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.

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.

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.

scholarly journals New Therapeutics to Treat Castrate-Resistant Prostate Cancer

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Ömer Acar ◽  
Tarık Esen ◽  
Nathan A. Lack
Keyword(s):  
Prostate Cancer ◽  
Late Stage ◽  
Endocrine Disruptor ◽  
Patient Survival ◽  
Abiraterone Acetate ◽  
Phase Iii ◽  
Bone Targeting ◽  
Phase Iii Trials ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

The effective treatment of castrate-resistant prostate cancer (CRPC) has proven to be very challenging. Until recently, docetaxel was the only therapeutic demonstrated to extend overall patient survival. Yet recently, a considerable number of new therapeutics have been approved to treat CRPC patients. These remarkable advances now give new tools for the therapeutic management of late-stage prostate cancer. In this review, we will examine mechanistic and clinical data of several newly approved therapeutics including the chemotherapeutic cabazitaxel, antiandrogen enzalutamide, endocrine disruptor abiraterone acetate, immunotherapy sipuleucel-T, and bone-targeting radiopharmaceutical alpharadin. In addition, we will examine other promising therapeutics that are currently in Phase III trials.

scholarly journals Metastatic Castration-Resistant Prostate Cancer: Critical Review of Enzalutamide

2013 ◽  
Vol 7 ◽  
pp. CMO.S11670 ◽  
Author(s):  
Joelle El-Amm ◽  
Nihar Patel ◽  
Ashley Freeman ◽  
Jeanny B. Aragon-Ching
Keyword(s):  
Prostate Cancer ◽  
Clinical Trials ◽  
Survival Benefit ◽  
First Generation ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant ◽  
Overall Survival Benefit

Enzalutamide, previously known as MDV300, is an oral, second-generation androgen receptor (AR) signaling inhibitor or antagonist that was approved by the Food and Drug Administration in 2012 for the treatment of metastatic castrate-resistant prostate cancer (mCRPC) postdocetaxel. Preclinical studies have demonstrated impressive affinity to the AR compared to the first-generation AR inhibitors. The landmark Phase III AFFIRM trial demonstrated improved overall survival benefit compared to placebo in addition to improvement in all tested parameters. Enzalutamide is currently being studied in several trials prechemotherapy and in earlier settings of prostate cancer. This review will discuss the mechanism of action of enzalutamide, its pharmacokinetics, the preclinical and clinical trials that led to its approval, the ongoing clinical trials, its safety and efficacy, as well as patterns of resistance, and discusses its place in therapy within the context of several recently approved agents for mCRPC.

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.

The sequential use of abiraterone and enzalutamide in metastatic castrate resistant prostate cancer patients: Experience from seven U.K. centers.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 125-125 ◽  
Author(s):  
Robert Stevenson ◽  
David Gareth Fackrell ◽  
Daniel Ford ◽  
John Glaholm ◽  
Ahmed El-Modir ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Randomised Trial ◽  
Specific Antigen ◽  
Phase Iii ◽  
Early Access ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant ◽  
The Uk ◽  
Taxane Chemotherapy ◽  
Patients Experience

125 Background: Phase III studies have demonstrated survival benefits from abiraterone (Abi), and enzalutamide (Enz) following disease progression in metastatic castrate resistant prostate cancer (mCRPC). Abi is now available for treatment of mCRPC in the UK in patients previously treated with docetaxel. Enz has recently become available, via the UK cancer drugs fund (CDF), for progressive disease post docetaxel, prior to exposure to Abi. There has been no randomised trial on sequential usage of Enz post-Abi. We therefore, report the experience of hospitals in Coventry, Cardiff, and five centers in Birmingham. Methods: We searched the pharmacy database for patients who have received Enz as part of an early access scheme, and identified 79 patients who started treatment between the August 2012 and April 2013. A detailed notes review was carried out of these patients. Results: Median age was 74 (range of 55 to 87). All patients had received hormone androgen deprivation therapy and taxane chemotherapy (docetaxel and/or cabazitaxel) 75 patients had received previous Abi, 62 of these patients receiving Abi as the last treatment prior to Enz. The mean time to progression (TTP) for Abi in these 62 patients was 37.44 weeks (range 4 to 104). At the time of submission 55 patients had stopped Enz due to prostate-specific antigen progression with a mean TTP of 15.87 weeks and 28 patients had died. Conclusions: The AFFIRM study demonstrated TTP of 36 weeks in patients post-docetaxel. In this audit of patients receiving Enz post-Abi the TTP was only 15.87 weeks, suggesting possible reduced efficacy in patients receiving Enz post-Abi and docetaxel. Trials are underway comparing Abi alone or in combination with Enz which may improve efficacy.

