Symptomatic Skeletal-related Event Research Articles

Health-related quality of life (HRQoL) and pain outcomes for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) who received abiraterone (abi) and olaparib (ola) versus (vs) abi and placebo (pbo) in the phase III PROpel trial.

5012 Background: PROpel (NCT03732820) met its primary endpoint and showed significantly prolonged investigator-assessed rPFS with abi + ola vs abi + pbo at primary analysis (data cut-off [DCO]: 7/30/21; median 24.8 vs 16.6 months (m); hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.54–0.81; P<0.001). HRQoL (based on The Functional Assessment of Cancer Therapy-Prostate [FACT-P] total score) was not different when ola was combined with standard-of-care abi. We present data at the final prespecified overall survival (OS) DCO (10/12/22). Methods: PROpel is a randomised, double-blind trial in 1L mCRPC. Time to pain progression (TTPP) was based on the Brief Pain Inventory-Short Form (BPI-SF) Item 3 ‘worst pain in 24 hours’ and opiate analgesic use (analgesic quantification algorithm) score. Time to first symptomatic skeletal related event (SSRE) was time to use of therapy to prevent/relieve skeletal symptoms, new bone fractures, spinal compression or surgery on bone metastases. HRQoL was assessed by change from baseline (BL) in FACT-P total and subscale scores, BPI-SF pain severity, pain interference and worst pain score between arms using a mixed model for repeated measures. Results: At median follow-up of 33.6 m with abi + ola and 32.1 m with abi + pbo, 17.0% pts (68/399) in the abi + ola arm and 15.1% pts (60/397) in the abi + pbo arm had pain progression (PP) events. The % of pts who had not experienced PP with abi + ola vs abi + pbo was 76.9% vs 77.2% at 24 m and 70.7% vs 71.0% at 36 m. No meaningful difference in TTPP was observed (16% maturity, HR 1.06, 95% CI 0.75–1.50, P=0.75 [nominal], median not reached [NR] either arm). The % of pts who had not had a SSRE with abi + ola vs abi + pbo was 86.1% vs 82.2% at 24 m and 80.8 vs 78.5% at 36 m. No meaningful difference in time to SSRE was observed (12% maturity, HR 0.82, 95% CI 0.55–1.22, P=0.32 [nominal], median NR vs NR). Least-squares mean changes from BL between arms in BPI-SF pain severity (difference, −0.06; 95% CI −0.23–0.12), pain interference (difference, −0.12; 95% CI −0.31–0.06), worst pain score (difference, −0.12; 95% CI −0.35–0.11) and FACT-P total score (difference, −0.54; 95% CI –3.00–1.92) suggest no clinically meaningful difference in HRQoL with abi + ola vs abi + pbo. Least-squares mean change from BL values for FACT-P subscale scores were consistent with FACT-P total score result. Conclusions: PROpel demonstrated a significant delay in rPFS for pts receiving abi + ola vs abi + pbo. Most pts in the trial did not experience a PP event. Abi + ola showed no difference in HRQoL (assessed by FACT-P total and subscale scores, BPI-SF domain and worst pain scores) vs abi + pbo, suggesting pts can derive clinical benefit from abi + ola while maintaining a similar HRQoL compared with a current standard-of-care treatment. Clinical trial information: NCT03732820 .

Pembrolizumab (pembro) plus abiraterone acetate (abi) and prednisone (p) in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC): Results from KEYNOTE-365 cohort D.

