Treatment of non-metastatic castration-resistant prostate cancer: focus on apalutamide.
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ABSTRACT:
SUBMITTER: Gul A
PROVIDER: S-EPMC6682169 | biostudies-literature | 2019
REPOSITORIES: biostudies-literature
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Treatment of non-metastatic castration-resistant prostate cancer: focus on apalutamide.
Gul Anita A Garcia Jorge A JA Barata Pedro C PC
Cancer management and research 20190801
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 dis ...[more]
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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: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:Management of non-metastatic castration-resistant prostate cancer (nmCRPC) has undergone a paradigm shift with next-generation androgen receptor inhibitors. However, direct comparative data are not available to inform treatment decisions and/or guideline recommendations. Therefore, we performed network meta-analysis to indirectly compare the efficacy and safety of currently available treatments. Multiple databases were searched for articles published before June 2020. Studies that compared overall and/or metastasis-free and/or prostate-specific antigen (PSA) progression-free survival (OS/MFS/PSA-PFS) and/or adverse events (AEs) in nmCRPC patients were considered eligible. Three studies (n = 4117) met our eligibility criteria. Formal network meta-analyses were conducted. For MFS, apalutamide, darolutamide, and enzalutamide were significantly more effective than placebo, and apalutamide emerged as the best option (P score: 0.8809). Apalutamide [hazard ratio (HR): 0.85, 95% credible interval (CrI): 0.77-0.94] and enzalutamide (HR: 0.86, 95% CrI: 0.78-0.95) were both significantly more effective than darolutamide. For PSA-PFS, all three agents were statistically superior to placebo, and apalutamide emerged as the likely preferred option (P score: 1.000). Apalutamide (HR: 0.71, 95% CrI: 0.69-0.74) and enzalutamide (HR: 0.76, 95% CrI: 0.74-0.79) were both significantly more effective than darolutamide. For AEs (including all AEs, grade 3 or grade 4 AEs, grade 5 AEs, and discontinuation rates), darolutamide was the likely best option. Apalutamide and enzalutamide appear to be more efficacious agents for therapy of nmCRPC, while darolutamide appears to have the most favorable tolerability profile. These findings may facilitate individualized treatment strategies and inform future direct comparative trials.
| S-EPMC7572325 | biostudies-literature
Project description:INTRODUCTION:Apalutamide and enzalutamide are next-generation androgen receptor inhibitors that demonstrated efficacy in placebo-controlled studies (SPARTAN for apalutamide; PROSPER for enzalutamide) when used in combination with androgen deprivation therapy (ADT) for treatment of non-metastatic castration-resistant prostate cancer (nmCRPC). In the absence of comparative studies between these agents, the present study sought to indirectly compare metastasis-free survival (MFS) and overall survival (OS) in patients with nmCRPC who received these therapies. METHODS:Individual patient-level data from SPARTAN (apalutamide plus ADT) and published data from PROSPER (enzalutamide plus ADT) were utilized. An anchored matching-adjusted indirect comparison (MAIC) was conducted by weighting the patients from the SPARTAN study to match baseline characteristics reported for PROSPER. Hazard ratios (HRs) for MFS and OS were re-estimated for SPARTAN using weighted Cox proportional hazards models and indirectly compared with those of PROSPER using a Bayesian network meta-analysis. RESULTS:From the SPARTAN population (N?=?1207), a total of 1171 patients were matched to the PROSPER population (N?=?1401). The recalculated HRs (95% confidence interval) for apalutamide versus ADT based on the reweighted SPARTAN data to mimic the PROSPER patient population were 0.26 (0.21; 0.33) for MFS and 0.62 (0.41; 0.94) for OS. MAIC-based HRs (95% credible interval) for apalutamide versus enzalutamide were 0.91 (0.68; 1.22) for MFS and 0.77 (0.46; 1.30) for OS. The Bayesian probabilities of apalutamide being more effective than enzalutamide were 73.6% for MFS and 83.5% for OS. CONCLUSIONS:MAIC results suggest that nmCRPC patients treated with apalutamide have a higher probability of a more favorable MFS and OS compared with those treated with enzalutamide.
