ALSYMPCA Trial Research Articles

Real-world evaluation of access-driven Canadian treatment sequences in progressive prostate cancer (REACTIVATE).

The results of the phase 3 ALSYMPCA trial showed that Radium-223 (Ra-223) improves overall survival (OS) and delays onset of first symptomatic skeletal event vs. placebo in patients with metastatic castration-resistant prostate cancer (mCRPC). The purpose of the REACTIVATE study was to inform the optimal placement of Ra-233 in the treatment sequence by evaluating clinical outcomes and healthcare resource utilization using real-world data from multiple Canadian provinces. This retrospective cohort study analyzed patient outcomes according to Ra-223 placement using administrative databases of four Canadian provinces, encompassing 4301 patients with mCRPC who received at least two lines of life-prolonging therapy (LPT) for mCRPC. Outcomes included OS, event-free survival (EFS), and healthcare resource utilization. Each province was analyzed separately. OS, measured from the start of second-line LPT, differed between provinces: those in Ontario receiving second-line Ra-223 had a longer OS vs. those receiving it in third-line or later (hazard ratio [HR ] 0.79, 95% confidence interval [CI] 0.66-0.95). There was no difference between lines of therapy in patients in British Columbia (HR 1.165, 95% CI, 0.894-1.518, p=0.2576), and OS was numerically worse but not statistically significant in patients receiving Ra-223 in second-line in Quebec (HR 1.44, 95% CI, 0.93-2.24). Other outcomes also varied across provinces, with second-line use of Ra-223 being associated with longer EFS and reduced healthcare utilization vs. third-line use in Ontario but not in Quebec. Significant heterogeneity exists in the management and outcomes of mCRPC between provinces, particularly regarding the placement of Ra-223 in the treatment sequence.

Real-world evaluation of access-driven Canadian treatment sequences in progressive prostate cancer (REACTIVATE).

The results of the phase 3 ALSYMPCA trial showed that Radium-223 (Ra-223) improves overall survival (OS) and delays onset of first symptomatic skeletal event vs. placebo in patients with metastatic castration-resistant prostate cancer (mCRPC). The purpose of the REACTIVATE study was to inform the optimal placement of Ra-233 in the treatment sequence by evaluating clinical outcomes and healthcare resource utilization using real-world data from multiple Canadian provinces. This retrospective cohort study analyzed patient outcomes according to Ra-223 placement using administrative databases of four Canadian provinces, encompassing 4301 patients with mCRPC who received at least two lines of life-prolonging therapy (LPT) for mCRPC. Outcomes included OS, event-free survival (EFS), and healthcare resource utilization. Each province was analyzed separately. OS, measured from the start of second-line LPT, differed between provinces: those in Ontario receiving second-line Ra-223 had a longer OS vs. those receiving it in third-line or later (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.66-0.95). There was no difference between lines of therapy in patients in British Columbia (HR 1.165, 95% CI, 0.894-1.518, p=0.2576), and OS was numerically worse but not statistically significant in patients receiving Ra-223 in second-line in Quebec (HR 1.44, 95% CI, 0.93-2.24). Other outcomes also varied across provinces, with second-line use of Ra-223 being associated with longer EFS and reduced healthcare utilization vs. third-line use in Ontario but not in Quebec. Significant heterogeneity exists in the management and outcomes of mCRPC between provinces, particularly regarding the placement of Ra-223 in the treatment sequence.

Safety outcomes in patients with metastatic castration-resistant prostate cancer treated with radium-223 following external beam radiation therapy: REASSURE US subset.

