High-risk Nonmetastatic Castration-resistant Prostate Cancer Research Articles

Real-world study: Impact of multidisciplinary management of apalutamide-associated adverse events in prostate cancer.

To analyse the adverse events (AEs) associated with apalutamide and the impact of a multidisciplinary team (MDT) protocol on its management at a tertiary care hospital in a real-world setting. This was an observational, prospective, cohort study based on real-world evidence at the Hospital Clínic de Barcelona. Includes patients diagnosed with metastatic hormone-sensitive prostate cancer (mHSPC) or high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC) and who started treatment with apalutamide between May 2019 and March 2023 in a real-world clinical setting. Of the 121 patients treated with apalutamide, 52.1% experienced an AE, 19.8% experienced temporarily interruption or a reduction in the dose of apalutamide, and 13.2% discontinued treatment due to AEs. Without MDT protocol (49 patients), 24.5% of patients had to temporarily interrupt or reduce the dose of apalutamide due to AEs, with a median time from the start of treatment of 10.1 months, and 24.5% discontinued apalutamide due to AEs, with a median time from the start of treatment of 3.1 months. Meanwhile, whit MDT protocol (72 patients), 16.7% of patients had to temporarily interrupt or reduce the dose of apalutamide due to AEs, with a median time from the start of treatment of 1.6 months, and 5.6% discontinued apalutamide due to AEs, with a median time from the start of treatment of 4 months. The risk reduction associated with treatment discontinuation was statistically significant (p-value = 0.003). This study highlights the importance of MDT management of AEs associated with apalutamide to reduce treatment discontinuation.

Improving the identification of high-risk non-metastatic castration-resistant prostate cancer patients in clinical practice.

Non-metastatic castration-resistant prostate cancer (nmCRPC) represents a challenging disease state in prostate cancer care. nmCRPC patients with a high risk of progression to metastatic disease who are identified by a prostate-specific antigen doubling time (PSADT) ≤10 months are eligible for treatment with the novel androgen receptor inhibitors (ARIs), shown to delay disease progression and extend survival. However, nmCRPC is often unexploited in clinical practice due to a lack of standardization in the methodology and in the tools used for its identification. In this article, a group of Urology and Oncology specialists with acknowledged expertise in prostate cancer reviews the state of the art in the management of high-risk nmCRPC patients, identifies gaps and unmet needs, and proposes strategies to optimize the identification of this patient subgroup in the clinical practice and improve their health outcomes.

Prostate-specific membrane antigen ligand positron emission tomography (PSMA-PET) disease extent and overall survival (OS) in patients (pts) with high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC): An international multicenter retrospective study.

5010 Background: PSMA-PET was positive for distant metastases (39% distant nodes, 24% bone, 6% visceral organ) in >50% of nmCRPC pts who were nonmetastatic by conventional imaging (Fendler et al. CCR 2019). However, the prognostic impact of PSMA-PET disease extent and its association with oncologic outcomes is unknown. We assessed the prognostic utility of PSMA-PET disease extent in nmCRPC pts defined by conventional imaging for OS and new metastases-free survival (nMFS). Methods: 200 pts (6 centers) with nmCRPC by conventional imaging and prostate-specific antigen doubling time (PSADT) ≤10 mo and/or ISUP grade group ≥4 underwent PSMA-PET. Clinical course and treatment management after PSMA-PET imaging were recorded for 4-9 y. Pt characteristics and PSMA-PET disease extent were analyzed retrospectively. OS and PSMA-PET nMFS (time from primary PSMA-PET to appearance of new distant metastases by PSMA-PET or death) were analyzed for pt subgroups based on disease extent by univariate Cox regression. Results: Median OS was 74 mo, similar to the SPARTAN study of nmCRPC pts (74 mo; Smith et al. Eur Urol 2021). Polymetastatic disease (≥5 distant lesions by PSMA-PET) was associated with shorter OS (median 61 mo vs not reached [NR]) and shorter PSMA-PET nMFS (HR 1.8, 95% CI 1.1-2.9; median 38 vs 60 mo; p=0.021). Any metastatic disease by PSMA-PET and whole-body PSMA tumor volume were not prognostic for OS and PSMA-PET nMFS (all p>0.05). Initial pN1 status was associated with shorter OS (median 55 mo vs NR), but not with PSMA-PET nMFS (p>0.05). Baseline age, baseline Gleason grade ≥8, prior radiotherapy (RT), and PSA and PSADT at time of primary PSMA-PET were not associated with outcomes (all p>0.05). Management after PSMA-PET imaging was mostly local/targeted therapy in pts with no visible/locoregional disease (40/30%) and androgen receptor signaling inhibition therapy in pts with nodal/bone distant metastases (35/43%). Conclusions: Polymetastases (>5) by PSMA-PET and initial pN1 status were significantly associated with worse OS. PSMA-PET disease extent provides a potential novel additional risk stratification for pts with nmCRPC without distant metastasis based on conventional imaging. Further validation is needed to prove its independent prognostic value. Clinical trial information: NCT01946204 . [Table: see text]