| S-EPMC6979453 | biostudies-literature
Project description:IntroductionApalutamide and darolutamide are next-generation androgen receptor inhibitors that have demonstrated superior efficacy compared to placebo in men with non-metastatic castration-resistant prostate cancer (nmCRPC) receiving androgen deprivation therapy (ADT). In the absence of head-to-head studies, the present study sought to indirectly compare the efficacy and tolerability between these two treatments.MethodsThis anchored matching-adjusted indirect comparison (MAIC) used patient-level data from the phase 3, randomized, controlled SPARTAN study (apalutamide + ADT), weighted to match aggregate published data from the ARAMIS study (darolutamide + ADT) for clinically relevant baseline measures. Hazard ratios (HR) and 95% credible intervals (CrI) were estimated for efficacy endpoints: metastasis-free survival (MFS), prostate-specific antigen (PSA) progression, progression-free survival (PFS), and overall survival (OS). Odds ratios were estimated for tolerability outcomes: adverse events and serious adverse events.ResultsBefore weighting, baseline characteristics from SPARTAN versus ARAMIS were different for median PSA (7.8 vs. 9.2 ng/mL), Eastern Cooperative Oncology Group performance status of 1 (23% vs. 31%), use of bone-targeted agents (10% vs. 4%), median time from initial diagnosis (94.9 vs. 85.4 months), and proportion of patients from North America (35% vs. 12%) and Europe (50% vs. 64%). After matching (n = 455), our analysis demonstrated that apalutamide + ADT had a Bayesian probability of being more effective than darolutamide + ADT for MFS [98.3%; HR 0.70 (95% CrI 0.51, 0.98)], PSA progression [~ 100%; HR 0.46 (95% CrI 0.33, 0.64)], and PFS [93.2%; HR 0.79 (95% CrI 0.59, 1.08)]. Results for OS and tolerability were similar between apalutamide + ADT and darolutamide + ADT.ConclusionThis anchored MAIC analysis of pivotal phase 3 studies in patients with nmCRPC suggests that apalutamide + ADT is more effective than darolutamide + ADT for MFS, progression-free survival (PFS), and prostate-specific antigen (PSA) progression, with a similar OS benefit and tolerability profile.Trial registrationARAMIS ClinicalTrials.gov number: NCT02200614; SPARTAN ClinicalTrials.gov number: NCT01946204.
| S-EPMC8799579 | biostudies-literature
Project description:The arrival of several new agents--cabazitaxel, abiraterone acetate, enzalutamide, and radium-223--is changing the treatment options and management of patients with metastatic castration-resistant prostate cancer (mCRPC). Many other novel agents are also being investigated. As new drugs become approved, new treatment strategies and markers to best select which patients will best respond to which drug are needed. This review article is a summary of a European Treatment Practices Meeting, which was convened to discuss these latest data on novel agents and current treatment strategies in the mCRPC setting.
| S-EPMC3662847 | biostudies-other
Project description:Non-metastatic castration-resistant prostate cancer (nmCRPC) is a heterogeneous disease with variable potential in developing into overt metastases. It is an area of increased unmet need in advanced prostate cancer and for which there had been no great treatments until recent US Food and Drug Administration (FDA) approval of 2 novel anti-androgens apalutamide and enzalutamide, which were both approved given benefit in metastasis-free survival. Early data on the use of darolutamide, another novel anti-androgen, are also explored. This review discusses the pivotal trials that led to the approval of apalutamide and enzalutamide in the nmCRPC setting and discusses the key promises and challenges with the use of these agents.
| S-EPMC6407161 | biostudies-literature
Project description:In the past 4 years, five new agents have been approved for metastatic, castration-resistant prostate cancer. Four of them are non-chemotherapeutic and generally well tolerated. However, each has toxicities that can negatively impact patients, particularly the elderly. This review covers the epidemiology of prostate cancer in elderly men. It discusses the efficacy data for sipuleucel-T, abiraterone in chemotherapy-naïve patients, enzalutamide in chemotherapy-naïve patients and radium-223 and presents any additional studies done for those over 75 years of age. Disease burden, such as the presence or absence of visceral disease, and comorbid conditions weigh into the selection of therapy and are discussed here. Drug-drug interactions between these agents and other drugs commonly used in the elderly population are also considered. The emerging therapies tasquinimod and ipilimumab are reviewed. With the arrival of so many agents for prostate cancer, selection of the most appropriate agent can be perplexing, particularly because these agents were tested against placebo, not one another. Furthermore, the study population differs significantly from those seen in clinical practice. This review addresses these issues.