106 Background: In the Phase 3 ALSYMPCA trial, radium-223 (Ra-223) demonstrated an overall survival (OS) benefit and a favorable safety profile in patients with metastatic castration-resistant prostate cancer (mCRPC). REASSURE (NCT02141438) is a global, prospective, single-arm, observational study of Ra-223 use in patients with mCRPC with bone metastases within routine clinical settings. Utilizing data from the second planned interim analysis, we evaluated safety outcomes in patients with mCRPC treated with Ra-223 following external beam radiation therapy (EBRT) in the US. Methods: In this descriptive analysis (data cutoff 3-20-2019), we included patients who received EBRT to bone prior to Ra-223 (≤2 years prior to Ra-223 first dose); results are presented relative to the overall US subset of patients enrolled into REASSURE. The focus of this abstract is on incidence of hematological toxicities, bone fractures, and second primary malignancies (SPM). Results: Of N=498 patients in the US subset, 118 patients received prior EBRT to bone. Median duration of observation was 11.7 months among patients who received EBRT and 11.9 months for the overall US subset. Any-grade drug-related hematological treatment-emergent adverse events (TEAEs) occurred in 8% (10/118) and 9% (47/498) of patients who received EBRT and the overall subset, respectively (Table). Grade ≥3 drug-related hematological TEAEs occurred in 5% (6/118) and 6% (32/498) of patients who received EBRT and the overall subset, respectively. Bone fractures occurred in 7% (8/118) and 4% (19/498) of patients who received EBRT and the overall subset, respectively. Six SPMs occurred in 5/118 patients who received EBRT (4%), and 11 SPMs occurred in 10/498 patients in the overall subset (2%). Results of bone fracture events by bone health agent use will be included in the full presentation. Conclusions: In this descriptive analysis of real-world data, patients who received EBRT prior to Ra-223 did not demonstrate an increased incidence of hematological toxicities relative to the overall US subset. Although percent of SPMs and bone fractures seems higher among patients treated with EBRT relative to the overall US subset, the real-world incidence of these events remains low. [Table: see text]

Real-world safety and effectiveness of radium-223 (223Ra) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) treated in the US: The non-interventional REASSURE study.

5050 Background: 223Ra improved overall survival (OS) and quality of life and demonstrated a favorable safety profile in pts with mCRPC in the phase 3 ALSYMPCA trial. REASSURE (NCT02141438) is a global, prospective, single-arm, observational study of 223Ra use in pts with mCRPC and bone metastases in routine clinical practice. Here, we present clinical outcomes from the second planned interim analysis of REASSURE for pts treated in the US. Methods: This analysis included pts with confirmed mCRPC with bone metastases scheduled to receive 223Ra in the US. All pts received ≥1 dose of 223Ra. Primary endpoints are short- and long-term safety, including incidence of bone marrow suppression and second primary malignancies (SPM). Secondary endpoints included OS and pt-reported pain (Brief Pain Inventory – Short Form [BPI–SF] scores). A clinically meaningful pain response was defined as a decrease from baseline of ≥2 points in BPI-SF worst pain item. Results: Pts were enrolled from 2014–2017. Overall, 498 pts were included in this analysis. At the data cut-off (20 March 2019), the median duration of observation was 11.9 months (0.4–41.3). Most pts (81%) had bone metastases only; 69% of pts received 5–6 223Ra injections. Overall, 77% of pts had received ≥1 prior life-prolonging therapies: abiraterone (45%), enzalutamide (48%), docetaxel (25%), cabazitaxel (6%), or sipuleucel-T (24%). Concomitant enzalutamide was received by 31% of pts, and 47% received concomitant bone health agents. After 223Ra, 31% of pts received ≥1 life prolonging therapies. During treatment, 208/358 (58%) pts with a baseline BPI-SF ≥2 had a clinically meaningful pain response. Any-grade and grade ≥3 drug-related treatment-emergent adverse events (TEAEs) occurred in 32% and 10% of pts, respectively. Drug-related TEAEs resulted in 223Ra discontinuation in 4% of pts. Treatment-emergent and drug-related serious AEs (SAEs) occurred in 21% and 6% of pts, respectively. The most common (>5% of pts) any-grade drug-related TEAEs were diarrhea (10%), fatigue (9%), anemia (8%) and nausea (7%). Overall, 4% of pts had fractures; 2% of pts developed bone disorders. Eleven SPMs occurred in 10 pts (2%). In total, 60% of pts died during study follow-up. Median OS was 17.8 months (95% CI 15.6–19.4). Conclusions: Within the current treatment landscape in routine clinical practice in the US, median OS after 223Ra treatment was close to 18 months. A majority of pts completed 5–6 223Ra injections. The known safety profile of 223Ra was confirmed with no new safety signals. Over half of pts with pain at baseline had a clinically meaningful pain response during 223Ra treatment. Clinical trial information: NCT02141438 .

Radium-223 for mCRPC, a real-world experience study from 7 Galician medical centers.