Apalutamide as a therapeutic option in case of local failure in the nmCRPC

Apalutamide is a non-steroidal selective androgen receptor inhibitor approved for the treatment of high-risk non-metastatic castration-resistant prostate cancer and metastatic hormone-sensitive prostate cancer. The paper describes a case of a patient diagnosed with prostate cancer with a long-term course of the disease. The patient was diagnosed with a non-metastatic castration-resistant stage 18 years after primary treatment. Systemic treatment with apalutamide was recommended. Initially, the treatment was carried out as part of the extended access to apalutamide program and from March 2022 as part of the B.56 drug program. The study presents the effectiveness and safety of the therapy in a 12-month follow-up period and discusses controversial aspects of the patient's previous treatments.

Darolutamide in Spanish patients with nonmetastatic castration-resistant prostate cancer: ARAMIS subgroup analysis.

Aim: Darolutamide significantly prolonged metastasis-free survival (MFS) versus placebo in the Phase III ARAMIS study. We analyzed outcomes in Spanish participants in ARAMIS. Patients & methods: Patients with high-risk nonmetastatic castration-resistant prostate cancer were randomized 2:1 to darolutamide 600 mg twice daily or placebo, plus androgen-deprivation therapy. The primary end point was MFS. Descriptive statistics are reported for this post hoc analysis. Results: In Spanish participants, darolutamide (n=75) prolonged MFS versus placebo (n=42): hazard ratio 0.345, 95% confidence interval 0.175-0.681. The incidence and type of treatment-emergent adverse events were comparable between treatment arms. Conclusion: For Spanish participants in ARAMIS, efficacy outcomes favored darolutamide versus placebo, with a similar safety profile, consistent with the overall ARAMIS population. Clinical Trials Registration: NCT02200614 (ClinicalTrials.gov).

Cost-Utility Analysis of Darolutamide Combined with Androgen Deprivation Therapy for Patients with High-Risk Non-Metastatic Castration-Resistant Prostate Cancer in China.

The increasing incidence of prostate cancer (PC) in China leads to a significant disease burden. Although three novel androgen inhibitors (darolutamide, apalutamide, and enzalutamide) have been approved for patients with high-risk non-metastatic castration-resistant prostate cancer (nmCRPC), the economic evaluation of these novel treatments in China remains unknown. In this study, we aimed to evaluate the cost-utility of darolutamide combined with androgen deprivation therapy (ADT), comparing with apalutamide + ADT and enzalutamide + ADT, in patients with high-risk nmCRPC from a healthcare system perspective in China. A partitioned survival model was developed to capture time spent by patients in three health states: nmCRPC, metastatic CRPC (mCRPC), and death. Clinical outcomes from the ARAMIS, PROSPER, and SPARTAN studies were obtained. In the absence of head-to-head studies, indirect treatment comparisons were conducted to capture the comparative effectiveness between darolutamide + ADT, apalutamide + ADT, and enzalutamide + ADT. The prices of apalutamide and enzalutamide were assumed to be the same as the initial launch price of darolutamide, since post-negotiation prices after national reimbursement drug list (NRDL) inclusion remain confidential. Other health resources costs, baseline characteristics, treatment patterns, and utility were collected through literature or clinical expert interviews. Selected sensitivity analyses were also performed. For a 20-year time horizon, darolutamide + ADT was associated with lower cost per quality-adjusted life years (QALYs) than apalutamide + ADT and enzalutamide + ADT (202,897 Chinese yuan (CNY)/QALY vs. 228,998CNY/QALY and 221,409CNY/QALY, respectively) (exchange rate, 1USD = 6.7871CNY). Darolutamide + ADT had better health outcomes and lower total costs compared to both apalutamide + ADT (+ 0.22QALYs and - 72,818CNY) and enzalutamide + ADT (+ 0.09QALYs and - 67,451CNY). Across the modelled sensitivity analyses (including hazard ratios and drug costs), darolutamide + ADT remained dominant or cost-effective. This economic evaluation suggested that, in comparison with apalutamide + ADT and enzalutamide + ADT, darolutamide + ADT was a dominant or cost-effective treatment option for patients with high-risk nmCRPC in China.

