Non-metastatic Castration-resistant Prostate Cancer Patients Research Articles

Prognostic Outcomes and Predictive Factors in Non-Metastatic Castration-Resistant Prostate Cancer Patients Not Treated with Second-Generation Antiandrogens.

Background/Objectives: Patients with non-metastatic castration-resistant prostate cancer (nmCRPC) and high-risk features frequently have progression to life-threatening metastasis without second-generation antiandrogens. This study investigated nmCRPC patients for the survival and prognostic factors from a cohort before the approved use of second-generation antiandrogens. Methods: From March 2016 to January 2021, 326 patients treated with second-generation antiandrogens for metastatic castration-resistant prostate cancer (mCRPC) or metastatic castration-sensitive prostate cancer were retrieved. Forty-four patients experiencing nmCRPC with no use of second-generation antiandrogens were reviewed. The prognostic factors, at initial diagnosis or at nmCRPC, associated with metastasis-free survival (MFS) and overall survival (OS) were analyzed. Results: The median follow-up time after nmCRPC was 46 months. The median PSA level at nmCRPC was 2.7 ng/mL. Thirty-eight of forty-four patients with nmCRPC had a PSA doubling time (PSADT) of 10 months or shorter, and the median PSADT was 4 months. The median OS from nmCRPC was 53 months, and the median interval for nmCRPC patients progressing to mCRPC was 20 months. Upon univariate analysis, PSADT < 10 months (p = 0.049) and the very-high-risk group at the initial diagnosis (p = 0.043) were associated with significantly shorter post-nmCRPC MFS. The very-high-risk group (p = 0.031) was associated with significantly worse post-nmCRPC OS. In terms of survivals from the initial diagnosis of prostate cancer, Gleason grade ≥ 8 was the only independent factor with MFS and OS. Conclusions: Without second-generation antiandrogens, nmCRPC patients with PSADT <10 months and in the initial very-high-risk group developed subsequent mCRPC in a significantly faster fashion. Patients of the very-high-risk group had shorter survival rates after nmCRPC.

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.

Adverse events and costs among non-metastatic castration-resistant prostate cancer patients

Background Limited real-world evidence exists on the economic burden of adverse events (AEs) to the healthcare system among patients with non-metastatic castration-resistant prostate cancer (nmCRPC) treated with second-generation androgen receptor antagonists (ARAs). Current data is needed to understand real-world clinical event rates among ARAs and the cost of these events. Objectives Describe the incidence of non-central nervous system (CNS)-related AEs and CNS-related AEs among nmCRPC patients treated in the United States with second-generation ARAs (apalutamide and enzalutamide) and evaluate healthcare resource utilization (HCRU) and costs for these patients. Methods and study design This was a retrospective observational cohort study using claims data from Optum Clinformatics Data Mart to identify adult males with prostate cancer, castration, no metastases, and >1 claim for apalutamide or enzalutamide. The study was conducted from January 2017 to March 2020, with a patient index identification period from January 2018 to December 2019. AEs were classified as CNS-related or non-CNS-related. Results Of 605 patients (156 apalutamide and 449 enzalutamide), most were ≥65 years (94%) and had ≥1 non-CNS-related AE (55%). Many had ≥1 CNS-related AE (32%). Pain (12%) and arthralgia (11%) were the most frequently reported non-CNS-related AEs. Fatigue/asthenia (14%) and dizziness (7%) were the most frequently reported CNS-related AEs. Among patients with versus without non-CNS-related AEs, 34% versus 8% had emergency room (ER) events, and 25% versus 2% had inpatient events. Among patients with versus without CNS-related AEs, 41% versus 14% had ER events, and 38% versus 4% had inpatient events. Adjusted per-patient per-year cost (in 2020 USD) differences were significant between patients with and without non-CNS-related AEs ($30,765, p = 0.0018) and between patients with and without CNS-related AEs ($40,689, p = 0.0017). Conclusion There is significant HCRU and cost burden among nmCRPC patients treated with ARAs developing AEs, highlighting the need for treatments with improved tolerability. Additional studies are warranted to include recently approved agents.