96 Background: Radium-223 represents an option for symptomatic metastatic castration-resistant prostate cancer (mCRPC) after demonstrated an overall survival improvement in the ALSYMPCA trial. Radium-223 real-life experiences are scarce, particularly after the results of the ERA-223 trial. To describe Radium-223 outcomes in real life practice, and specifically those related with bone health, sequence of treatment, and prognostic factors. Methods: Multicenter retrospective study of a cohort of 143 patients with mCRPC treated with Radium-223 in either the second line or third line of therapy or beyond in the context of routine clinical practice between 11 March 2013 and 26 July 2022, in seven Galician hospitals. Survival estimates were calculated by the Kaplan-Meier method, and groups were compared with the log-rank test. The Cox proportional hazards regression model was used to evaluate factors independently associated with OS. Between March 11, 2013, and July 26, 2022, 143 patients were enrolled from 5 Galician hospitals. With a median follow-up of 9.68 months. All patients signed an informed consent form agreeing to participate in this observational study, that was approved by the Galician Ethics Committee, registration code 2018/282. Results: Baseline patient and disease characteristics are summarized. Median follow-up was 9.68 months. Median overall survival (OS) was 12 months (95% CI 9.7 – 16.0). Best OS outcomes were achieved in second and third line, 18 months (95% CI 12.0 – 26.0) and 9.4 months (95% CI 8.0 – 12.0) months, respectively. Among those baseline clinic-analytical factors analyzed, only alkaline phosphatase level >354 UI/L was correlated with a worse OS (HR 2.56 (95% CI 1.39 – 4.72; p=0.003) and the number of cycles of Radium-223 received (HR 0.63 (95% CI 0.54 – 0.73; p<0.001) were prognostic factors for Radium-223. Importantly, ninety-nine of patients (80%) were treated with bone-targeted therapy for bone metastases with no OS differences (p=0.66). Conclusions: In our study, Radium-223 efficacy was consistent with previously reported. Best efficacy was achieved in the second or third line of therapy, independently of docetaxel use. Patients with high baseline alkaline phosphatase had worse OS. Few patients presented skeletal-related events, which could be explained by an adequate use of bone-targeted therapy (zoledronic acid or denosumab). [Table: see text]

Impact of pre-existing anemia and/or packed red blood cell transfusion prior to Radium-223 administration on oncologic outcomes.

67 Background: Radium-223 (Ra-223), a targeted alpha-emitting radiopharmaceutical approved for the treatment of metastatic prostate cancer (mPC), can cause myelosuppression. In the ALSYMPCA trial 30% of patients developed cytopenias, including 13% with grade 3/4 anemia. Therefore, it is recommended that only men with a hemoglobin ≥10 g/dL, platelet count ≥100,000/mm3, and ANC ≥1,500/mm3 be considered for Ra-223. Since the FDA approval of Ra-223 in 2013, several new treatments have been approved for men with mPC. With the changing therapeutic landscape, we anticipate more patients (pts) will have preexisting cytopenia prior to Ra-223 consideration. Hence, clinicians are increasingly likely to face the dilemma of whether it is safe and efficacious to administer Ra-223 in the setting of Hgb ≤10 with/without RBC transfusion support. Methods: We retrospectively identified pts with mPC treated with Ra-223, including a subset of men with Hgb <10g/dl at the Medical College of Wisconsin and Tulane Cancer Center from 2014 – 2019. Clinical data including demographics, prior cancer treatments, laboratory data, blood product transfusion data, and oncologic outcomes were collected. Survival was estimated using Kaplan-Meier method and statistical analysis was conducted using student’s t-test. Results: Sixty-two pts were identified. Median age at the time of Ra-223 was 75.3 years. Of these, nearly 20% (n=12) had a Hgb <10 g/dL and/or received RBC transfusions to meet “eligibility criteria” prior to beginning Ra-223 treatments. Compared to men who had Hgb >10g/dL, men with Hgb <10g/dL required more RBC transfusions both during and after Ra-223 treatment and had significantly worse oncologic outcomes. No patients experienced treatment delays of more than 1 week. There were no significant differences in the median number of treatments prior to Ra-223, median number of Ra-223 treatments received, platelet count nadir, or ANC nadir. Conclusions: Pre-existing Hgb < 10 g/dl and/or RBC transfusions prior to Ra-223 therapy is associated with worse oncologic outcomes in mPC, suggesting that the benefit of Ra-223 is limited in this subset. A larger sample size is needed to further validate our findings. Multivariable analysis is planned. [Table: see text]

Alpha emitter radium-223 in patients with metastatic castration-resistant prostate cancer: A cost-utility analysis.