118 Background: Abi + p is a standard of care for mCRPC. Cohort D of the phase 1b/2 KEYNOTE-365 study (NCT02861573) was used to evaluate safety and efficacy of the PD-1 inhibitor pembro + abi and p in patients (pts) who had not received chemotherapy for mCRPC. Methods: Chemotherapy-naive pts who had not previously used next-generation hormonal agents (NHAs) for mCRPC or were intolerant to enzalutamide or for whom enzalutamide was ineffective for mCRPC, whose disease progressed ≤6 months before screening, and who had ECOG PS score 0/1 were eligible. Enrolled pts received pembro 200 mg IV Q3W + abi 1000 mg PO QD and p 5 mg PO BID. Primary end points were PSA response rate (PSA decrease ≥50% from baseline), confirmed ORR per RECIST v1.1 by blinded independent central review, and safety. Secondary end points included rPFS per PCWG3-modified RECIST v1.1, DCR (CR + PR + SD or non-CR/non-PD ≥6 mo), DOR, OS, time to symptomatic skeletal-related event, radiographic bone progression, and radiographic soft tissue progression. Results: Of 103 treated pts, 35.9% had RECIST-measurable disease and 26.2% had previously received enzalutamide. Median (range) time from enrollment to data cutoff was 17.6 (9.7-27.0) months. Confirmed PSA response rate in all 103 pts was 56.3%. Overall, 78.6% of pts had a reduction in PSA level from baseline (confirmed and unconfirmed). For 37 pts with RECIST-measurable disease, ORR was 16.2% (1 CR; 5 PRs) overall, 7.7% for those who previously received enzalutamide (n = 13) and 21.7% for those who had not previously received NHAs (n = 23). Two pts with RECIST-nonmeasurable disease had a CR. DOR was not reached (NR; range, 2.1+ to 19.4+ mo); 4 pts had a response ≥12 months. DCR was 44.7% overall, 11.1% in pts who previously received enzalutamide (n = 27), and 57.3% in pts who had not previously used NHAs (n = 75). Additional analyses are listed in the table. Treatment-related AEs (TRAEs) were experienced by 90.3% of pts; 36.9% experienced grade 3-5 TRAEs. Overall, 18.4% of pts had a grade 3/4 ALT laboratory elevation and 12.6% had a grade 3/4 AST elevation. Five pts died of AEs; 1 was treatment-related (myasthenic syndrome). Conclusions: Pembro + abi and p showed antitumor activity in chemotherapy-naive pts with mCRPC. Safety was generally consistent with individual profiles of each agent, although there was an increased incidence of grade 3/4 ALT/AST laboratory elevations than reported for the individual treatments. Clinical trial information: NCT02861573. [Table: see text]

Symptomatic skeletal-related events in patients receiving longer term bone-modifying agents for bone metastases from breast and castration resistant prostate cancers

Symptomatic skeletal-related events in patients receiving longer term bone-modifying agents for bone metastases from breast and castration resistant prostate cancers

Pembrolizumab (pembro) plus enzalutamide (enza) and androgen deprivation therapy (ADT) for patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC): The phase III KEYNOTE-991 study.

TPS184 Background: The combination of pembro, an anti–PD-1 antibody, added to enza, a nonsteroidal antiandrogen agent, has shown antitumor activity in abiraterone-resistant metastatic castration-resistant prostate cancer (mCRPC) in the KEYNOTE-365 trial (NCT02861573) and in pts with mCRPC for whom enza was ineffective in the KEYNOTE-199 trial (NCT02787005). The efficacy of enza may be proimmunogenic, suggesting that it may be additive or synergistic in antitumor activity when combined with pembro. These data indicate that pembro + enza with ADT warrants phase 3 evaluation. Methods: KEYNOTE-991 (NCT04191096) is a randomized, double-blind, placebo-controlled, multicenter phase 3 trial evaluating the efficacy and safety of enza + ADT (luteinizing hormone-releasing hormone agonist/antagonist during study treatment or bilateral orchiectomy) + pembro or placebo in pts with mHSPC. Eligibility criteria include age ≥18 years, mHSPC, ≥2 bone lesions or visceral disease, no prior treatment with next-generation hormone agents, adequate organ function, and ECOG PS 0 or 1. Pts must provide tissue for biomarker analysis. Approximately 1232 pts will be randomized in a 1:1 ratio to receive enza 160 mg orally once daily + ADT + pembro 200 mg intravenously (IV) every 3 weeks (Q3W) or enza 160 mg orally once daily + ADT + placebo IV Q3W. Treatment will continue with pembro up to 35 cycles and treatment with enza will proceed continuously from day 1 of cycle 1 until disease progression, unacceptable toxicity, or withdrawal of consent. The stratification factors are prior docetaxel therapy (yes or no) and presence of high-volume disease (yes or no). Computed tomography or magnetic resonance imaging and radionuclide bone imaging will be used to assess response according to Prostate Cancer Working Group 3 (PCWG3)–modified RECIST v1.1 by blinded independent central review (BICR) every 12 weeks (Q12W) from the date of randomization. Imaging will continue until the end of treatment and will resume Q12W during the posttreatment period. The dual-primary endpoints are BICR-assessed radiographic progression-free survival (rPFS; according to PCWG3-modified RECIST v1.1) and overall survival (OS). Key secondary endpoints are time to first subsequent anticancer therapy (TFST) and time to symptomatic skeletal-related event (TTSSRE). Safety and tolerability will be evaluated using a tiered approach. The dual-primary (rPFS and OS) and key secondary (TFST and TTSSRE) endpoints will be evaluated using a stratified log-rank test. Event rates will be summarized using the Kaplan-Meier method, and hazard ratios will be estimated using a stratified Cox regression model. KEYNOTE-991 is enrolling at 40 sites in Australia, Chile, Colombia, Germany, Israel, Japan, Poland, South Korea, Spain, Switzerland, Taiwan, and the United States. Clinical trial information: NCT04191096.

