Symptomatic Castration-resistant Prostate Cancer Research Articles

Real-world utilization patterns of radium-223 in metastatic prostate cancer in the United States: An administrative claims database study.

79 Background: Radium (Ra)-223 is approved for use in men with symptomatic castration resistant prostate cancer (CRPC) with bone metastases, demonstrating benefits in terms of overall survival and quality of life with a reliable safety profile. In the rapidly evolving treatment landscape for prostate cancer, real-world (RW) data on Ra-223 utilization are limited. We aimed to examine the RW utilization patterns of Ra-223 in patients with metastatic prostate cancer using a large administrative claims database in the US. Methods: A retrospective cohort of men treated with Ra-223 was identified using the closed claims private payor database of the Komodo Research Dataset covering the period from 01/01/2017 to 06/30/2022. The earliest administration of Ra-223 in men with bone metastatic prostate cancer was considered as index date. Individuals were required to have continuous insurance coverage at least 12-month pre-index (baseline) and least 6-month post index or until death if patients survived < 6 months (follow-up). Logistic regression was used to identify baseline demographic, clinical, medications, or healthcare resource use-related factors associated with receiving 5+ cycles of Ra-223. Results: The study cohort comprised of 1,376 men with a median age of 68 years at the time of Ra-223 initiation. Most men were treated by oncologists (52.2%), having bone only metastases (51.5%), having Charlson comorbidity index (CCI) ≥ 1 (76.2%). Diabetes (34.1%), peripheral vascular disease (29.9%), pulmonary disease (25.9%) and mild liver disease (25.1%) were the most common pre-existing comorbidities. Therapies received prior to Ra-223 were androgen receptor pathway inhibitors (75.4%), chemotherapy (32.1%), sipuleucel-T (13.7%) and bone health agents (73.7%). Ra-223 was utilized as a combination therapy by 26.0% of the overall population, predominately with enzalutamide. Nearly 15%, 38%, and 31% received Ra-223 (mono or combination therapy) as 1st, 2nd, and 3rd line therapy, respectively. Approximately 46% of the overall cohort and 54% of those who survived ≥ 6 months had received 5+ cycles, respectively. In regression analysis, men with short survival (<6 month) [Odds ratio, OR: 0.05, 95% confidence interval (CI): 0.03, 0.10], low CCI (0 vs. 4+) (OR: 0.38, 95% CI:0.19, 0.76), and pulmonary disease (OR: 0.71, 95% CI: 0.52, 0.97) had lower likelihood of completion of 5+ cycles. Conclusions: Nearly half of men completed 5+ cycles of Ra-223 therapy in a large US cohort of relatively young mCRPC men with private health insurance. Advanced disease state with short survival and low comorbidity were key factors associated with lower completion of 5+ cycles. The findings highlight the importance of utilizing Ra-223 early after mCRPC diagnosis, when the probability of >6-month survival is higher, to enhance treatment completion that has been shown to result in better outcomes.

Health-related quality of life with enzalutamide versus flutamide in castration-resistant prostate cancer from the AFTERCAB study

BackgroundPatient-reported outcome (PRO) measures can provide valuable information in evaluating patients’ health-related quality of life (HRQoL). Post hoc analysis of the AFTERCAB study was conducted to evaluate the HRQoL benefit of enzalutamide plus androgen deprivation therapy (ADT) compared to flutamide plus ADT for the treatment of patients with castration-resistant prostate cancer (CRPC) in Japan.MethodsThe open-label AFTERCAB study was conducted from November 2016 to March 2020 in Japanese men aged ≥ 20 years with asymptomatic or mildly symptomatic CRPC. Patients received enzalutamide plus ADT or flutamide plus ADT, respectively, as first-line alternative androgen therapy (AAT). HRQoL was analyzed through the Functional Assessment of Cancer Therapy–Prostate, EuroQoL 5-Dimension 5-Level instruments, Brief Pain Inventory–Short Form, and Brief Fatigue Inventory. The longitudinal changes in HRQoL, HRQoL deterioration based on minimally important difference (MID), and time to HRQoL deterioration were evaluated for first-line AAT.ResultsOverall, HRQoL between the enzalutamide and flutamide groups was similar during first-line treatment. No statistically significant HRQoL difference in change from baseline to week 61 (least square mean difference; p value) was observed. Furthermore, proportions of pain progression, symptom worsening, and HRQoL deterioration based on MID, were not significantly different between groups.ConclusionsThe results were similar in all subscales of each PRO, demonstrating similar HRQoL deterioration based on MID criteria between the enzalutamide and flutamide groups.