Objective: To assess the cost effectiveness of radium-223 dichloride for patients with metastatic castration-resistant prostate cancer (mCRPC) in China. Materials and methods: A Markov model was developed to estimate the long-term health and economic outcomes of radium-223 plus best standard care (BSC) treatment and BSC only for bone mCRPC patients over a lifetime horizon. The patients and interventions were modeled according to the ALSYMPCA trial. Costs were collected from a Chinese health system perspective. Utility values were derived from the published literature. The base-case model results were quality-adjusted life year (QALY), total cost, and incremental cost-utility ratio (ICUR). Uncertainty analyses were performed to assess the robustness of our conclusions. Results: Compared with the BSC arm, radium-223 achieved an excess 0.344 QALYs with an incremental cost of $29,459, resulting in an ICUR of $85,647 per QALY. The probability of Ra-223 being cost effective for the patients with bone mCRPC was sharply low (<0.5%) at a willingness-to-pay threshold of $38,136/QALY. Uncertainty analyses revealed that the model is robust to all the input parameters. Conclusion: Radium-223 is unlikely to be cost effective in patients with bone mCRPC at the current WTP threshold, from a Chinese health system perspective. In affluent areas with a high per-capita GDP, radium-223 therapy may be cost effective.

Administration of radium-223 and the prognosis in Japanese bone metastatic castration-resistant prostate cancer patients: A large database study.

BackgroundThe ALSYMPCA trial revealed radium‐223 (Ra‐223) to be a life‐prolonging agent for bone metastatic castration‐resistant prostate cancer (CRPC). However, only 2.8% of enrolled patients in that clinical trial were Asian, and no Japanese patients were enrolled. Several retrospective studies have been published concerning Japanese bone metastatic CRPC patients receiving Ra‐223. However, no study has yet reported the correlation between Ra‐223 induction and the survival in Japanese bone metastatic CRPC patients. This study investigated the effect of Ra‐223 as a life‐prolonging agent in a large Japanese healthcare fee database.MethodsA total of around 410 000 prostate cancer patients were extracted from this database, and 25 934 were diagnosed with CRPC. In these patients, the age, date of the CRPC diagnosis, date of Ra‐223 induction, and prognosis were analyzed.ResultsA total of 1628 patients received Ra‐223, and 6693 patients were diagnosed with bone metastasis CRPC, with the remaining 17 613 patients diagnosed with CRPC without bone metastasis. The patients who completed six courses of Ra‐223 showed a significantly more favorable overall and cancer‐specific survival than those who received ≤5 courses (p < 0.0001 and p < 0.0001, respectively). For time from CRPC diagnosis date to death, the Ra‐223 induction group showed a significantly more favorable prognosis with regard to both the overall and cancer‐specific survival than the bone metastatic CRPC patients without Ra‐223 (p < 0.0001 and p < 0.0001, respectively).ConclusionsBone metastatic CRPC patients who received Ra‐223 showed a significantly better prognosis than bone metastatic CPRC patients who did not receive Ra‐223.

Real-world patient characteristics associated with survival of 2 years or more after radium-223 treatment for metastatic castration-resistant prostate cancer (EPIX study)