Overall survival in mCPRC patients treated with Radium-223 in association with bone health agents: a national multicenter study

Purpose Radium-223 has demonstrated efficacy in improving overall survival (OS) and in delaying symptomatic skeletal-related events (SREs). Bone Health Agents (BHA), i.e. RANK ligand inhibitor (Denosumab) and bisphosphonate such as zoledronic acid, are indicated to prevent SREs without a clear survival benefit. SREs on patient health have a high impact and it is, therefore, important to consider the role of new therapies with BHA to better understand the involvement of combination therapy. The primary aim of this multicentric study is to assess OS in mCRPC patients treated with Radium-223 in combination with BHA. Materials and methods 430 consecutive patients treated with Radium-223 alone or in combination with BHA, affected by mCRPC, from January 2015 to July 2019 in six Italian Nuclear Medicine Units, were included. Furthermore, data were collected at baseline, after every Radium-223 administration, and during follow-up, at 3 and 6 months and 1 year after the 6th cycle. Clinical data have been evaluated before starting treatment with Radium-223 and at the end of treatment and/or at progression. Patients who received target bone therapy with BHA before Radium-223 treatment together with patients who did not receive this therapy at all (NO BHA GROUP), were compared to patients treated with concomitant Radium-223 and BHA (BHA GROUP). Results In univariate models (p < .05) several clinical aspects have an impact on OS: concomitant BHA (p = .018), BMI (p .001), ECOG PS (p = .000), Baseline Hb (p = .000), Baseline PSA (p = .000), Baseline tALP (p = .000), Baseline LDH (p = .000), and Baseline neutrophils (p = .009). Baseline Hb, Baseline tALP, and Baseline LDH have been confirmed as statistically significant parameters in multivariate models. Indeed, concomitant BHA has not a significant impact on OS (p = .244) in multivariate models. Conclusions At univariate analysis, our data showed that NO BHA GROUP and BHA GROUP differ in OS by 7 months (95%CI: (1–16.4), p = .02). This is not confirmed at multivariate analysis where after adjusting for other baseline factors, BHA is not significant anymore. This is clearly explained as bias by indication: patients with the same levels of tALP, Hb, and LDH receiving or not receiving BHA are expected to have a similar survival. Our results support and confirm the role of Radium-223 therapy on OS and, furthermore, appear to confirm that BHA treatment has not a survival benefit.

Assessing the quality of life of patients with metastatic castration-resistant prostate cancer with bone metastases receiving [223Ra]RaCl2 therapy.