263MO Enzalutamide versus abiraterone plus prednisolone for Japanese non-metastatic castration-resistant prostate cancer patients: Sub-analysis from ENABLE for PCa, a multicenter, randomized controlled trial

263MO Enzalutamide versus abiraterone plus prednisolone for Japanese non-metastatic castration-resistant prostate cancer patients: Sub-analysis from ENABLE for PCa, a multicenter, randomized controlled trial

Real-world burden of adverse events for apalutamide- or enzalutamide-treated non-metastatic castration-resistant prostate cancer patients in the United States

BackgroundSecond-generation androgen receptor inhibitors (ARIs) have been associated with adverse events (AEs) such as fatigue, falls, fractures, and rash in non-metastatic castration-resistant prostate cancer (nmCRPC) patients as identified in clinical trials. The objectives of this study were to describe the incidence and management of AEs in patients receiving apalutamide and enzalutamide.MethodsThis retrospective chart review study was conducted in nmCRPC-treating sites in the United States. Patients starting apalutamide or enzalutamide between February 1, 2018 and December 31, 2018 were included and any AEs they experienced were recorded. AEs, including those considered to be of special interest as defined in the pivotal clinical trials of the second-generation ARIs, were analyzed and grouped retrospectively in this study. Detailed chart data (patient demographics, clinical characteristics, treatment history, type of AE, outcomes, and resource utilization) were then collected for a randomly selected subset among patients with ≥1 AE to characterize AEs and their management. Descriptive results were summarized.ResultsForty-three sites participated in the study. A total of 699 patients were included, of whom 525 (75.1%) experienced ≥1 AE. The most common AEs were fatigue/asthenia (34.3%), hot flush (13.9%), and arthralgia (13.6%). In the subset of 250 patients randomly selected from those who experienced ≥1 AE, patients were primarily White (72.0%), the mean age was 71 years, 86.0% had an Eastern Cooperative Oncology Group score of 0–1 at nmCRPC diagnosis, and the average prostate specific antigen (PSA) value at diagnosis was 23.2 ng/mL. PSA-doubling time < 10 months was chosen as reason to initiate treatment in 40% of patients. The median duration of follow-up was 1.1 years, with 14.4% of patients progressing to metastasis by end of study period. Grade 3–4 and Grade 5 AEs occurred in 14.4 and 0.4% of patients, respectively. Actions taken to manage AEs included AE-directed treatment (38.0%), ARI discontinuation (10.4%), dose reduction (7.6%), and AE-related hospitalization (4.8%).ConclusionsThis study highlights the burden of AEs among nmCRPC patients treated with apalutamide or enzalutamide, providing a relevant real-world benchmark as clinical trial evidence and the treatment landcape for nmCRPC continues to evolve.

Health-related Quality of Life at the SPARTAN Final Analysis of Apalutamide for Nonmetastatic Castration-resistant Prostate Cancer Patients Receiving Androgen Deprivation Therapy

BackgroundIn SPARTAN, apalutamide improved metastasis-free and overall survival for patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) with a prostate-specific antigen doubling time of ≤10 mo. ObjectiveWe evaluated health-related quality of life (HRQoL) at the final analysis of the SPARTAN study. InterventionPatients received apalutamide (240 mg/d) or placebo in 28-d cycles. All patients continued androgen deprivation therapy (ADT). Design, setting, and participantsA total of 1207 patients with nmCRPC were randomized 2:1 to apalutamide or placebo. Outcome measurements and statistical analysisHRQoL was assessed using Functional Assessment of Cancer Therapy-Prostate (FACT-P) and EQ-5D-3L questionnaires at day 1 of cycle 1 (predose/baseline), cycles 2–6, every two cycles during cycles 7–13, every four cycles thereafter, at the end of treatment, and every 4 mo after progression to 1 yr. Results are presented using descriptive statistics. A mixed model for repeated measures was fitted to estimate the mean scores at each scheduled visit during treatment. ResultsAt final analysis, with 52 mo follow-up for survival, the median treatment duration was 32.9 mo for apalutamide and 11.5 mo for placebo. Patients had good baseline HRQoL. At each scheduled collection during treatment, >90% per group completed the questionnaires. The change in FACT-P total score from baseline to cycles 21 and 25 significantly favored apalutamide over placebo (p = 0.0138 and 0.0009, respectively). The apalutamide group generally maintained favorable FACT-P (total and subscales) and EQ-5D-3L scores, while placebo scores tended to decline over time (starting in cycles 11–13 and pronounced by cycles 21–25). Notably, patient-reported fatigue did not worsen with apalutamide. Most patients reported being “not at all bothered” by side effects, and bother did not increase over time with apalutamide or placebo. Patients receiving apalutamide had minimal change in side-effect bother following symptomatic adverse events. ConclusionsFinal analysis of SPARTAN confirms that HRQoL is preserved in patients with nmCRPC receiving apalutamide plus ADT, but declines in patients receiving placebo plus ADT after approximately 1 yr. Patient summaryResponses from patients with prostate cancer who were included in the SPARTAN study indicated that treatment with apalutamide, even after the most extensive follow-up time possible, did not reduce their quality of life. These results, along with improved survival and longer time to the development of metastases (reported separately), confirm the benefits of apalutamide for patients with nonmetastatic castration-resistant prostate cancer.