ETCTN 10437: A single-arm phase II study of bone-targeted sn-117m-DTPA in symptomatic castration-resistant prostate cancer with skeletal metastases.

TPS5095 Background: Most patients with metastatic castration resistant prostate cancer (mCRPC) develop bone metastases with debilitating pain that is itself associated with shorter survival. Several bone-seeking radionuclides have been developed for palliation of metastatic bone pain. To date, radium-223 dichloride is the first and only approved targeted alpha therapy for mCRPC; the major dose limitation is bone marrow toxicity with modest pain relief. Sn-117m-diethylenetriaminepentaacetic acid (DPTA), is a complex of a radioisotope of tin with DTPA. It emits a low-energy conversion electron and also yields a gamma emission. Sn-117m-DPTA localizes selectively in bone, and the limited range (0.2-0.3 mm) of its conversion electrons resulting in deeper tissue penetration with less radiation effects on bone marrow as compared to radium-223 dichloride. Srivastava et al. (1998) reported in a phase I/II study of patients with painful bone metastases from a variety of solid tumors, 45% of patients obtained reduction of pain by at least 50%, and 30% had complete relief of pain for more than two weeks after one injection. Thus, Sn-117m-DTPA has high palliative efficacy with little significant toxicity. Additional evaluation of this agent in mCRPC patients is urgently required. Methods: The study is a phase 2 single-arm clinical trial of Sn-117m-DPTA (20 mCi/70Kg or 0.28 mCi/kg) intravenously every 8 weeks for two injections for patients with mCRPC metastatic to at least two bone sites with at least one clinically meaningful pain site at baseline. Re-treatment with additional two cycles is allowed if patients meet re-treatment criteria. Key eligibility criteria include 1) refractory mCRPC patients who progressed on any lines of therapies 2) self-reported bone pain (≥4 on an 11-point pain intensity scale), and 3) must be on either regular pain medication or have undergone palliative radiation for bone pain within 12 weeks prior to starting study treatment. Key exclusion criteria include 1) visceral metastases and 2) malignant lymphadenopathy exceeding 3cm in short-axis diameter. Twenty-five patients will be enrolled with a primary objective to assess the efficacy of Sn-117m-DTPA on sustained pain response; defined as 1) achieving pain index ≤3 index within a 12-week period and 2) maintaining pain index ≤3 over a 16-week period. Secondary endpoints include patient reported outcomes, adverse events, progression-free survival and overall survival. Correlative aims include assessing blood (systemic inflammatory markers) and tissue biomarkers (gene sequencing and polo-like kinase-1) for association with clinical benefit. An interim analysis will be performed to assess efficacy after 10 patients become evaluable. The study began enrolling patients in December 2021 and is ongoing. Clinical trial information: NCT04616547.

A single arm phase II study of bone-targeted Sn-117\xa0m-DTPA in symptomatic castration-resistant prostate cancer with skeletal metastases

BackgroundSeveral bone-seeking radionuclides have been developed for palliation of metastatic bone pain since 1956, however, so far radium-223 dichloride is the first and only Food and Drug Administration (FDA) approved targeted alpha therapy for metastatic castration-resistant prostate cancer (mCRPC) based on ALSYMPCA phase 3 study. While radium-223 does improve pain and overall survival outcomes, the improvement can come at the expense of side effects such as bone marrow toxicity. The development of new and better treatment with long-standing pain relief is clearly an unmet medical need.MethodsThe study is a non-randomized phase II study. The study population consists of 25 patients with CRPC who had progressed on any lines of prior therapies and whose serum testosterone level is less than 50 ng/dl and have metastatic lesions to at least two bone sites, with at least one site that has clinically meaningful pain at baseline (≥ 4 on an 11-point intensity scale). Eligible patients will be given two cycles of Sn-117 m-DTPA every 8 weeks or 56 days. Treatment will be administered by slow IV injection over 5–10 min. Retreatment after two cycles is allowed if patients meet the following retreatment criteria. The primary objective is to evaluate the efficacy of Sn-117 m-DTPA on sustained pain response in patients with CRPC metastatic to at least two bone sites and at least one with clinically meaningful pain at baseline (≥ 4 on an 11-point pain intensity scale). Sustained pain response is defined as: 1) achieving pain index ≤ 3 within a 12-week period and 2) maintaining pain index ≤ 3 over a 16-week period. The secondary objectives are: safety and tolerability, measurement of Sn-117 m-DTPA activity by gamma-camera dosimetry scans, therapeutic efficacy, time to the first symptomatic skeletal event, duration of pain response, changes in PSA and ALP levels, patient-reported outcomes and progression free survival and overall survival.DiscussionSn-117 m-DTPA is a unique bone-targeting theranostic radiopharmaceutical agent that selectively binds most heavily to bone metastases sites. This study will be the first prospective phase II trial to assess the pain efficacy and anti-tumor activity of Sn-117 m-DTPA in mCRPC with at least one clinically meaningful pain at baseline.Trial registration.ClincialTrials.gov Identifier: NCT04616547.