1410P Real-world first-line (1L) treatment patterns in patients (pts) with high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC)

Pts with nmCRPC are at high risk of developing metastases if they have a prostate-specific antigen (PSA) doubling time (PSADT) of ≤10 months (mo) or Gleason score (GS) ≥8. Combining androgen deprivation therapy (ADT) with novel hormone therapies (NHTs; apalutamide/darolutamide/enzalutamide) prolongs metastasis-free survival (MFS) and overall survival (OS) in nmCRPC, but data on use of these therapies in real-world settings are minimal. We assessed the real-world use of NHTs in men with high-risk nmCRPC in the United States.

Deep Prostate-specific Antigen Response following Addition of Apalutamide to Ongoing Androgen Deprivation Therapy and Long-term Clinical Benefit in SPARTAN

BackgroundApalutamide plus androgen deprivation therapy (ADT) significantly improved metastasis-free survival (MFS), overall survival (OS), and time to prostate-specific antigen (PSA) progression in the placebo-controlled SPARTAN study of high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC). ObjectiveTo assess the relationships between PSA kinetics, outcomes, and molecular subtypes in SPARTAN. Design, setting, and participantsThe authors conducted a post hoc analysis of nmCRPC patients randomized to receive apalutamide (n = 806) or placebo (n = 401) plus ADT and a subset stratified by molecular classifiers. InterventionApalutamide 240 mg/d. Outcome measurements and statistical analysisThe association between PSA kinetics and MFS, OS, time to PSA progression, and molecular subtypes was evaluated using the landmark analysis and Kaplan-Meier methods. Results and limitationsBy 3 mo, PSA decreased in most apalutamide-treated patients and increased in most placebo-treated patients. After apalutamide, the median time to PSA nadir, confirmed ≥50% PSA reduction, ≥90% PSA reduction, and PSA ≤0.2 ng/ml were 7.4, 1.0, 1.9, and 2.8 mo, respectively. By 6 mo, 90%, 57%, and 32% of apalutamide patients had ≥50% PSA reduction, ≥90% PSA reduction, and PSA ≤0.2 ng/ml, respectively, while only 1.5% of placebo patients experienced ≥50% PSA reduction. PSA reductions were observed within 3 mo and up to 12 mo of apalutamide treatment, and were similar across molecular subtypes. Deep PSA responses (≥90% PSA reduction or PSA ≤0.2 ng/ml) at landmark 6-mo apalutamide treatment were significantly associated with improved time to PSA progression (hazard ratio {HR} [95% confidence interval {CI}] 0.25 [0.18–0.33] or 0.13 [0.08–0.21]), MFS (0.41 [0.29–0.57] or 0.3 [0.19–0.47]), and OS (0.45 [0.35–0.59] or 0.26 [0.18–0.38]; p < 0.001 for all). ConclusionsApalutamide plus ADT produced rapid, deep, and durable PSA responses by 6-mo treatment regardless of assessed molecular prognostic markers. An early PSA response with apalutamide was associated with clinical benefits, supporting prognostic value of PSA monitoring. Patient summaryIn this report, we describe how prostate-specific antigen (PSA) levels relate to outcomes in patients with nonmetastatic castration-resistant prostate cancer treated with apalutamide plus androgen deprivation therapy (ADT). We found that treatment with apalutamide plus ADT resulted in rapid, deep, and durable PSA responses in the majority of patients, including those with high-risk molecular subtypes, which were associated with improved survival.