[223Ra]RaCl2 dichloride treatment in patients with metastatic castration-resistant prostate cancer (mCRPC) is associated with improved overall survival (OS) and a delay in the time to the first symptomatic skeletal-related event. The aim of this study was to evaluate the quality of life (QoL) of patients with mCRPC receiving [223Ra]RaCl2 treatment using the European Organization for Research and Treatment of Cancer (EORTC) validated questionnaire form.Thirty patients with mCRPC were included in this study. The patients were administered the EORTC QLQ-C30 (version 3.0) questionnaire at 5 time points: before [223Ra]RaCl2 treatment, after the first cycle, after the third cycle, after the fifth cycle, and at the end of the treatment.Median age at diagnosis was 65.2 years (range, 49.1–75.5). There was a significant 25% drop in the median alkaline phosphatase levels: 101 U/L (range, 58–594) vs. 75 U/L (39–649) before and during treatment, respectively (P = .003). The median dose of [223Ra]RaCl2 for all patients was 4.1 MBq (range, 3.35–6.55), and the majority of patients received 5 treatment cycles (range 3–6). Seventeen patients were alive at the end of treatment (56.7%). The median OS was 26 months (range, 19.8–32.2). All of the patients filled out the questionnaires at the first 3 time points; the fourth survey included 28 patients, and only 23 patients completed the fifth questionnaire. Compared to the baseline, only the scale “role functioning” showed a temporary worsening after the first therapy cycle (P = .03). In subsequent cycles, its mean value rose to initial levels. All other functional and symptom scales, as well as global health status, remained constant over all 5 time points and showed no significant changes (P > .05).[223Ra]RaCl2 therapy does not adversely impair the health-related QoL of patients with mCRPC and bone metastasis. Only patients’ role functioning worsened temporarily after the first therapy cycle but stabilized in subsequent treatment cycles.

Phase III study of pembrolizumab (pembro) plus enzalutamide (enza) and androgen deprivation therapy (ADT) for patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC): KEYNOTE-991.

TPS5595 Background: Pembro, an anti–PD-1 antibody, has shown antitumor activity as monotherapy and in combination with other agents in metastatic castration-resistant prostate cancer (mCRPC). As the antitumor effects of enza may be pro-immunogenic, we hypothesized that combining pembro and enza could show additive or synergistic antitumor activity. Furthermore, pembro + enza previously showed antitumor activity in pts with mCRPC for whom abiraterone failed (KEYNOTE-365, NCT02861573) and in pts with mCRPC for whom enza monotherapy failed (KEYNOTE 199, NCT02787005). These data warrant further evaluation of the combination of pembro + enza when given at the initiation of ADT. Methods: KEYNOTE-991 (NCT04191096) is a phase III trial to evaluate the efficacy and safety of enza + ADT + either pembro or placebo in patients with mHSPC. Approximately 1232 pts will be randomly assigned 1:1 to receive enza 160 mg orally once daily + ADT + pembro 200 mg IV every 3 weeks (Q3W) or enza 160 mg orally once daily + ADT + placebo IV Q3W. ADT is receipt of an LHRH agonist or antagonist during study treatment or bilateral orchiectomy. Treatment will be stratified by prior docetaxel therapy (yes or no) and presence of high-volume disease (yes or no). Pts with mHSPC, with ≥2 bone lesions and/or visceral disease, who are naive to next-generation hormone agents, and who have ECOG PS 0 or 1 are eligible. Pts must provide tissue for biomarker analysis. Responses will be assessed by CT or MRI and radionuclide bone imaging per Prostate Cancer Working Group 3 (PCWG3)–modified RECIST v1.1 by blinded independent central review (BICR) Q12W from the date of randomization. Treatment will continue with pembro for up to 35 cycles, and treatment with enza will proceed continuously from day 1 of cycle 1 until disease progression, unacceptable toxicity, or withdrawal of consent. Dual primary end points are radiographic progression-free survival (PFS) per PCWG3-modified RECIST v1.1 assessed by BICR and overall survival. Secondary end points are time to first subsequent anticancer therapy, time to symptomatic skeletal-related event, PFS2 (progression after next line of therapy or death), prostate-specific antigen (PSA) response rate, time to PSA progression, PSA undetectable rate, objective response rate, duration of response, and time to radiographic soft tissue progression. Other end points are safety and patient-reported outcomes (eg, time to pain progression). Clinical trial information: NCT04191096 .