Pelvic exenteration in patients with locally advanced, symptomatic castration-resistant prostate cancer

Ziel der ArbeitDie retrospektive Evaluation der klinischen Ergebnisse nach palliativer pelviner Tumorchirurgie (ppTC) bei subvesikalen und supravesikalen Komplikationen eines lokal symptomatisch fortgeschrittenen kastrationsresistenten (CRPC) Prostatakarzinoms.Patienten und MethodenInsgesamt 84 Patienten mit lokal fortgeschrittenem und symptomatischem CRPC erhielten eine radikale Zystoprostatektomie (n = 71, 83,3 %) oder anteriore und posteriore Exenteration (n = 13, 16,7 %). Das lokale Staging erfolgte mittels MRT des Beckens, Zystoskopie und Rektoskopie. Ein systemisches Staging erfolgte mittels Computertomographie von Thorax, Abdomen, Becken sowie Skelettszintigraphie. Die perioperativen Komplikationen wurden nach Clavien-Dindo-Klassifikation evaluiert. Das primäre Studienziel war das symptomfreie Überleben (sÜL, Fehlen von Symptomen am unteren oder oberen Harntrakt, fehlende endoluminale oder perkutane Intervention).ErgebnisseNach einem medianen Follow-up von 43,5 (3–139) Monaten betrug das sÜL nach einem und drei Jahren 95,2 % bzw. 86,7 %. Insgesamt 86,7 % der Patienten blieben für ihre gesamte verbleibende Lebensdauer bezüglich lokaler Symptome beschwerdefrei. Das OS nach einem und drei Jahren betrug 92,9 % bzw. 54,7 %. Clavien-Dindo-Grad-2-, -3- und -4-Komplikationen ergaben sich in 19 (22,6 %), 7 (8,3 %) bzw. 3 (3,6 %) Patienten.SchlussfolgerungenDie ppTC ist mit einer geringen Komplikationsrate möglich und führt zu deutlicher Symptomlinderung bei ca. 90 % der Patienten, von denen > 80 % für die verbleibende Lebenszeit beschwerdefrei verbleiben. Voraussetzung sind die Patientenauswahl, ein interdisziplinäres Vorgehen und eine entsprechende chirurgische Expertise.

Enzalutamide + androgen deprivation therapy (ADT) versus flutamide + ADT in Japanese men with castration-resistant prostate cancer: AFTERCAB study.

ObjectivesThe objective of the study is to compare the efficacy and safety of alternative androgen therapy (AAT) with enzalutamide + androgen deprivation therapy (ADT) and flutamide + ADT in the treatment of Japanese men with metastatic or nonmetastatic castration‐resistant prostate cancer (CRPC) who progressed despite combined androgen blockade (CAB) with bicalutamide + ADT. AAT treatment sequence was also investigated.Materials and methodsThe open‐label, Phase 4 AFTERCAB study (NCT02918968) was conducted from November 2016 to March 2020 in Japanese men aged ≥20 years with asymptomatic or mildly symptomatic CRPC. Patients were initially randomized to enzalutamide (160 mg/day) + ADT (enzalutamide first) or flutamide (375mg/day [125mg three times daily]) + ADT (flutamide first) as first‐line therapy. Following prostate‐specific antigen (PSA) progression, other disease progression, or discontinuation of first‐line therapy due to an adverse event (AE), patients switched to the other treatment as second‐line therapy. The primary endpoint was time to PSA progression with first‐line therapy (TTPP1). Secondary endpoints included TTPP2 (TTPP1 + time to PSA progression with second‐line therapy). AEs were monitored to assess safety.ResultsOverall, 206 men were randomized (enzalutamide first, n = 102; flutamide first, n = 104) and stratified by study site and disease stage; 133 patients transitioned to second‐line therapy (enzalutamide first, n = 48; flutamide first, n = 85). TTPP1 was significantly improved with enzalutamide first versus flutamide first (median 21.4 months vs. 5.8 months; hazard ratio [HR] 0.42; 95% confidence interval [CI] [0.29, 0.61]). TTPP2 was numerically improved with enzalutamide first versus flutamide first (median not reached vs. 21.2 months; HR 0.76; 95% CI [0.48, 1.19]). Both treatments were generally well tolerated, with AEs consistent with their known safety profiles.ConclusionFirst‐line AAT with enzalutamide + ADT provided a significant improvement in time to PSA progression versus flutamide + ADT. Enzalutamide + ADT may therefore be the preferred first‐line AAT option in Japanese men with metastatic or nonmetastatic CRPC who progress despite CAB with bicalutamide + ADT.