Blood Biomarker Landscape in Patients with High-risk Nonmetastatic Castration-Resistant Prostate Cancer Treated with Apalutamide and Androgen-Deprivation Therapy as They Progress to Metastatic Disease.

In the placebo-controlled SPARTAN study, apalutamide added to androgen-deprivation therapy (ADT) improved metastasis-free survival, second progression-free survival (PFS2), and overall survival (OS) in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC). Mechanisms of resistance to apalutamide in nmCRPC require evaluation. In a subset of patients from SPARTAN, aberrations were assessed at baseline and end of study treatment (EOST) using targeted next-generation sequencing or qRT-PCR. Circulating-tumor DNA (ctDNA) levels were assessed qualitatively. Select aberrations in androgen receptor (AR) and other common PC-driving genes were detected and summarized by the treatment group; genomic aberrations were summarized in ctDNA-positive samples. Association between detection of aberrations in all patients and outcomes was assessed using Cox proportional-hazards models and multivariate analysis. In 247 patients, the overall prevalence of ctDNA, AR aberrations, and TP53 inactivation increased from baseline (40.6%, 13.6%, and 22.2%) to EOST (57.1%, 25.4%, and 35.0%) and was comparable between treatment groups at EOST. In patients who received subsequent androgen signaling inhibition after study treatment, detectable biomarkers at EOST were significantly associated with poor outcomes: ctDNA with PFS2 or OS (HR, 2.01 or 2.17, respectively; P < 0.0001 for both), any AR aberration with PFS2 (1.74; P = 0.024), and TP53 or BRCA2 inactivation with OS (2.06; P = 0.003; or 3.1; P < 0.0001). Apalutamide plus ADT did not increase detectable AR/non-AR aberrations over ADT alone. Detectable ctDNA, AR aberrations, and TP53/BRCA2 inactivation at EOST were associated with poor outcomes in patients treated with first subsequent androgen signaling inhibitor.

CE1 A Modeled Health Outcomes Evaluation of Darolutamide Plus Androgen Deprivation Therapy for High-Risk NON-Metastatic Castration-Resistant Prostate Cancer in China

Novel antiandrogens have demonstrated clinical benefit for patients with non-metastatic castration resistant prostate cancer (nmCRPC). We modeled the incremental life-years and QALYs of darolutamide+ADT compared to apalutamide+ADT and enzalutamide+ADT, for high-risk nmCRPC, in a Chinese setting. A partitioned survival model with three health states (nmCRPC, metastatic CRPC and death) was devised. Data from the ARAMIS, PROSPER and SPARTAN trials were used, in the absence of head-to-head studies. Hazard ratios (HRs) characterizing overall survival (OS) were derived from formal indirect treatment comparisons of the OS HRs between the three trials; the point estimates of the OS HRs characterizing the indirect comparison of darolutamide+ADT vs apalutamide+ADT and enzalutamide+ADT were 0.88 and 0.95, respectively. Parametric survival functions were selected for extrapolation based on the goodness of fit. The baseline characteristics, treatment patterns and utilities for this modeled Chinese cohort were validated with 12 urologists from 11 hospitals. A discount rate of 5% was applied. Univariate and probabilistic sensitivity analyses were performed. With a 20-year modeling horizon, darolutamide+ADT yielded more life years (5.98LYs) and QALYs (4.61QALYs) than both apalutamide+ADT (5.64LYs, 4.43QALYs) and enzalutamide+ADT (5.82LYs, 4.55QALYs). The incremental QALY gains with darolutamide+ADT vs. apalutamide+ADT (+0.18QALYs) and vs. enzalutamide+ADT (+0.06QALYs) were mainly driven by the improved life years during post-progression survival (+0.92LYs vs. apalutamide+ADT and +0.65LYs vs. enzalutamide+ADT). Results were sensitive to the HRs and utility inputs; however, the probabilities of darolutamide+ADT having incremental QALYs reached 70.4% and 56.8% when compared to apalutamide+ADT and enzalutamide+ADT, respectively. This modeled evaluation indicates that darolutamide+ADT is likely to be associated with incremental health outcomes over apalutamide+ADT and enzalutamide+ADT, for a high-risk nmCRPC Chinese cohort, over a 20-year time-frame.