Diagnosis and management of prostate cancer in the older man

2010 ◽  
Vol 20 (3) ◽  
pp. 193-204
Author(s):  
SRC McCracken ◽  
GC Durkan ◽  
RS Pickard ◽  
CN Robson
Keyword(s):  
Prostate Cancer ◽  
Clinical Trials ◽  
Treatment Options ◽  
Phase Iii ◽  
Phase Iii Clinical Trials ◽  
Novel Drugs ◽  
Castrate Resistant Prostate Cancer ◽  
The Mean ◽  
Castrate Resistant ◽  
Common Malignancy

SummaryProstate cancer is the most common malignancy and the second leading cause of cancer death, in men, in western countries. Prostate cancer is diagnosed in very few people aged younger than 50 years (<0.1% of all patients). The mean age of patients with this disorder is 72–74 years. Most men aged older than 85 years have histological prostate cancer. Androgen deprivation reduces tumour activity in approximately 80% of patients with advanced disease, but most tumours relapse within 2 years to an incurable castrate-resistant state. Treatment options for patients with castrate-resistant prostate cancer are very limited and, even with toxic therapy, such as docetaxel, the life expectancy is only improved by a median of 2 months. Hence earlier diagnosis and improved treatments for prostate cancer are urgently required. Novel drugs, such as Abiratorone acetate and MDV-3100 have shown promise in pre-clinical and early clinical trials, and a number are now in phase III clinical trials, alone or in combination with docetaxel.

Association of health-related quality of life (HRQOL) variations with biological biomarkers for patients with metastatic castrate-resistant prostate cancer (MCRPC) treated by abiraterone/prednisone combination or prednisone.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 54-54
Author(s):  
Morgan Goujon ◽  
Amelie Anota ◽  
Alexandre Frontczak ◽  
Emilie Charton ◽  
Tristan Maurina ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Prostate Cancer ◽  
Phase Iii ◽  
Health Related Quality ◽  
Meaningful Improvement ◽  
Related Quality ◽  
Health Related ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

54 Background: A potential link between Health-Related Quality of life (HRQoL) and oncologic outcomes such as overall survival or progression-free survival has been underlined for endocrine therapies in patients with metastatic castrate resistant prostate cancer (mCRPC). Other surrogates such as circulating tumor cells (CTCs) or PSA can be used to evaluate disease control. This study explored the associations between HRQoL and biological biomarkers for patients with mCRPC treated by abiraterone / prednisone or prednisone within registration phase III trial COU-AA-301. Methods: Baseline differences of HRQoL evaluated with FACT-P total score (FACT-P TS) according to biological parameters (including CTCs and PSA) and links between HRQoL's change and variations of these parameters were assessed. The primary objective was to estimate the association between improvement or deterioration in FACT-P TS and the variations of CTCs and PSA. All analyses were conducted using clinically meaningful improvement and deterioration in FACT-P TS and subscales. Results: Among 1130 patients enrolled, 1111 (98.3%) had a baseline FACT-P TS available. At baseline, a favorable CTCs count was associated with higher FACT-P TS compared to unfavorable CTCs (difference in means 8 points, [95% CI, 4 to 12] p < 0.001). At 3 months, there were differences in mean change from baseline FACT-P TS favoring patients with biomarkers response, with clinically meaningful difference for CTCs (12.7 points, [95% CI, 6 to 19.5%] p < 0.001) and PSA (11.64 points, [95% CI, 9.3 to 14] p < 0.0001). Biological progression was associated with higher risk of FACT-P TS worsening for PSA (Odds Ratio (OR) 2.8 [95% CI, 1.9 to 4.2]) with more frequent FACT-P TS improvement in case of response for CTCs (OR 3.14 [95% CI, 1.3 to 7.7]) and PSA (OR 2.9 [95% CI 2.1 to 4]). Significantly longer time until definitive deterioration was observed for patients with CTCs or PSA response (p < 0.001) and shorter time in case of progression (p < 0.001). Conclusions: QUA-lify is the first study to show an association between HRQoL and biomarkers outcomes in patients with mCRPC treated with endocrine therapy in a post-taxane setting. This concept is reinforced by the consistency of the association for all analyses carried out.

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