Enzalutamide plus androgen deprivation therapy (ADT) versus flutamide plus ADT in men with castration-resistant prostate cancer (CRPC): AFTERCAB.

81 Background: Enzalutamide has been approved for the treatment of CRPC in Japan since 2014. This study compared the efficacy and safety of enzalutamide + ADT and flutamide + ADT in the treatment of men with CRPC who progressed despite combined androgen blockade with bicalutamide + ADT. The sequential order of treatment was also investigated. Methods: The open-label, Phase 4 AFTERCAB study (NCT02918968) was conducted from November 2016–March 2020 in Japanese men aged ≥20 years with asymptomatic or mildly symptomatic CRPC (metastatic or nonmetastatic) and an Eastern Cooperative Oncology Group performance status of 0 or 1 who progressed despite bicalutamide + ADT. Patients were initially randomized to enzalutamide (160 mg/day) + ADT (enzalutamide first) or flutamide (375 mg/day [125 mg 3 × daily]) + ADT (flutamide first) as first-line therapy. Following prostate-specific antigen (PSA) progression, other disease progression, or discontinuation of first-line therapy due to an adverse event (AE), patients switched to the other treatment as second-line therapy. The primary endpoint was time to PSA progression with first-line therapy (TTPP1). Secondary endpoints included TTPP2 (TTPP1 + time to PSA progression with second-line therapy). AEs were monitored to assess safety. Results: 206 men were randomized, stratified by study site and disease stage. Baseline demographics and disease characteristics were similar between treatment arms. Median treatment exposure was 14.3 months (range 0.8–35.9) with enzalutamide first and 5.6 months (range 0.3–37.7) with flutamide first. 133 patients transitioned to second-line therapy (n=48 for enzalutamide first and n=85 for flutamide first). TTPP1 was significantly improved with enzalutamide first versus flutamide first; numerically longer TTPP2 was observed with enzalutamide first versus flutamide first (Table). With first-line therapy, 92.2% (n=94) of patients reported treatment-emergent AEs (TEAEs) and 28.4% (n=29) reported serious TEAEs for enzalutamide first. Corresponding numbers for flutamide first were 76.0% (n=79) for TEAEs and 14.4% (n=15) for serious TEAEs. Conclusions: Treatment with enzalutamide + ADT provided a significant improvement in time to PSA progression versus flutamide + ADT as first-line therapy. Both treatments were generally well tolerated, with AEs consistent with the known safety profiles. Clinical trial information: NCT02918968. [Table: see text]

High Health-Related Quality of Life During Dendritic Cell Vaccination Therapy in Patients With Castration-Resistant Prostate Cancer.

BackgroundMaintaining health-related quality of life (HRQoL) is highly desirable during systemic therapies for patients with castration-resistant prostate cancer (CRPC). Patient-reported outcome measures (PROs) were studied in our phase IIa trial on cellular-based immunotherapy with dendritic cells (DC).MethodsWe treated 21 chemo-naive asymptomatic or minimally symptomatic patients with CRPC with maximally three cycles of DC vaccinations (ClinicalTrials.gov, NCT02692976). Here, we report the impact of DC vaccination on HRQoL. PROs were assessed using the EORTC-QLQ-C30, the EORTC-QLQ-PR25, Checklist Individual Strength (CIS20-R), and Beck Depression Inventory Primary Care questionnaires. Short-term and long-term vaccine-related effects on HRQoL were studied.ResultsQuestionnaires were collected at baseline (n=20), week 6 (n=19), week 12 (n=18), week 24 (n=13), week 50 (n=8) and week 100 (n=2). No clinically relevant differences in symptom-related outcome, functioning-related outcome, and Global Health Status were observed directly after the first cycle of DC vaccinations (week 6) and at follow-up (week 12) compared to baseline. HRQoL remained high throughout the vaccination cycle and six weeks afterward. In radiographic non-progressive patients, who continued DC vaccination, high HRQoL scores were observed up to one and two years after study enrolment.ConclusionsPatients with asymptomatic or minimally symptomatic CRPC show high HRQoL throughout DC-based immunotherapy. This is a clinically relevant finding in this older-aged patient population with advanced prostate cancer.