PCN158 Potential Drug-Drug Interactions to Novel Anti-Androgen Therapies Among Non-Metastatic Castration-Resistant Prostate Cancer Patients

PCN158 Potential Drug-Drug Interactions to Novel Anti-Androgen Therapies Among Non-Metastatic Castration-Resistant Prostate Cancer Patients

Prevalence of potential drug-drug interactions among nonmetastatic castration-resistant prostate cancer patients treated with apalutamide and enzalutamide.

e18690 Background: Patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) are often treated with concurrent medications for the management of comorbid conditions. This increases the risk of drug interactions which may lead to compromised efficacy and safety of nmCRPC therapies. This study aimed to characterize potential drug-drug interactions (pDDIs) with the novel anti-androgen (AA) agents enzalutamide (Enza) and apalutamide (Apa) in a real-world nmCRPC population. Methods: We analyzed Optum Clinformatics Data Mart, a large claims database from January 1, 2017, through March 31, 2020. The study population included adult males with prostate cancer, evidence of castration, &gt;1 pharmacy claim for Apa or Enza (index date defined as drug initiation), and without codes for metastases. Darolutamide, a more recently approved AA, was not included due to lack of data. Concomitant medications were defined as therapy with at least 1 day overlap with Apa and Enza. The top concomitant medications covering 99% of Apa and Enza population were assessed for pDDI using Micromedex, Lexicomp, and Drugs.com compendia. Results: We identified 149 Apa and 319 Enza patients with mean age 77 years across groups. The study population was primarily white (56.3% Apa; 56.7% Enza) and had Medicare insurance (81.0% Apa; 82.2% Enza). Mean Charlson comorbidity index scores were similar for each group (Apa: 2.3 [SD: 4.1]; Enza: 2.4 [SD: 2.4]). Polypharmacy was common in both groups, with the majority taking ≥5 medications (Apa: 79.8%; Enza: 75.9%). Of the co-medications included in this analysis, Micromedex, Lexicomp and Drugs.com flagged 12, 38 and 53 pDDIs for Apa, and 7, 35 and 49 pDDIs for Enza, respectively. A pDDI was identified for 35% Apa and 21% Enza patients using Micromedex and &gt;80% of Apa and Enza patients using other compendia. The pDDIs by severity and risk rating as defined by the respective compendia are shown in Table. Specifically, 4 interactions for Apa and 1 for Enza were rated X (i.e., avoid combination). Conclusions: This study finds a high prevalence of pDDIs among Apa and Enza patients signifying the need for strict monitoring while initiating these therapies. Given the high prevalence of polypharmacy and comorbidities among nmCRPC, these patients may benefit from drugs with lower interaction potential. Future real-world analyses should be conducted to characterize the clinical and economic impact of these pDDIs as well as to assess pDDI for darolutamide. [Table: see text]

890P - Assessing the clinical relevance of drug-drug interactions (DDI) with darolutamide (DARO)