Phase III study of pembrolizumab (pembro) plus enzalutamide (enza) versus placebo plus enza for metastatic castration-resistant prostate cancer (mCRPC): KEYNOTE-641.

TPS258 Background: The mechanisms of action of pembro, a PD-1 inhibitor, and enza, an androgen receptor inhibitor, may be synergistic in the treatment of patients (pts) with mCRPC. The phase 1b/2 KEYNOTE-365 (NCT02861573) study showed antitumor activity with pembro + enza in pts with mCRPC pretreated with abiraterone acetate. A phase 2 study (NCT02312557) of enza-pretreated patients with mCRPC showed that some pts had a profound and durable anticancer response to pembro + enza. Methods: KEYNOTE-641 (NCT03834493) is a randomized, double-blind, phase 3 trial to evaluate efficacy and safety of pembro + enza versus placebo + enza in pts with mCRPC. An estimated 1200 patients will be randomly assigned 1:1 to receive enza 160 mg/day + pembro 200 mg IV Q3W or enza 160 mg/day + placebo. Treatment will be stratified by prior abiraterone acetate treatment (yes/no), metastases location (bone only/liver/other), and prior docetaxel treatment for metastatic hormone-sensitive prostate cancer (yes/no). Adults (≥18 years) with histologically or cytologically confirmed mCRPC who experienced biochemical or radiographic progression, ECOG PS 0/1, and adequate organ function are eligible. Pts will be required to provide tissue for biomarker analysis. Intolerance to or progression while receiving prior abiraterone acetate therapy is permitted, but not required. Prior chemotherapy for mCRPC, checkpoint inhibition, or any treatment with a second-generation androgen receptor inhibitor is prohibited. Responses will be assessed by CT/MRI and radionuclide bone imaging per PCWG3-modified RECIST v1.1 Q9W during the first year and Q12W thereafter. Treatment will continue until progression, unacceptable toxicity, or consent withdrawal, with up to 2 years of pembro/placebo. Dual primary end points are OS and rPFS by blinded independent central review. Secondary end points are time to subsequent anticancer therapy or death, ORR, DOR, PSA response rate, PSA undetectable rate, time to PSA progression, time to pain progression, time to soft tissue progression, time to symptomatic skeletal-related event, and safety. Accrual began July 28, 2019. Clinical trial information: NCT03834493.

815P - Symptomatic skeletal related events (SSE) and SSE-free-survival in real world castration-resistant prostate cancer (CRPC) patients: Results from CAPRI

815P - Symptomatic skeletal related events (SSE) and SSE-free-survival in real world castration-resistant prostate cancer (CRPC) patients: Results from CAPRI

Harnessing the potential of therapeutic agents to safeguard bone health in prostate cancer

BackgroundPatients with prostate cancer are at risk of impaired bone health. Prostate cancer has a propensity to metastasize to bone, after which patients are at risk of skeletal-related events (SREs). These complications are associated with increased mortality, substantial pain, and reduced quality of life. Patients are also at risk of bone loss due to androgen deprivation therapy (ADT), which can be compounded in elderly patients with reduced bone density. It is essential, therefore, that aspects of bone health and therapies able to prevent the occurrence of SREs are considered throughout the clinical course of prostate cancer.MethodsWe reviewed the literature regarding the molecular mechanisms underpinning bone lesion formation, the modes of action of therapies that prevent SREs, and the efficacy and safety of these therapies in patients with hormone-sensitive or castration-resistant prostate cancer (CRPC).ResultsTherapies such as denosumab (a RANKL inhibitor) and zoledronic acid (a bisphosphonate) were indicated for prevention of SREs. Radium-223 dichloride also has proven efficacy in delaying symptomatic SREs, as well as in improving overall survival through effects on bone metastases. Before development of bone metastases, low-dose denosumab may also be used for treatment of ADT-associated bone loss. Denosumab may also have the potential to delay bone metastases development in patients with CRPC, although this is not currently an approved indication. The safety profile of therapies to prevent SREs should be considered. This review consolidates the available evidence on use of denosumab and bisphosphonates in prostate cancer, differentiated by hormone-sensitive and castration-resistant disease.ConclusionsThere is convincing evidence to support the use of denosumab and bisphosphonates to maintain bone health in patients with prostate cancer. Clinicians should be mindful of the adverse event risk profile of these therapies.