Pelvic exenteration surgery in patients with locally advanced castration‐naïve and castration‐resistant, symptomatic prostate cancer

To evaluate retrospectively the surgical, symptomatic and oncological outcomes of pelvic exenteration surgery (PES) in men with significant intrapelvic complications of locally advanced castration-sensitive (CSPC) and castration-resistant prostate cancer (CRPC). A total of 103 patients with locally advanced progressive and symptomatic CSPC or CRPC underwent PES (radical cystoprostatectomy, n = 71 [68.9%]; radical prostatectomy with continent vesicostomy, n = 9 [8.7%]; total exenteration, n = 23 [22.3%]). All patients underwent local staging via magnetic resonance imaging, cystoscopy and rectoscopy. Systemic staging was carried out with chest, abdominal and pelvic computed tomography scans and bone scans. Peri-operative complications were assessed according to Clavien-Dindo classification. Symptom-free and overall survival were evaluated using the Kaplan-Meier method. Statistical tests were two-tailed with a P value <0.05 taken to indicate statistical significance. After a median (range) follow-up of 36.5 (3-123) months, the symptom-free survival rate at 1 and 3years was 89.2% (n = 89) and 64.1% (n = 66), respectively. The median symptom-free survival was 27.9months. A total of 78.6% of the patients were symptom-free during their remaining lifetime. The overall survival rate at 1 and 3years was 92.2% and 43.7%, respectively, and the median overall survival was 33.6months. Clavien-Dindo grades 2, 3 and 4 complications developed in 31 (30.6%), 12 (11.6%) and eight patients (8.1%), respectively. Pelvic exenteration surgery is technically feasible in well-selected patients, resulting in symptom relief in >90% of patients, covering 80% of their remaining lifetime.

Exenterative surgery to improve quality of life on men with locally advanced, symptomatic castration-resistant prostate cancer.

77 Background: Invasion of the urinary bladder and/or the rectum by locally advanced castration sensitive (CSPC) or castration resistant PCA (CRPC) can result in debilitating symptoms with a significant negative impact on the patient’s well-being. Local progression might develop despite the application of new life prolonging agents. It was the purpose to retrospectively review the surgical and oncological outcome following pelvic exenteration surgery (PES) for locally advanced and symptomatic CRPC. Methods: Retrospective, single-centre, dual surgeon study of 103 men with symptomatic locally progressive and symptomatic CS- and CRPC treated between 2008 and 2019. Primary endpoint was symptomatic free survival (SFS) and the secondary endpoint were overall survival (OS) and complications defined by Clavien-Dindo criteria. Statistical tests were two-tailed with a p-value &lt;0.05 considered to indicate significance. Symptom-free survival and cancer specific survival were calculated using Kaplan-Meier analysis. Results: 9 (8.7%), 71 (68.8%) and 21 (22.4%) patients underwent radical prostatectomy, radical cystoprostatectomy or anterior and posterior exenteration, resp. After a median follow-up of 36.5 (3 – 123) months, the SFS at 1 and 3 years was 89.2% (n=89) and 64.1% (n=66). The median SFS was 27.9 months. 78.6% of the patients were symptom-free during their remaining lifetime. OS at 1 and 3 years was 92.2% and 43.7%, respectively, and the median OS was 33.6 months. Clavien-Dindo grade 2, 3 and 4 complications developed in 31 (30.6%), 12 (12%) and 8 (8.1%), respectively. Conclusions: PES is a technically feasible approach in well-selected patients resulting in symptom relief of &gt; 90% of patients which covered almost 80% of the remaining life time. Adequate preoperative imaging studies, endoscopic evaluation and extensive surgical experience is mandatory to achieving a benefit for the individual patient with improvement of quality of life.

Circulating tumor cells and γH2AX as biomarkers for responsiveness to radium-223 in advanced prostate cancer patients.