BackgroundDARO is an androgen receptor antagonist with a distinct molecular structure, which has demonstrated prolonged metastasis-free survival vs placebo (PBO) in the phase 3 ARAMIS study in non-metastatic castration-resistant prostate cancer patients. These typically older patients often receive multiple comedications. We assessed DDIs with DARO both in vitro and in clinical trial development. MethodsThe effects of induction and inhibition of transporters and CYP enzymes on DARO, and the effect of DARO on other comedications were studied in vitro and in several phase 1 trials using rifampicin (CYP3A4, P-gp inducer), itraconazole (ICZ; CYP3A4, P-gp inhibitor), rosuvastatin (BCRP, OATP1B1, OATP1B3 and OAT3 substrate), midazolam (CYP3A4 substrate) and dabigatran etexilate (P-gp substrate). The impact of comedication on DARO was investigated in a population pharmacokinetic (popPK) and covariate analysis of a subset of ARAMIS patients. The adverse event (AE) profile for comedication use between PBO and DARO was also analysed. ResultsConcomitant rifampicin led to a 3.5-fold decrease in DARO area under the curve (AUC) vs DARO alone. ICZ resulted in 1.8-fold increase in DARO AUC vs DARO alone. No significant effect of comedications that are CYP or P-gp inhibitors was identified in the popPK analysis; proton pump inhibitors did not significantly affect the PK of DARO. Effects of DARO on CYP inhibition in vitro were negligible and coadministration of midazolam or dabigatran showed no clinically relevant effects. Rosuvastatin AUC increased by 5.2-fold with DARO vs rosuvastatin alone, attributed mainly to BCRP inhibition. The incidence of AEs in ARAMIS was low; comedication use (98.7% in DARO, 98.0% in PBO arms) and AE profile were similar between study arms. ConclusionsDDIs with DARO and P-gp or CYP enzyme substrates, e.g. antithrombotics, calcium channel blockers or proton pump inhibitors, are not expected. Strong CYP3A4 inducers, e.g. rifampicin and carbamazepine, showed some interaction with DARO. Effects of CYP3A4 or P-gp inhibitors on DARO were not considered clinically relevant. DARO may increase the exposure of concomitant BCRP substrates, e.g. statins, although a safety and AE analysis from ARAMIS did not indicate any relevant impact of DARO. Clinical trial identificationNCT03237416, NCT03048110, NCT02671097, NCT02200614. Editorial acknowledgementMedical writing support: Lucy Smithers, PhD, and editorial support: Beth King, both of Scion Medica, London, supported by Bayer according to Good Publication Practice guidelines. Legal entity responsible for the studyBayer. FundingBayer and Orion Corporation. DisclosureC.R. Zurth: Full / Part-time employment: Bayer. K. Fizazi: Honoraria (self), Advisory / Consultancy: Merck, Sharp & Dohme; Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Astellas; Advisory / Consultancy: Orion; Advisory / Consultancy: CureVac; Advisory / Consultancy: Clovis. R. Fricke: Full / Part-time employment: Bayer. H. Gieschen: Full / Part-time employment: Bayer. K. Graudenz: Full / Part-time employment: Bayer. M. Koskinen: Full / Part-time employment: Orion Corporation. B.A. Ploeger: Full / Part-time employment: Bayer. O. Prien: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bayer. M.R. Smith: Advisory / Consultancy: Bayer; Advisory / Consultancy: Amgen; Advisory / Consultancy: Astellas; Advisory / Consultancy: Clovis; Advisory / Consultancy: Gilead; Honoraria (self): Hinova; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: Eli Lilly; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Pfizer. T. Tammela: Honoraria (self), Research grant / Funding (institution): Bayer; Advisory / Consultancy: Janssen; Advisory / Consultancy, Research grant / Funding (institution): Lidds AB; Advisory / Consultancy, Research grant / Funding (institution): Astellas. N.D. Shore: Advisory / Consultancy, Research grant / Funding (self): Ferring; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Honoraria (self), Research grant / Funding (self): Amgen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Janssen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Dendreon; Advisory / Consultancy, Research grant / Funding (self): Tolmar; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Astellas.

Darolutamide For Castration-Resistant Prostate Cancer.

The treatment landscape of advanced prostate cancer continues to evolve rapidly, with newer and more active drugs being used in earlier phases of the disease based on improved overall survival. After adoption of docetaxel for metastatic castration-sensitive disease, large trials with next-generation androgen receptor-signaling inhibitors (abiraterone, enzalutamide and apalutamide) have demonstrate significant improvements in survival and important secondary endpoints. For non-metastatic castration-resistant prostate cancer, recent phase III placebo-controlled trials with enzalutamide, apalutamide and darolutamide all demonstrated benefits in improving metastasis-free survival. This review aims to summarize the clinical development of darolutamide, a novel next-generation androgen receptor antagonist, including preclinical data, clinical studies and the potential of darolutamide for the treatment of advanced prostate cancer. To date, darolutamide efficacy and tolerability has been demonstrated in the ARAMIS trial, which demonstrated an improvement in metastasis-free survival compared to placebo for non-metastatic castration-resistant prostate cancer patients with a rapid PSA doubling time. Ongoing studies will further evaluate the role of darolutamide in metastatic castration-sensitive prostate cancer in combination with docetaxel (ARASENS trial) and also in other stages of the disease.