BackgroundThe real-world EPIX study was conducted to gather information about the characteristics of patients with metastatic castration-resistant prostate cancer (mCRPC) who survived ≥2 years after treatment with the alpha-emitter radium-223.MethodsThis retrospective study of electronic health records in the US Flatiron database (NCT04516161) included patients with mCRPC treated with radium-223 between January 2013 and June 2019. Median overall survival (OS) and prostate-specific antigen (PSA) response (≥50% reduction) from start of radium-223 treatment were the primary and secondary endpoints, respectively. Patient characteristics were compared between those who survived ≥2 years versus <2 years, including a subgroup who survived <6 months.ResultsIn the 1180 patients identified, median OS was 12.9 months (95% CI: 12.1–13.7), and 13% of patients with data at 6 months had a PSA response. The survival groups included 775 patients (65.7%) who survived <2 years (including 264 (22.4%) who survived <6 months) and 185 patients (15.7%) who survived ≥2 years; 220 patients (18.6%) had incomplete follow-up data and were censored. On multivariate analysis, age >75 years, Eastern Cooperative Oncology Group performance status (ECOG PS) 2–4, visceral metastases, prior symptomatic skeletal events (SSEs), and prior chemotherapy were independently prognostic of reduced OS. For patients with survival ≥2 years versus <2 years, median age was 71 versus 75 years, 4% versus 14% had ECOG PS 2–4, 4% versus 10% had visceral metastases, 38% versus 44% had prior SSEs, and 16% versus 32% had prior chemotherapy.ConclusionsIn this study of men with mCRPC treated in real-world clinical practice, median OS was consistent with that seen in the phase 3 ALSYMPCA trial. Patients who survived ≥2 years after the start of radium-223 were younger and had better ECOG PS, lower disease burden, and less use of prior chemotherapy than those who survived <2 years.

Prognostic role of inflammatory biomarkers from peripheral blood and clinical factors in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated with radium-223 (Ra-223) (BIO-Ra-223 study).

e17026 Background: Ra-223 is a treatment option for mCRPC pts with bone metastases according to the survival benefit observed compared to placebo in the ALSYMPCA trial. In the last years, many studies showed this benefit in the real-life pts is lower than that reported in the trial, probably due to a suboptimal selection of pts with poor prognostic characteristics. Therefore, the identification of prognostic factors to select mCRPC pts most likely to benefit from Ra-223 is needed. The multicentre retrospective BIO-Ra-223 study has investigated the prognostic role of peripheral blood immune cells and clinical factors to develop a novel prognostic score for mCRPC pts treated with Ra-223. Methods: Complete blood count was assessed before Ra-223 treatment calculating neutrophil-to-lymphocyte ratio (NLR), derived NLR (dNLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), systemic inflammation index (SII). Clinical factors included pre-treatment Eastern Cooperative Oncology Group performance status (ECOG PS), Gleason Score (GS) group, number of bone metastases, alkaline phosphatase (ALP), line of therapy, previous chemotherapy and the presence of lymphadenopathies. Statistical analyses included survival ROC curves for biomarkers’ cutoffs, univariable and multivariable Cox analyses, internal validation, c-index calculation and Schneeweiss scoring system. Results: From September 2013 to July 2020, 519 mCRPC pts received Ra-223 as 1st-2nd, 3rd-4th and further-line in 48%, 38% and 14% of pts. The median overall survival (mOS) of the entire cohort was 19.9 months. All biomarkers and clinical factors (except for GS group) significantly predicted OS at the univariable analyses. In the multivariable ones, all biomarkers, ECOG PS, number of bone metastases and ALP significantly correlated with OS. The multivariable model with NLR (&lt; 3.1 vs ≥3.1), ECOG PS (0-1 vs 2-3), number of bone metastases (&lt; 6, 6-20, &gt; 20) and ALP (&lt; 220 vs ≥220) showed the highest c-index (0.711), which was maintained after internal validation (bootstrap re-sampling) (c-index: 0.707). Using the Schneeweiss scoring system, ten categories were identified in 494 pts with complete data and merged in two prognostic groups with distinctive OSs: group 1 (score 0-4, 337 pts) with a mOS of 27.8 months and group 2 (score 5-10, 157 pts) with a mOS of 9.7 months (HR 4.03, p &lt; 0.001). Conclusions: The obtained score, composed of NLR, ECOG PS, number of bone metastases, and ALP identifies two distinctive prognostic groups of mCRPC pts. Moreover, this score is easily and widely applicable for clinical practice and trials at no additional costs. Although external validation is needed, these preliminary results showed that this novel prognostic score is promising and could help the patients’ selection for Ra-223 treatment.

Efficacy and safety of radium-223 in routine clinical practice

Several treatment options are currently available for patients with metastatic castration-resistant prostate cancer in routine clinical practice. However, clear standards of sequential use of registered drugs have not yet been developed. Affecting bone metastases, radium-223 is one of therapeutic options for patients with castration-resistant prostate cancer and bone metastases, which was included in foreign and Russian guidelines for prostate cancer management. This article analyzes the results of treatment with radium-223 in patients with metastatic castration-resistant prostate cancer in foreign non-interventional clinical trials conducted in routine clinical practice. These trials confirmed high efficacy and safety of radium-223 demonstrated earlier in the ALSYMPCA trial. Some protocols ensured better overall survival rates and lower incidence of symptomatic skeletal events and adverse events than those in the registration study.