A Multi-Disciplinary Review of the Evidence Supporting Metastasis-Free Survival (MFS) and the Benefit of Delaying Metastasis in High-Risk Non-Metastatic Castration-Resistant Prostate Cancer (nmCRPC)

Until recently, men diagnosed with high-risk non-metastatic castrate-resistant prostate cancer (nmCRPC) were faced with the prospect of a relatively short reprieve from symptomatic progression before the onset of metastatic disease. Crossing this red line represents a turning point in the disease, characterised by debilitating pain, greater functional and emotional impairment, a need for additional treatments, and, eventually, death. Delaying time to metastatic progression has the potential to limit symptomatic progression, reduce morbidity and mortality, and maintain quality of life in nmCRPC, and efforts have been made to establish the validity of metastatic-free survival (MFS) as a valid and meaningful clinical endpoint in this setting. The approval in Europe of apalutamide and enzalutamide based on the Phase III SPARTAN (NCT01946204) and PROSPER (NCT02003924) trials, respectively, with MFS as a primary endpoint (defined as time from randomisation to first radiographic detection of distant metastases, or death) sets a new precedent for future trials in nmCRPC. Although median overall survival (OS) has not yet been reached in either trial, meta-analyses of the two studies suggest a significant improvement in OS alongside a confirmed improvement in MFS for novel anti-androgens versus placebo. A third drug, darolutamide, has also been submitted for regulatory approval to treat nmCRPC. This review aims to summarise the evidence supporting the use of MFS as a clinical endpoint and the benefit of delaying metastasis in men with high-risk nmCRPC, and to discuss the influence of next-generation imaging on prostate cancer staging.

Updated analysis of progression-free survival with first subsequent therapy (PFS2) and safety in the SPARTAN study of apalutamide (APA) in patients (pts) with high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC).

144 Background: In the phase 3 SPARTAN study, compared with placebo (PBO), APA, a next-generation androgen receptor inhibitor, decreased the risk of distant metastasis or death by 72% (hazard ratio [HR], 0.28; p &lt; 0.0001) in men with high-risk nmCRPC. After 1 year of additional follow-up, PFS2 and safety were reevaluated to ensure maintenance of benefit against potential harm. Methods: Pts with nmCRPC and prostate-specific antigen doubling time of ≤ 10 mos were randomized 2:1 to APA (240 mg QD) + androgen deprivation therapy (ADT) or PBO + ADT. All pts who developed distant metastasis, determined by blinded independent central review, were eligible to receive subsequent therapy including open-label treatment with abiraterone acetate + prednisone, provided by the sponsor. The exploratory PFS2 end point (time from randomization to disease progression on subsequent anticancer therapy or death) was evaluated, as was incidence of treatment-emergent adverse events (TEAEs). Results: Median treatment duration with APA was 25.7 mos; with PBO, 11.5 mos (original analysis, mos: APA, 19.2; PBO, 11.2). Pts randomized to APA continued to show significant benefit in PFS2 (HR, 0.5; 95% CI, 0.39-0.63; p &lt; 0.0001) vs PBO (APA median time to PFS2 not reached vs PBO 39.3 mos). At a median follow-up of 32 mos, 51.3% of pts receiving APA, 8% of the 75 pts who crossed over from PBO to APA, and 99.7% of remaining PBO pts had discontinued study treatment. Rates of discontinuations due to progressive disease and AEs were 27.3% and 12.7%, respectively, in the APA group and 73.4% and 8.4% in the PBO group. There was no substantial change in the incidence of TEAEs in the APA group at the 1-year update. With regard to drug specific TEAEs, there were no grade 4 or 5 events; grade 3 TEAEs consisted of rash, 5.2%; falls, 2.4%; fractures, 3.1%; hypothyroidism, 0%; and seizures, 0%. Conclusions: APA was previously shown to result in an improvement in metastasis-free survival and symptomatic progression. With a median APA treatment duration of 25.7 mos, APA continues to show significant benefit in PFS2, and its safety profile remains unchanged. Clinical trial information: NCT01946204.