Impact of prostate specific antigen doubling time on time to metastasis and overall survival in non-metastatic castration-resistant prostate cancer patients.

211 Background: Prostate-Specific Antigen Doubling Time (PSADT) can help predict prostate cancer (PC) patient outcomes, particularly in hormone sensitive disease. However, PSADT has not been well validated in non-metastatic castration-resistant (nmCR) PC patients. This study examined the prognostic impact of PSADT on time to metastasis (TTM) and overall survival (OS) among nmCRPC patients in the Veterans Health Administration (VHA) database. Methods: VHA patients in this retrospective study were males with PC who had medical or surgical castration between Jan 1, 2012 and Dec 31, 2016. Patients actively receiving luteinizing hormone-releasing hormone treatment with ≥2 PSA post-castration increases were identified. The 3rd PSA value ≥25% and 2 ng/ml &gt; the 1st PSA value was the CRPC (index) date; patients had continuous VHA enrollment for ≥12-months pre- to post-index date. Patients were followed until the earliest of death or disenrollment. PSADT was calculated as the natural log of 2 divided (Ln2) by the log slope of PSA using all PSA values after CRPC until metastases, and patients were categorized into 2-month cohorts. A demographically and clinically adjusted Cox regression model explored associations between PSADT cohorts and TTM and OS. Results: We identified 3,579 patients from which 1,389 (38.8%) progressed to mCRPC while 2,190 (61.2%) remained nmCRPC. Overall, patients averaged 73 years of age. PSADT was calculable in 2,800 patients with an average PSA value of 25.49 ng/mL. After a median follow-up of 820 days, the median PSADT was 17 months. Compared with the PSADT &gt; 12 months cohort, PSADT ≤2, &gt; 2 to ≤4, &gt; 4 to ≤6, &gt; 6 to ≤8, and &gt; 8 to ≤10 month cohorts were associated with higher risk of metastasis (hazard ratio [HR]: 33.77, CI: 25.93-43.96; HR: 14.32, CI: 11.83-17.32; HR: 6.58, CI: 5.42-7.98, HR: 4.14, CI: 3.27-5.25; HR: 3.14, CI: 2.45-4.03, respectively) and death (HR: 12.27, CI: 9.20-16.35; HR: 5.32, CI: 4.26-6.64; HR: 3.50, CI: 2.74-4.47, HR: 2.29, CI: 1.68-3.14; HR: 1.64, CI: 1.14-2.37, respectively). Conclusions: Short PSADT strongly associated with TTM and poor OS in nmCRPC patients. Newer nmCRPC treatments are advisable for high-risk patients.

Long-term outcomes of definitive external-beam radiotherapy for non-metastatic castration-resistant prostate cancer.

Although definitive external-beam radiotherapy (EBRT) is one of the treatment options for non-metastatic castration-resistant prostate cancer (NM-CRPC), there are limited data on the long-term outcomes of this treatment. We retrospectively evaluated 31 NM-CRPC patients consecutively treated with definitive EBRT. The median age was 74years upon EBRT initiation. The initial T stage distribution was as follows: T1c in 3, T2 in 11, T3 in 14, and T4 in 3 cases, respectively. The median prostate dose was 70.4Gy. A castration-resistant status was defined as continuously increasing serum prostate-specific antigen levels despite ongoing hormonal therapy (HT). The median follow-up duration after EBRT was 66.6months. The median period of primary HT was 18.0months. The 5- and 8-year overall survival rates were 74.6 and 49.8%, respectively. The 5- and 8-year prostate cancer-specific survival rates were 77.4 and 51.7%, respectively. Fourteen patients died, and prostate cancer was the cause of death in 12 of these patients. The 5- and 8-year relapse-free survival rates were 32.3 and 25.8%, respectively. Among 23 patients who experienced biochemical or clinical failure, the median duration to recurrence after EBRT was 19.3months. The 5- and 8-year clinical failure-free survival rates were 56.0 and 51.4%, respectively. Among the 14 patients who experienced clinical failure, the median duration after EBRT was 16.0months. The local relapse-free rates at 5 and 8years were 91.0 and 91.0%, respectively. Grade 3 or higher adverse events were observed in four patients. Definitive EBRT achieved a long-term disease-free and clinical failure-free status in approximately one-third of and half of the treated NM-CRPC patients, respectively. This approach was also associated with favorable local relapse-free rates and overall survival outcomes. Definitive EBRT is a promising approach for NM-CRPC patients.