Aim:Radium-223 improves overall survival in patients with metastatic castration-resistant prostate cancer to the bone. Radium-223 causes double-strand DNA breaks and produces γH2AX, a potential biomarker for response. We examined the feasibility of tracking γH2AX positivity and numeration in circulating tumor cells.Patients & methods:Ten patients with biopsy-confirmed symptomatic M1b castration-resistant prostate cancer received radium-223 as standard of care and were assessed for γH2AX level changes following doses 1, 3 and 6.Results:Trend tests confirmed that patients with ≥50% increase in circulating tumor cells positive for γH2AX postradium-223 therapy had a lower risk of death (p = 0.035).Conclusion:Regular interval measurements of γH2AX are feasible. The potential correlation between γH2AX changes and overall survival warrants further investigation.

Case series of reports of pruritus and sipuleucel-T submitted to the Food and Drug Administration Adverse Event Reporting System

Sipuleucel-T, an autologous active cellular immunotherapy, is indicated for the treatment of asymptomatic or minimally symptomatic castration-resistant prostate cancer. The U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) received a report of pruritus without rash following the second dose of sipuleucel-T in a patient who had otherwise not started any new medications concurrent with the first and second doses of sipuleucel-T. No further sipuleucel-T was administered, but symptoms persisted for at least 6 weeks despite treatment with several medications aimed at symptomatic relief of pruritus. Rash is the only dermatologic adverse event included in the sipuleucel-T U.S. package insert. A search of the FAERS database yielded seven additional U.S. reports of pruritus and sipuleucel-T identified as the primary suspect medication; two of these occurred prior to the administration of sipuleucel-T (following leukapheresis). In data mining analyses, pruritus following sipuleucel-T was not reported more frequently than expected when compared to all other adverse event-drug/biologic combinations in FAERS. Thus, pruritus following sipuleucel-T administration was rarely, but not disproportionately, reported to FAERS. Although we cannot exclude the possibility that diabetes, malignancy, or other conditions may have contributed to pruritus in our index patient, in view of the timing of sipuleucel-T therapy and onset of symptoms, a drug/biologic-related reaction is plausible. In the appropriate clinical scenario, sipuleucel-T (or its components) should not be overlooked as a potential etiological agent in pruritus.

Adverse Events Associated With the Use of Sipuleucel-T Reported to the US Food and Drug Administration’s Adverse Event Reporting System, 2010-2017

Sipuleucel-T was the first therapeutic cancer vaccine approved by the US Food and Drug Administration (FDA) in 2010. Although almost a decade has passed since its approval for the treatment of asymptomatic or minimally symptomatic castration-resistant prostate cancer (CRPC), there remains a paucity of literature describing safety data in the postmarketing period. To describe the postmarketing safety experience for sipuleucel-T. In this case series study, US reports for sipuleucel-T submitted to the FDA's Adverse Event Reporting System were searched and reviewed between April 29, 2010, and December 31, 2017. This system is a spontaneous safety surveillance database for drug and therapeutic biologic products. The analysis of 3216 reports and select case reviews were undertaken between February and November 2018. Descriptive statistics were used to assess adverse event reports for sipuleucel-T. Empirical Bayes Geometric Means (EBGM) and their 90% confidence intervals (CIs) were computed to identify disproportionate (ie, at least twice the expected) reporting of sipuleucel-T-event pairs. Selected adverse events and death reports were individually reviewed. In total, 3216 reports were identified for sipuleucel-T, of which 2014 (62.6%) were serious. For all included reports, the patients' median (interquartile range) age was 73 (67-79) years, and 3149 were specified to be males. Chills (n = 318), malaise (n = 196), pyrexia (n = 189), culture positive (n = 184), fatigue (n = 180), and nausea (n = 173) were among the most commonly reported adverse events. Infusion-related reactions (EBGM, 12.1; 90% CI, 9.4-15.3), infections, vascular events, and transient ischemic attacks (EBGM, 2.9; 90% CI, 2.2-3.9) were reported disproportionately. Among 249 deaths for which relevant dates were available, 128 (51.4%) were reported within 30 days of a sipuleucel-T infusion, of which 81.2% included a specified cause of death; of these 104 deaths, there were 37 neoplasms (35.6%), 25 cardiac disorders (24.0%), 18 nervous system disorders (17.3%), and 9 infections (8.7%). Reported adverse events were generally consistent with the safety experience observed in prelicensure studies and described in the sipuleucel-T package insert. Off-label use among overtly symptomatic men with CRPC, reporting bias, or lack of product effectiveness may have influenced the reporting of deaths within 30 days of treatment initiation. With this overview of sipuleucel-T experience, the present study serves as a resource for health care professionals and patients as they weigh the risks and benefits of treatment in the context of all available therapeutic options for CRPC.

