRPC. This trial tested the survival impact of A + docetaxel (D) vs. D+ placebo (P) in CRPC pts with bone mets. Methods: Eligible CRPC pts, stratified for progression type, baseline pain index (BPI), extraskeletal mets and bisphosphonate (BisP) use, were randomized 1:1 to D+A vs. D+P for 12 3-wk cycles. Non-progressors could continue blinded drug alone for 16 more wks. Co-primary endpoints: overall (OS) and progression-free survival (PFS). 930 pts were needed to detect a 25% increase in med OS with D+A (1-sided log-rank, α=0.025, 87% power). Results: 991/1,038 pts were eligible: med age 69, 16% non-white, 61% on BisP, 31% prior prostatectomy, 42% worst pain by BPI ≥ 4, 20% PSA only progression and 56% extraskeletal mets. Multivariate analysis of baseline prognostic factors predicting worse OS were: measurable or evaluable disease progression, high BPI and extraskeletal mets (all p<0.02). No differences in median OS, PFS, or response between arms. Toxicities were similar between arms. Most common toxicities were fatigue, dyspnea, neutropenia and anemia. Addition of A trended to worse OS in pts with visceral mets (HR=1.13 p=0.21) and better OS in those without: bone only (HR=0.86, p=0.20). 357 pts continued A or P up to 52 weeks, no OS difference was seen post-chemo for this subset (p=0.92). Conclusions: This phase III study found no benefit for the addition of A to D in CRPC. Unless specific biomarkers can stratify a population for benefit, endothelin modulators have limited future use in advanced CRPC. Further analyses will test putative surrogacy effects of PSA, serum bone markers and circulating tumor cell kinetics for OS. [Table: see text]

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