Survival outcomes of pre-metastatic castration-resistant prostate cancer and the burden of developing metastasis: A systematic literature review.

293 Background: Surgical or medical castration is an important component of prostate cancer treatment. However, resistance develops in almost all men and poor prognosis has been established once the disease metastasizes. A systematic literature review (SLR) was conducted to explore the treatment options and survival outcomes associated with non-metastatic castration-resistant prostate cancer (CRPC) and to understand the humanistic and economic impact of developing metastasis. Methods: The SLR was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement guidelines and guidance from the National Institute of Health and Care Excellence, Centre for Reviews and Dissemination and Institute for Quality and Efficiency in Healthcare. The search designed to identify clinical and humanistic evidence from all countries and epidemiology, guidelines and economic evidence in Brazil, China, France, Germany, Japan, UK, and US. Results: Median overall survival for non-metastatic CRPC patients ranged from 44 to 74 months; median progression-free survival from 9 to 22 months; and median metastasis-free survival from 16 to 53 months. The most common form of metastasis was bone metastasis, which was associated with an increased risk of skeletal-related events (SREs). Quality-of-life was widely reported to decrease upon metastasis, driven by increased pain and SREs. Higher healthcare costs associated with metastatic CRPC were attributable to physician visits and treating bone-metastasis-related complications. Conclusions: Currently, there is a lack of approved therapies specifically for non-metastatic CRPC patients, who will invariably develop metastases with associated adverse clinical and economic implications. Delaying the onset of metastasis is an unmet clinical need for improved patient outcomes and couldl also lead to economic benefits for healthcare delivery systems.

Nonmetastatic Castration-Resistant Prostate Cancer

After the introduction of prostate cancer screening with the prostate-specific antigen (PSA) test, we have witnessed a dramatic stage migration. As a result, an increasing number of patients are diagnosed at earlier stages and receive local treatments including surgery or radiation. When these local treatments fail by the definition of increasing PSA levels, patients are usually treated with androgen-deprivation therapy. A fraction of these patients will finally reach a state of castration-resistant prostate cancer (CRPC) even without radiological evidence of metastasis, which is referred to as nonmetastatic CRPC (NM-CRPC). Most men with advanced or metastatic prostate cancer initially respond to various types of androgen ablation, but a considerable portion of them eventually progress to NM-CRPC. Among patients with NM-CPRC, about one-third will develop bone metastasis within 2 years. In these patients, PSA kinetics is the most powerful indicator of progression and is usually used to trigger further imaging studies and enrollment in clinical trials. Although CRPC remains largely driven by the androgen receptor, the benefit of second-line hormonal manipulations, including first-generation antiandrogens, adrenal synthesis inhibitors, and steroids, has not been investigated in men with NM-CRPC. To date, denosumab is the only agent that has been shown to delay the onset of bone metastasis. However, overall survival did not differ. In treating NM-CRPC patients, physicians should recognize the heterogeneity of the disease and acknowledge that the recently approved second-line treatments have been studied only in advanced stages of the disease.

Detection of metastatic disease as a leading cause of screening failure in a phase III trial of zibotentan versus placebo in patients with nonmetastatic castration-resistant prostate cancer (CRPC).