223Ra-chloride therapy in men with hormone-refractory prostate cancer and skeletal metastases: Real-world experience.

Radium-223 (223Ra) chloride, an alpha emitter, has been shown to improve overall survival (OS) and pain control, and to delay skeletal-related events, in patients with castration-resistant prostate cancer (CRPC) and bone metastases. Our retrospective observational study presents the first Italian experience on the efficacy and safety of 223Ra therapy in routine clinical practice. A total of 83 patients with metastatic CRPC were treated with 223Ra at 3 Italian centers between August 2013 and August 2016. 223Ra-chloride (55 kBq/kg) was administered every 4 weeks for a total of 6 cycles. Primary endpoints were OS and progression-free survival (PFS). Secondary endpoints included toxicity, pain evaluation using numeric rating scale (NRS), symptomatic skeletal-related events and biomarkers response. Patients had a median age of 75 (range 53-89) years. The majority of men showed a Gleason score of 7, 8, or 9. Forty-one patients completed 6 treatment cycles; 33 stopped treatment before completing 6 cycles. Nine were still receiving therapy at the time of data collection. At the end of therapy, NRS pain scores significantly improved ( p < .000001). OS was a mean of 10.1 months, while median OS had not been attained. According to Kaplan-Meier estimation, OS and PFS were 17.5 and 7.7 months, respectively. There was a significant correlation between OS and PFS with the number of 223Ra cycles; patients receiving all 6 cycles experienced the major benefit from the therapy. 223Ra was well-tolerated. 223Ra alpha therapy is an important therapeutic option for men with CRPC and symptomatic skeletal metastases.

EANM guideline for radionuclide therapy with radium-223 of metastatic castration-resistant prostate cancer.

Radium Ra-223 dichloride (radium-223, Xofigo®) is a targeted alpha therapy approved for the treatment of castration-resistant prostate cancer (CRPC) with symptomatic bone metastases and no known visceral metastatic disease. Radium-223 is the first targeted alpha therapy in this indication providing a new treatment option, with evidence of a significant survival benefit, both in overall survival and in the time to the first symptomatic skeletal-related event. The skeleton is the most common metastatic site in patients with advanced prostate cancer. Bone metastases are a clinically significant cause of morbidity and mortality, often resulting in bone pain, pathologic fracture, or spinal cord compression necessitating treatment. Radium-223 is selectively accumulated in the bone, specifically in areas of high bone turnover, by forming complexes with the mineral hydroxyapatite (the inorganic matrix of the bone). The alpha radiation generated during the radioactive decay of radium-223 produces a palliative anti-tumour effect on the bone metastases. The purpose of this guideline is to assist nuclear medicine specialists in evaluating patients who might be candidates for treatment using radium-223, planning and performing this treatment, understanding and evaluating its consequences, and improving patient management during therapy and follow-up.

Dutch Economic Value of Radium-223 in Metastatic Castration-Resistant Prostate Cancer.