Apalutamide and its use in the treatment of prostate cancer.

High-risk nonmetastatic castration-resistant prostate cancer is a lethal disease that previously lacked clear treatment options. Progression to bone metastases is associated with significant morbidity and high cost. Apalutamide, an androgen receptor inhibitor, has substantial clinical response in nonmetastatic castration-resistant prostate cancer. Apalutamide + androgen deprivation therapy is well tolerated and improves metastasis-free survival, progression-free survival and time to symptomatic progression, and is associated with a favorable trend of improved overall survival. Future research is needed to elucidate mechanisms of resistance to treatment with androgen signaling inhibitors.

Clinical Development of Darolutamide: A Novel Androgen Receptor Antagonist for the Treatment of Prostate Cancer.

Prostate cancer (PC) is the second most common cancer in men and is the fifth leading cause of cancer-related deaths among men. Androgen receptor (AR) signaling plays a key role in PC tumor growth and progression, with androgens stimulating PC proliferation and survival. Castration-resistant PC (CRPC) is characterized by increasing levels of prostate-specific antigen or radiographic progression despite androgen-deprivation therapy (ADT). In most patients, castration resistance results from aberrations in AR or the AR signaling pathway. Up to one-third of patients with localized high-risk PC will have disease progression on local therapy and develop CRPC. This review summarizes the key clinical data, including ongoing trials, for hormonal therapies in CRPC and provides an overview of the clinical development of darolutamide, a novel, nonsteroidal AR antagonist currently in phase III development for the treatment of nonmetastatic CRPC and metastatic hormone-sensitive PC. In phase I/II trials, darolutamide has demonstrated a favorable safety profile, antitumor activity, and significant decreases in prostate-specific antigen in patients with metastatic CRPC. In the phase III ARAMIS (NCT02200614; A Multinational, Randomized, Double-Blind, Placebo-Controlled, Phase III Efficacy and Safety Study of Darolutamide [ODM-201] in Men With High-Risk Non-metastatic Castration-Resistant Prostate Cancer) study, metastasis-free survival is being evaluated in men with nonmetastatic CRPC who will receive ADT in combination with darolutamide or placebo. The ARASENS (NCT02799602; A Randomized, Double-Blind, Placebo Controlled Phase III Study of Darolutamide [ODM-201] Versus Placebo in Addition to Standard Androgen Deprivation Therapy and Docetaxel in Patients With Metastatic Hormone Sensitive Prostate Cancer) study is a placebo-controlled trial assessing whether the addition of darolutamide to ADT and docetaxel significantly prolongs overall survival in men with metastatic hormone-sensitive PC.

Impact of intervening in high-risk nonmetastatic castration-resistant prostate cancer (HRnmCRPC) on metastatic castration-resistant prostate cancer (mCRPC) disease burden.

e17010Background: Approved treatments for patients with mCRPC are associated with meaningful improvements in progression-free and overall survival. The burden of mCRPC remains high, however, as it ...

PF1-091 - ARAMIS trial: Efficacy and safety of ODM-201 in men with high-risk nonmetastatic castration-resistant prostate cancer

PF1-091 - ARAMIS trial: Efficacy and safety of ODM-201 in men with high-risk nonmetastatic castration-resistant prostate cancer

ARAMIS trial: Efficacy and safety of ODM-201 in men with high-risk nonmetastatic castration-resistant prostate cancer.