4655 Background: Many patients with biochemical relapse after definitive therapy for prostate cancer receive androgen deprivation therapy. PSA levels eventually will rise despite castrate levels of testosterone. Many of these patients have nonmetastatic disease and do not develop metastases for a median of 30 mos (Smith MR JCO, 2005). However, there is no standard therapy for patients with nonmetastatic CRPC. ENTHUSE M0 (Study 15) is a global phase III study, now closed to enrollment, comparing zibotentan 10 mg vs placebo in nonmetastatic CRPC patients. Coprimary endpoints are overall survival and radiographic progression or death. Patients are screened for metastases by bone and CT/MRI scans. An unexpectedly high number of patients failed screening, prompting this analysis. Methods: All screened patients were included. For each investigator, the number of patients who enrolled and who failed screening were recorded. Screen fail reasons were recorded. Screen failure rates were computed by clinical specialty (oncology or urology) and geographic region by dividing the number of screen failures by the number of enrolled patients in each category. Results: As of January 14, 2011, 2583 patients completed screening, and 1169 (45%) failed screening. Screen failure rates were not different by clinical specialty or by geographic region. The leading causes of screen failures by clinical specialty are listed in the table. Conclusions: These data suggest that detectable asymptomatic metastatic disease may exist in about 30% of presumed nonmetastatic CRPC. These findings stress the value of periodic staging studies in men with CRPC, as those with detectable metastatic CRPC may benefit from emerging therapies. Screen failure criteria, n (%) Oncology (631 patients enrolled) Urology (1,885 patients enrolled) Detection of metastatic disease 184 (29) 566 (30) Creatinine clearance of <50 mL/min 45 (7) 156 (8) Long QTc interval 24 (4) 82 (4) Absence of biochemical progression 27 (4) 76 (4) Testosterone level >70 ng/dL (noncastrate) 15 (2) 71 (4) Total screen failures, n 283* 873* * Some patients had >1 reason for screening failure.

Role of detection of metastatic disease as a leading cause of screening failure in an ongoing phase III trial of zibotentan versus placebo in patients with nonmetastatic castration-resistant prostate cancer (CRPC).

135 Background: Many patients with biochemical relapse after definitive therapy for prostate cancer receive androgen deprivation therapy. Although most patients experience a decline in PSA, PSA eventually rises despite a castrate level of testosterone. Many of these patients have non-metastatic disease and do not develop metastases for a median of 30 mos (Smith MR. JCO, 2005). However, there is no standard therapy for asymptomatic patients with non-metastatic CRPC. ENTHUSE M0 (Study 15) is an ongoing global phase III study comparing zibotentan 10 mg (an oral specific endothelin A receptor antagonist) vs placebo in non-metastatic CRPC patients. Co-primary endpoints are overall survival and progression-free survival; secondary endpoints are safety, PSA, quality of life, and time to symptomatic progression. Eligible patients are screened for metastases by bone and CT/MRI scan and other parameters. An unexpectedly high number of patients failed screening, prompting this analysis. Methods: All patients who were screened were included in the analysis. Reasons for exclusion were recorded. Results: As of June 3, 2010, 1,756 patients completed screening. Of these patients, 960 (55%) were randomized and 796 (45%) failed screening. The leading causes of screen failures are listed in the table. Exclusion rates by investigator specialty and country will be reported. Conclusions: As 30% of patients had metastatic disease on screening and were excluded, these data suggest that the frequency of asymptomatic metastases is high in men thought to have non-metastatic CRPC. These findings stress the value of periodic staging studies in men progressing from hormone sensitive to non-metastatic CRPC as metastatic CRPC patients may benefit from standard treatments or research treatments on other protocols. [Table: see text] [Table: see text]

Salvage Therapy With Bicalutamide 150 mg in Nonmetastatic Castration-resistant Prostate Cancer

To evaluate the rate and duration of prostate-specific antigen (PSA) response to high-dose bicalutamide (150 mg) in nonmetastatic castration-resistant prostate cancer patients and its impact on metastasis-free survival. This single center, prospective study included 38 prostate cancer patients surgically or medically castrated who had PSA increases above their nadir after previous antiandrogen manipulation and in absence of bone metastases. Patients were given daily dose of bicalutamide 150 mg. Clinical evaluations and serum PSA testing were performed every 3 months. Response was defined according to PSA decline from baseline as if ≥ 50% or ≥ 85%. The duration of response was the time from entering into study until PSA increased ≥ 25% or ≥ 2 ng/ml from the nadir. Bone scintigraphy was repeated at PSA increase or at symptom appearance. The mean follow-up was 34.5 months (range, 3-75.2). A PSA decline was observed in 17 of 38 patients (44.7%): 7 (18.4%) ≥ 85% and 10 (26.3%) ≥ 50 but < 85% responders. The median duration of response was 18.5 months for partial and 37.4 months for complete responders. The median time to metastasis was 52.5 months for responders and 15.7 months for nonresponders (Log-Rank test 9.3, P = .002). High-dose bicalutamide can induce a second response in almost half of castration-resistant prostate cancer patients without metastasis. The duration of response is more than 1.5 years on average and responders have prolonged metastasis-free survival.