Review of Palliative 223Ra in Metastatic Castration-Resistant Prostate Cancer: Experience at West Virginia University Cancer Center

The ALSYMPCA trial of the α-emitter 223Ra in symptomatic bone-predominant metastatic castration-resistant prostate cancer (mCRPC) reported a median overall survival (OS) of 14.9 mo, versus 11.3 mo for placebo. However, subsequently reported real-world experience with 223Ra in smaller mCRPC patient cohorts has appeared less successful. We performed a retrospective observational study to review our own 223Ra experience at West Virginia University (WVU). Methods: Demographic, clinical, laboratory, and imaging data were reviewed in all bone-predominant mCRPC patients treated with 223Ra at WVU from 2014 to 2019. The number of bone metastases per patient at the start of treatment with 223Ra was quantified via nuclear bone scans (12 scans, 5 of which also included SPECT/CT), body CT scans (8 scans), and PET/CT scans (4 scans). Standard descriptive statistics were used to study institutional review board-exempted, deidentified patient data. Median survival in ALSYMPCA and WVU patients was compared using a 2-sided, 1-sample log-rank test based on the exponential distributions. The primary endpoint was patient OS after initiating 223Ra. Results: Twenty-four patients received 98 infusions of 223Ra; 83% of these patients were referred from outside WVU. Before the first infusion, all 24 had received androgen deprivation therapy. In total, 73 sequential combinations of androgen deprivation therapy were used, 68 of which (93%) preceded the first 223Ra infusion. Also, before 223Ra, 19 (79%) patients had received docetaxel and 19 (79%) had received 33 courses of radiation, 24 of which targeted nonprostatic sites. Eleven patients (46%) completed all 6 planned 223Ra infusions; 13 (54%) stopped early because of clinical deterioration. As of August 2020, only 1 patient remained alive after completing 6 cycles of 223Ra. Median OS from the first 223Ra infusion to the last follow-up or death was 8.3 mo (range, 0-44 mo)-nearly 50% less than the ALSYMPCA median survival of 14.9 mo (P = 0.01). Compared with ALSYMPCA, more WVU patients received bisphosphonates and docetaxel, more had an Eastern Cooperative Oncology Group performance status of at least 2, more used opiates for pain, more had a greater bone metastasis burden by imaging, and more had lower hemoglobin, albumin, alkaline phosphatase, and prostate-specific antigen levels. Conclusion: Although the science supporting the development and clinical use of 223Ra is compelling, optimal clinical benefit will likely require earlier referral for 223Ra, before patients have exhausted most conventional therapies. At WVU, we found that practically all our referred patients had androgen deprivation therapy, radiation, and cytotoxic therapy before starting 223Ra. We continue to offer 223Ra therapy to patients with symptomatic bone-predominant mCRPC but are encouraging earlier patient referral.

Safety And Clinical Outcomes Of Radium-223 With Concomitant Radiotherapy Or Subsequent Treatment With The Investigational Agent 177Lu-PSMA In Patients With Metastatic Castration-Resistant Prostate Cancer: An Interim Analysis Of The REASSURE Study