BackgroundThe treatment of metastatic castration-resistant prostate cancer has changed with the introduction of radium-223, cabazitaxel, abiraterone and enzalutamide. To assess value for money, their cost effectiveness in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel from the Dutch societal perspective was investigated.MethodsA cost-effectiveness analysis was conducted using efficacy, symptomatic skeletal-related event and safety data obtained from indirect treatment comparisons. Missing skeletal-related event data for cabazitaxel were conservatively assumed to be identical to radium-223. A Markov model combined these clinical inputs with Dutch-specific resource use and costs for metastatic castration-resistant prostate cancer treatment from a societal perspective. Total quality-adjusted life-years and costs in 2017 euros were calculated over a 5-year (lifetime) time horizon.ResultsRadium-223 resulted in €6092 and €4465 lower costs and 0.02 and 0.01 higher quality-adjusted life-years compared with abiraterone and cabazitaxel, respectively, demonstrating dominance of radium-223. Sensitivity analyses reveal a 64% (54%) chance of radium-223 being cost effective compared with abiraterone (cabazitaxel) at the informal €80,000 willingness-to-pay threshold. Compared with enzalutamide, radium-223 resulted in slightly lower quality-adjusted life-years (−0.06) and €7390 lower costs, revealing a 61% chance of radium-223 being cost effective compared with enzalutamide. The lower costs of radium-223 compared with abiraterone and enzalutamide are driven by lower drug costs and prevention of expensive skeletal-related events. Compared with cabazitaxel, the lower costs of radium-223 are driven by lower costs of the drug, administration and adverse events.ConclusionRadium-223 may be a less costly treatment strategy offering similar gains in health benefits compared with abiraterone, cabazitaxel and enzalutamide in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel from the Dutch societal perspective.Electronic supplementary materialThe online version of this article (doi:10.1007/s40258-017-0350-x) contains supplementary material, which is available to authorized users.

Phase 3 prognostic analysis of the automated bone scan index (aBSI) in men with bone-metastatic castration-resistant prostate cancer (CRPC).

5006 Background: Quantitative measures of metastatic bone disease are needed in men with mCRPC. We recently demonstrated the validity/reproducibility of a computational approach to bone scan imaging that employs artificial intelligence called the automated BSI (aBSI), which quantifies the percent of skeletal mass involved by cancer. We aimed to extend the prognostic validation of aBSI in a multinational prospective phase 3 clinical study of men with bone-metastatic CRPC. Methods: Whole-body bone scans were acquired at screening in a placebo-controlled phase 3 trial of men with mCRPC and bone metastases and treated with tasquinimod/placebo (n = 1,245). The prospective aBSI biomarker analysis plan was locked in Sept 2014 prior to treatment unblinding. All scans generated at 241 trial sites in 37 countries were assessed for image quality and analyzed using the EXINI boneBSI v.2 software and were blindly associated with outcomes. Baseline aBSI was evaluated for its independent prognostic association with overall survival (OS), radiographic progression-free survival (rPFS), and symptomatic skeletal related events (SSEs). Results: The aBSI-population (721 pts) was representative of the entire trial population based on patient characteristics at screening and OS outcomes. Median aBSI was 1.07 (SE 0.05). The aBSI-population was divided into quartiles (n = 180-181) with aBSI-levels of 0 - 0.3 (Q1); &gt; 0.3 - 1.1 (Q2); &gt; 1.1 - 4.0 (Q3); and &gt; 4.0 (Q4) and median OS ranging from 35 months (Q1) to 13 mo (Q4) (p &lt; 0.0001). Baseline aBSI was significantly associated with OS (HR 1.2 per doubling of BSI; p &lt; 0.0001) and remained independently associated with OS after adjustment for treatment, PSA, CRP, LDH and albumin. Baseline aBSI was also strongly associated with rPFS (p = 0.0005), time to symptomatic progression (p &lt; 0.0001), and time to SSE (p = 0.001). Conclusions: This analysis represents the first phase 3 evaluation of aBSI as a clinically validated prognostic biomarker for OS, rPFS, and SSEs in men with bone-metastatic CRPC, providing independent prognostic information over commonly measured clinical characteristics. Clinical trial information: NCT01234311.

Radium-223 dichloride (Ra-223) in U.S. expanded access program (EAP).