TPS5094Background: Treatment for nonmetastatic castration-resistant prostate cancer (nmCRPC) other than continuing androgen deprivation therapy (ADT) remains an unmet need. There are no approved therapies for preventing metastatic disease in nmCRPC. Pts with nmCRPC who have shorter prostate-specific antigen doubling time (PSADT) are at higher risk for metastatic disease or death. ODM-201, a novel second-generation oral androgen receptor inhibitor, has demonstrated a tolerable safety profile and antineoplastic activity in progressive CRPC. The ARAMIS trial will evaluate the efficacy and safety of ODM-201 in high-risk nmCRPC pts. Methods: This randomized, double-blind, placebo-controlled phase 3 trial (NCT02200614) involves > 450 sites in > 33 countries. 1500 pts on ADT will be randomized 2:1 to ODM-201 600 mg or placebo BID. Pts will be stratified by PSADT and baseline bone-targeting agent use. Eligibility criteria include nmCRPC, PSADT ≤ 10 months, and screening PSA ≥ 2 ng/mL. 90% power to detect a target...

Phase 2 Study of the Safety and Antitumor Activity of Apalutamide (ARN-509), a Potent Androgen Receptor Antagonist, in the High-risk Nonmetastatic Castration-resistant Prostate Cancer Cohort

BackgroundApalutamide is a potent androgen receptor (AR) antagonist that targets the AR ligand-binding domain and prevents AR nuclear translocation, DNA binding, and transcription of AR gene targets. ObjectiveTo evaluate the activity and safety of apalutamide in patients with high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC). Design, setting, and participantsWe conducted a multicenter phase 2 study of nmCRPC patients with a high risk for progression (prostate-specific antigen [PSA] ≥8 ng/ml or PSA doubling time [PSA DT] ≤10 mo). InterventionPatients received 240mg/d apalutamide while continuing on androgen-deprivation therapy. Outcome measurements and statistical analysisPrimary end point was 12-wk PSA response (Prostate Cancer Working Group 2 criteria). Secondary end points included safety, time to PSA progression (TTPP), and metastasis-free survival (MFS). Results and limitationsA total of 51 patients were enrolled; four patients with metastatic disease were excluded from the efficacy analysis. Patient characteristics included median age, 71 yr; Eastern Cooperative Oncology Group performance status 0 (76%); Gleason score ≤7 (57%); median PSA 10.7 ng/ml; and PSA DT ≤10 mo (45%). At median follow-up of 28.0 mo, 18 patients (35%) remained in the study. Overall, 89% of patients had ≥50% PSA decline at 12 wk. Median TTPP was 24.0 mo (95% confidence interval [CI], 16.3 mo–not reached [NR]); median MFS was NR (95% CI, 33.4 mo–NR). Most of the patients discontinued study treatment (n=33) due to disease progression (n=11 [22%]) or adverse events (AEs) (n=9 [18%]). The most common AE was fatigue (any grade, n=31 [61%]) although grade ≥3 fatigue was uncommon (n=2 [4%]). These represent the first apalutamide nmCRPC patient clinical data. ConclusionsIn high-risk nmCRPC patients, apalutamide was safe with robust activity based on durable PSA responses and disease control. Patient summaryAntitumor activity and the safety of apalutamide in patients with nonmetastatic castration-resistant prostate cancer support continued development in this setting. Trial registrationClinicalTrials.gov identifier NCT01171898

ARAMIS trial: Efficacy and safety phase 3 trial of ODM-201 in men with high-risk non-metastatic castration-resistant prostate cancer (nmCRPC).

TPS5080 Background: There is no standard treatment for nmCRPC besides continuing androgen deprivation therapy (ADT). Preventing metastatic disease in nmCRPC is a major unmet need. Patients with nmC...