Three-year follow-up of a phase II study of radium-223 dichloride in Japanese patients with symptomatic castration-resistant prostate cancer and bone metastases

BackgroundRadium-223 is a first-in-class targeted alpha therapy to prolong overall survival (OS) in castration-resistant prostate cancer with bone metastases (mCRPC). The aim of the present analysis was to assess the long-term safety with radium-223 in Japanese patients with mCRPC.MethodsPatients with symptomatic mCRPC, ≥ 2 bone metastases and no known visceral metastases received up to 6 injections of radium-223 (55 kBq/kg), one every 4 weeks. Adverse events (AEs) considered to be related to radium-223 were reported until 3 years after the first injection. Pre-specified conditions, such as acute myelogenous leukemia, myelodysplastic syndrome, aplastic anemia, primary bone cancer, or other primary malignancies, were reported regardless of causality.ResultsOf the 49 patients enrolled in the study, 44 (89.8%) entered the survival follow-up period and 33 (67.3%) died. Throughout the entire study, there were no reports of second primary malignancy or other pre-specified conditions. Eight patients (16.3%) experienced post-treatment drug-related AEs, which were all hematological (anemia and decreased lymphocyte, platelet, and white blood cell counts). No serious post-treatment drug-related AEs were reported. Updated median OS was 19.3 months (95% CI: 14.2, 28.5).ConclusionsIn Japanese patients with symptomatic mCRPC and bone metastases, radium-223 had a favorable long-term safety profile with no second primary malignancies reported. Taken together with median OS, which was comparable to that in the pivotal phase III ALSYMPCA study, these results support continued benefit from radium-223 in Japanese patients with mCRPC.

PT285 - Multivisceral surgery in men with locally advanced, symptomatic castration-resistant prostate cancer

PT285 - Multivisceral surgery in men with locally advanced, symptomatic castration-resistant prostate cancer

Meaningful differences and validity for the NCCN/FACT-P Symptom Index: An analysis of the ALSYMPCA data.

The Functional Assessment of Cancer Therapy-Prostate (FACT-P) and the National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy-Prostate Symptom Index-17 (NFPSI-17) are 2 commonly used measures for patient-reported outcomes in prostate cancer trials. Their use may be enhanced by a better understanding of how change scores on the measures should be interpreted. Using data from the phase 3 Alpharadin in Symptomatic Prostate Cancer Patients trial, this study estimated important change scores on the FACT-P and the NFPSI-17 via a combination of distribution- and anchor-based methods. These data were also used to establish evidence for the validity of the NFPSI-17. The available data suggested the following important difference ranges: 2 to 4 points for the Prostate Cancer Subscale, 5.5 to 8.5 points for the Trial Outcome Index, 1 to 1.5 points for the 3-item Pain Scale, 1 to 2 points for the 4-item Pain Scale, 4 to 6 points for the NFPSI-17, 2 to 3.5 points for NFPSI-Disease-Related Symptoms-Physical, 0.5 points for NFPSI-Disease-Related Symptoms-Emotional, 1 to 1.5 points for NFPSI-Treatment Side Effects, and 0.5 to 1 point for NFPSI-Function/Well-Being. The internal consistency reliability of the NFPSI-17 and most of its subscales was good to excellent (>.70). Significant support was also found for the known groups validity of the NFPSI-17 (and most of its subscales) on the basis of the Eastern Cooperative Oncology Group performance status, the total alkaline phosphatase, the presence of a skeletal-related event during treatment, and the prostate-specific antigen response before the end of treatment. The secondary analysis supports the continued use of the FACT-P, the NFPSI-17, and its related subscales in future research on the quality of life of patients with symptomatic castration-resistant prostate cancer with bone metastases.