247 Background: The ALSYMPCA study (Parker, NEJM, 2013) was the basis for regulatory approval of Ra-223 for the treatment of castrate-resistant prostate cancer (CRPC) patients (pts) with symptomatic bone metastases. The aim of this prospective EAP was to monitor acute and long-term safety of Ra-223. Pt profiles and findings in the EAP setting are presented. Methods: In the EAP, CRPC pts with symptomatic bone metastases who either received or were not eligible for docetaxel received Ra-223 50 kBq/kg by injection q4wks for 6 cycles. Primary endpts: ECOG PS, symptomatic skeletal-related events (SSE), treatment-emergent adverse events [TEAEs], routine laboratory tests including PSA. Exploratory endpts: overall survival (OS), SSE rates, changes in total ALP (tALP)/PSA responses, time to tALP normalization, and to tALP and PSA progression. Descriptive statistics were used. Results: 184 pts entered treatment; baseline characteristics were similar as seen in ALSYMPCA (N=600) (exceptions in table); 67% had total ALP &lt;220 U/L and 47% mild/moderate pain. 81/184 (44%) received all 6 injections; 26 (14%) had a dose interruption/delay, 18 due to AEs. Median OS was 17m (50/184; 27% pts). TEAEs occurring at ≥10% were anemia, fatigue, diarrhea, and nausea. The most common Grade 3/4 hematologic TEAE was anemia (11%). Majority of pts had no change in ECOG PS within each trt cycle. 19 (10%) pts had an SSE, 13 received EBRT for bone pain. 33% of pts had a ≥30% confirmed ALP decline from baseline and 16% had a ≥50% decline. Median time to ALP progression was not reached. Median time to PSA progression was 4m and 6% had a confirmed PSA response. Conclusions: In heavily pretreated patients with CRPC and bone metastases and in an EAP setting, Ra-223 was well tolerated with no new safety concerns and a positive effect on efficacy parameters. Clinical trial information: NCT01516762. [Table: see text]

Contemporary use of radium-223 (Ra-223) in men with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC): Feasibility and safety.

210 Background: Ra-223 is an α-emitter that binds to the newly formed bone matrix and targets osteoblastic metastatic lesions. Treatment with Ra-223 delays symptomatic skeletal-related events (SREs) and improves overall survival (OS) in men with mCRPC. Concerns about the efficacy and safety of Ra-223 in the pre-chemotherapy space, given alone or in combination with Abiraterone Acetate (AA) or enzalutamide (ENZ), have been raised. Methods: To determine the feasibility, efficacy and safety profile of Ra-223 given alone or in combination with AA or ENZ to men with docetaxel-naïve mCRPC a retrospective study was conducted. PSA decline, rPFS and safety data for patients (pts) treated at Cleveland Clinic (CC) and Tulane University (TU) were analyzed. Results: Fifty-one (27 CC and 24 TU) chemo-naïve mCRPC pts with bone metastases were identified. The median age was 63 (46-87). Testosterone suppression was maintained during treatment. Pre-treatment alkaline phosphatase (ALP) was elevated in 16 pts (33%). In addition to bone, 24 pts (47%) had soft-tissue metastases. While 23 pts received Ra-223 alone, 22 pts (43%) received concomitant AA or ENZ therapy. To date, the median number of Ra-223 cycles received is 5 (1-6) with 39% of pts (20/51) receiving all 6 cycles. PSA declines &gt;30% were observed in 31% of pts. All but one pt had at least some decline in ALP. ALP decline &gt;30% was observed in 68% of pts. Reasons for treatment discontinuation included; completion of 6 cycles 39% (20/51); PD 35% (18/51); AEs 8% (4/51) and pt choice 4% (2/51). Grade (G) 3/4 AEs were observed in 4 pts; G3 anemia (n=3) and G4 thrombocytopenia (n=1). The vast majority of pts had PSA progression (81%) and 42% of pts have died. Estimated median time to PSA progression and OS are 3.9 (95% C.I. 1.84-4.82) and 11.0 months (95% C.I. 7.5-16.4), respectively. Pts with normal baseline hemoglobin levels and those who received concomitant AA tended to have better PSA progression-free and OS (p&lt;.06). Conclusions: Treatment with Ra-223 in combination with AA or ENZ in chemo-naïve mCRPC pts is feasible with no new safety signals of concern. Further evaluation of the combination of AA or ENZ with Ra-223 in this setting is warranted.