MP87-16 NOVEL ANTIANDROGEN ARN-509 IN HIGH-RISK NONMETASTATIC CASTRATION-RESISTANT PROSTATE CANCER

You have accessJournal of UrologyProstate Cancer: Advanced III1 Apr 2015MP87-16 NOVEL ANTIANDROGEN ARN-509 IN HIGH-RISK NONMETASTATIC CASTRATION-RESISTANT PROSTATE CANCER Neal D. Shore, Emmanuel S. Antonarakis, Charles J. Ryan, William R. Berry, Glenn Liu, Celestia Higano, Edna Chow Maneval, Rajesh Bandekar, Carla J. de Boer, Mary B. Todd, Margaret K. Yu, Dana E. Rathkopf, and Matthew R. Smith Neal D. ShoreNeal D. Shore More articles by this author , Emmanuel S. AntonarakisEmmanuel S. Antonarakis More articles by this author , Charles J. RyanCharles J. Ryan More articles by this author , William R. BerryWilliam R. Berry More articles by this author , Glenn LiuGlenn Liu More articles by this author , Celestia HiganoCelestia Higano More articles by this author , Edna Chow ManevalEdna Chow Maneval More articles by this author , Rajesh BandekarRajesh Bandekar More articles by this author , Carla J. de BoerCarla J. de Boer More articles by this author , Mary B. ToddMary B. Todd More articles by this author , Margaret K. YuMargaret K. Yu More articles by this author , Dana E. RathkopfDana E. Rathkopf More articles by this author , and Matthew R. SmithMatthew R. Smith More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.1961AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES ARN-509 selectively binds the androgen receptor and impairs its nuclear translocation and DNA binding to androgen response elements. Study ARN-509-001 evaluates ARN-509 activity in pts with high-risk nonmetastatic (M0) castration-resistant prostate cancer (CRPC), chemotherapy-naïve metastatic CRPC (mCRPC), and mCRPC post abiraterone acetate. We report the updated results for the M0 CRPC cohort as of February 2014. METHODS All pts had CRPC with no radiographic evidence of metastases (pelvic lymph nodes < 3 cm below the iliac bifurcation were allowed) and high risk for disease progression based on prostate-specific antigen (PSA) ≥ 8 ng/mL within 3 mos of enrollment and/or PSA doubling time (PSADT) ≤ 10 mos. All pts received ARN-509 240 mg/d. Primary end point: PSA response at 3 mos according to Prostate Cancer Working Group 2 (PCWG2) criteria. Secondary end points: safety, time to PSA progression, and metastasis-free survival (MFS). PSA was measured every month and tumor imaging was performed every 4 mos. RESULTS M0 CRPC cohort enrolled 51 pts from Nov 2011 to Jun 2012; 4 pts had metastatic disease and were excluded from the efficacy analysis. Median age was 71 years (range 51-88). Baseline characteristics were ECOG performance status 0 (76%); Gleason score ≤ 7 (57%); median PSA 10.7 ng/mL (range 0.5-201.7); and PSADT ≤ 10 mos (45%). All pts received prior treatment with a luteinizing hormone–releasing hormone analog. Forty-one pts (80%) also received a first-generation antiandrogen. At median follow-up of 20.2 mos, 29 (57%) pts remain on study. Pts discontinued due to disease progression (n = 7), adverse events (AEs) (n = 7), withdrew consent (n=3), or other reasons (n = 5). Most AEs were grade 1 or 2. Most common treatment-emergent AEs (all grades; grade ≥ 3): fatigue (57%; 4%), diarrhea (41%; 2%), nausea (29%; 0%), dysgeusia (20%; 0%), arthralgia (18%; 2%), and weight decreased (16%; 2%). The incidence of hypertension was low (10%; 2%). No seizures were reported. Other central nervous system events: headaches (10%; 0%), falls (4%; 0%), and hallucinations (0%). CONCLUSIONS ARN-509 is well tolerated in pts with high-risk M0 CRPC, with anti-tumor activity based on durable PSA response and delayed disease progression. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e1090 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Neal D. Shore More articles by this author Emmanuel S. Antonarakis More articles by this author Charles J. Ryan More articles by this author William R. Berry More articles by this author Glenn Liu More articles by this author Celestia Higano More articles by this author Edna Chow Maneval More articles by this author Rajesh Bandekar More articles by this author Carla J. de Boer More articles by this author Mary B. Todd More articles by this author Margaret K. Yu More articles by this author Dana E. Rathkopf More articles by this author Matthew R. Smith More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...