| S-EPMC4418948 | biostudies-literature
Project description:ImportanceThere is a need to identify prognostic biomarkers to guide treatment intensification in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC).ObjectiveTo examine whether molecular subtypes predict response to apalutamide, using archived primary tumor samples from the randomized, double-blind, phase 3 SPARTAN trial.Design, setting, and participantsIn this cohort study, gene expression data from 233 archived samples from patients with nmCRPC enrolled in the SPARTAN trial were generated using a human exon microarray. The present analysis was conducted from May 10, 2018, to October 15, 2020.InterventionsPatients were randomized (2:1) to apalutamide, 240 mg/d, with androgen deprivation therapy (apalutamide+ADT) or placebo+ADT.Main outcomes and measuresPatients were stratified into high-risk and low-risk categories for developing metastases based on genomic classifier (GC) scores for high (GC >0.6) and low to average (GC≤0.6) and into basal and luminal subtypes; associations between these molecular subtypes and metastasis-free survival (MFS), overall survival (OS), and progression-free survival 2 (PFS2) were evaluated using Cox proportional hazards regression and Kaplan-Meier analysis.ResultsMedian age of the 233 included patients was 73 (range, 49-91) years. A total of 116 of 233 patients (50%) in the SPARTAN biomarker subset had high GC scores. Although all patients receiving apalutamide+ADT had improved outcomes, having high GC scores was associated with the greatest improvement in MFS (hazard ratio [HR], 0.21; 95% CI, 0.11-0.40; P < .001), OS (HR, 0.52; 95% CI, 0.29-0.94; P = .03), and PFS2 (HR, 0.39; 95% CI, 0.23-0.67; P = .001) vs placebo+ADT. In total, 152 of 233 patients (65%) had the basal molecular subtype. Although there were no significant differences in MFS, PFS2, or OS between patients with the luminal vs basal subtype in the placebo+ADT arm, patients with the luminal subtype in the apalutamide+ADT arm had a significantly longer MFS (apalutamide+ADT: HR, 0.40; 95% CI, 0.18-0.91; P = .03; placebo+ADT: HR, 0.66; 95% CI, 0.33-1.31; P = .23) compared with patients with basal subtype; similar trends were observed for OS (apalutamide+ADT: HR, 0.50; 95% CI, 0.25-0.98; P = .04; placebo+ADT: HR, 0.78; 95% CI, 0.38-1.60; P = .50), and PFS2 (apalutamide+ADT: HR, 0.71; 95% CI, 0.42-1.22; P = .22; placebo+ADT: HR, 0.72; 95% CI, 0.38-1.39; P = .33). In regression analysis, the luminal-basal subtype score was significantly associated with MFS in patients receiving apalutamide+ADT (HR, 2.65; 95% CI, 1.15-6.08; P = .02), whereas GC score was significantly associated with MFS in placebo+ADT recipients (HR, 2.09; 95% CI, 1.02-4.27; P = .04).Conclusions and relevanceThe findings of this study suggest that the GC score and basal-luminal subtype derived from archived tumor specimens may be biomarkers of response to apalutamide+ADT in the nmCRPC setting. Although overall, the addition of apalutamide to ADT was beneficial, higher-risk and luminal subtypes appeared to benefit most. Obtaining GC scores may be useful for identifying patients for early treatment intensification with apalutamide, and basal-luminal subtyping may be a beneficial approach for patient selection for further treatment intensification in trials combining novel therapies with apalutamide.
| S-EPMC8176389 | biostudies-literature
Project description:In recent years, several nonhormonal and hormonal agents, including enzalutamide, have been approved for the treatment of metastatic castration-resistant prostate cancer (CRPC) on the basis of improved overall survival in prospective clinical trials. The incorporation of these agents has revolutionized the treatment of CRPC but has also raised the question of what is the ideal sequence of administering them. Enzalutamide is a nonsteroidal second-generation antiandrogen that has been approved for the treatment of metastatic CRPC both in the post-docetaxel and chemotherapy-naïve settings. This article reviews the pharmacological characteristics of enzalutamide, the efficacy studies which led to its approval, its safety profile, and quality of life-related parameters as well as its place in the sequential treatment and management of metastatic prostate cancer.
| S-EPMC4492664 | biostudies-literature