Radium-223 in the therapeutic sequence of metastatic castration-resistant prostate cancer

ContextRadium-223 is an α-particle transmitter with specific action on bone metastases. The Alpharadin in Symptomatic Prostate Cancer Patients (ALSYMPCA) study showed that radium-223 extended overall survival and delayed the onset of bone events in patients with symptomatic castration-resistant prostate cancer with bone metastases (mCRPC) and without visceral metastases, with a good safety profile. ObjectiveTo review the new scientific evidence on radium-223 based on prespecified and post hoc analyses of the ALSYMPCA study and on early-access programs after the publication of the ALSYMPCA study, thereby providing new data on the management of patients with mCRPC. Acquisition of evidenceWe searched for evidence on PubMed and in the abstracts of international urology and oncology congresses, as well as ongoing clinical trials (ClinicalTrials.gov). Synthesis of the evidenceThe results of the reviewed studies offer promising results that will broaden the therapeutic benefits of radium-223 to patients with mild symptoms and those with no symptoms. The results also provide preliminary evidence on the benefit of radium-223 treatment after the failure of docetaxel, enzalutamide or abiraterone or the combination of radium-223 with these agents or other therapeutic agents such as bone-targeted agents and immunotherapy. ConclusionRadium-223 can be a treatment option for patients with mild symptoms and can provide a therapeutic benefit after failure of currently available treatments or in combination with these treatments. This evidence should be corroborated in clinical trials before being added to clinical practice.

Phase II study of radium-223 dichloride in Japanese patients with symptomatic castration-resistant prostate cancer

BackgroundRadium-223 dichloride (radium-223) is the first targeted alpha therapy approved for the treatment of castration-resistant prostate cancer (CRPC) with bone metastases. This study investigated the efficacy and safety of radium-223 in Japanese patients with symptomatic CRPC and bone metastases.MethodsIn this open-label, multicenter, phase II study, patients with progressive, symptomatic CRPC and bone metastases were treated with radium-223 (55 kBq/kg, intravenously) in a 4-week cycle for six cycles. The primary endpoint was the percent change in total alkaline phosphatase (ALP) from baseline at 12 weeks. Secondary endpoints included the percent ALP change from baseline to end of treatment (EOT), ALP response rates, percent change in prostate-specific antigen (PSA) from baseline to 12 weeks and EOT, PSA response rates, overall survival (OS), and time to symptomatic skeletal events (SSEs). Adverse events were monitored throughout the study period.ResultsOf the 49 Japanese patients (median age 74 years), 28 completed all infusions. Mean percent change in total ALP and PSA from baseline to 12 weeks was −19.3 and +97.4%, respectively. One-year OS and SSE-free rate at the end of active follow-up were 78 and 89%, respectively. The ALP response rate was 31%, while the PSA response rate was 6%. Grade 3/4 treatment-emergent adverse events observed in ≥10% of patients included decreased lymphocyte count (14%), anemia (14%), anorexia (10%), and bone pain (10%).ConclusionsRadium-223 is effective and well tolerated in Japanese patients with CRPC and bone metastases. Results were comparable with the Alpharadin in Symptomatic Prostate Cancer Patients (ALSYMPCA) trial.Clinical trial registrationClinicalTrials.gov NCT01929655.

Radio-223 en la secuencia terapéutica del cáncer de próstata resistente a la castración metastásico

ContextRadium-223 is an □ -particle transmitter with specific action on bone metastases. The Alpharadin in Symptomatic Prostate Cancer Patients (ALSYMPCA) study showed that radium-223 extended overall survival and delayed the onset of bone events in patients with symptomatic castration-resistant prostate cancer with bone metastases (mCRPC) and without visceral metastases, with a good safety profile. ObjectiveTo review the new scientific evidence on radium-223 based on prespecified and post-hoc analyses of the ALSYMPCA study and on early-access programs after the publication of the ALSYMPCA study, thereby providing new data on the management of patients with mCRPC. Acquisition of evidenceWe searched for evidence on PubMed and in the abstracts of international urology and oncology congresses, as well as ongoing clinical trials (ClinicalTrials.gov). Synthesis of the evidenceThe results of the reviewed studies offer promising results that will broaden the therapeutic benefits of radium-223 to patients with mild symptoms and those with no symptoms. The results also provide preliminary evidence on the benefit of radium-223 treatment after the failure of docetaxel, enzalutamide or abiraterone or the combination of radium-223 with these agents or other therapeutic agents such as bone-targeted agents and immunotherapy. ConclusionRadium-223 can be a treatment option for patients with mild symptoms and can provide a therapeutic benefit after failure of currently available treatments or in combination with these treatments. This evidence should be corroborated in clinical trials before being added to clinical practice.

Palliative Radical (Cysto-)prostatectomy for Locally Advanced, Symptomatic Castration-resistant Prostate Cancer

Palliative radical (cysto-)prostatectomy is associated with a median symptom-free survival which covers 75-80% of the remaining lifetime in patients with symptomatic locally advanced castration-resistant prostate cancer.