Radium-223 (Ra-223) improved overall survival (OS) and demonstrated a favorable safety profile in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) in the phase 3 ALSYMPCA trial. REASSURE (NCT02141438) is a global, prospective, single-arm, observational study investigating the safety of Ra-223 in routine clinical practice in pts with mCRPC over 7 years. The objective of this investigation, using data from the second prespecified interim analysis, was to assess safety and clinical outcomes in pts from REASSURE, including the subgroups who received radiotherapy concomitant with Ra-223, or investigational 177Lu-PSMA subsequent to Ra-223. Results of this analysis may help to inform future treatment decisions in pts with mCRPC. This analysis (data cut-off: March 20, 2019) was conducted for the entire cohort and two subsets of pts treated with either concomitant radiotherapy or with subsequent 177Lu-PSMA. Incidence of second primary malignancy (SPM), pain response, incidence of adverse events (AEs), and OS are described. In total, 1465 pts with mCRPC were included. Median follow-up was 11.5 months, and a median of 6 Ra-223 injections was received. Overall, 14 pts (1%) developed a SPM. At Cycle 6, 222/657 pts (34%) had a clinically meaningful pain response (decrease ≥2 points from baseline) in the Brief Pain Inventory worst pain item. Overall, median OS was 15.6 months (95% CI 14.6, 16.5). The most frequent treatment-emergent serious AEs (any grade; ≤30 days after Ra-223) were anemia (n = 27; 2%), physical health deterioration (n = 14; 1%), and pneumonia (n = 13; 1%). Grade 3–4 hematologic AEs occurred in 214 pts (15%); 70 pts (5%) had fractures. 160/1465 pts (11%) had concomitant radiotherapy, mainly external beam radiation therapy (n = 117; 73%), brachytherapy (n = 14; 9%), and gamma knife or stereotactic therapy (n = 8; 5% for each). Of these 160 pts, 1 (<1%) developed a SPM. Safety, including hematologic toxicity fracture rate, and pain response in this pt group was acceptable and will be presented. 26/1465 pts (2%) received 177Lu-PSMA treatment after Ra-223. Median duration of 177Lu-PSMA was 3.5 months. 3/26 pts (12%) had drug-related serious AEs; 9/26 pts (35%) had grade 3–4 hematologic AEs. 2/26 pts (8%) had fractures. Median OS was 28.0 months (95% CI 19.5, 32.7) from start of Ra-223 and 13.2 months (8.4, 16.2) from start of 177Lu-PSMA. There was a low incidence of SPM, low rate of grade 3–4 hematologic AEs, and low incidence of fractures in this second interim analysis of REASSURE, in a real-life clinical practice setting. A pain response was observed in about one-third of pts. Treatment with 177Lu-PSMA in pts who had prior Ra-223 may be feasible in selected pts based on the subset analyzed.

Alkaline Phosphatase And Prostate-Specific Antigen Dynamics And Survival Outcomes In Patients With Metastatic Prostate Cancer Receiving Radium-223

Radium-223 (Ra-223) is a targeted alpha-emitter for metastatic castrate-resistant prostate cancer (mCRPC) patients that demonstrated overall survival (OS) benefit compared to placebo in the ALSYMPCA trial. A secondary analysis of the ALSYMPCA trial demonstrated that decreased alkaline phosphatase (ALP) values at 12 weeks after treatment initiation were associated with improved OS. We further investigate prostate-specific antigen (PSA) and ALP dynamics in a large real-world cohort of patients with mCRPC receiving Radium-223. The Flatiron Health database is a nationwide longitudinal de-identified database derived from electronic health record (EHR) data from 280+ cancer clinics (∼800 sites of care) representing 2.2 million patients in the United States. We included patients with mCRPC treated with Ra-223 between 2013 and 2017 with complete ALP and PSA data. We specified a priori the following factors in a Cox proportional hazards regression for OS: age, performance status, year of treatment, baseline PSA and ALP, occurrence of a PSA or ALP decrease at any point during treatment or within 12 weeks of last administration, timing of response (before cycle 3 versus after cycle 3). Date of first Radium-223 administration was considered the index date for time-dependent analyses. We analyzed data from 586 patients with mCRPC receiving Ra-223 at a median follow-up of 9.8 months, with 252 patients (29.7%) having received prior docetaxel or cabazitaxel. In total, 447 patients (76.3%) achieved any ALP decrease and 250 patients (42.3%) achieved an ALP decrease ≥30%. Of those who achieved an ALP decrease, the response occurred before cycle 3 in 301 patients (67.3%). The median percent change from baseline to ALP nadir was 27.9% (interquartile range [IQR] 10.3% to 46.8%). With respect to PSA, 192 patients (32.7%) achieved any PSA decrease and 124 patients (21.1%) achieved a PSA decrease ≥30%. The median percent change from baseline to PSA nadir was 43.9% (IQR 19.9% to 80.4%). In our survival analysis, we identified age, performance status, ALP value at baseline, PSA value at baseline, presence of an ALP decrease (hazard ratio [HR] 0.61; 95% CI 0.42-0.90; p = 0.012), and presence of a PSA decrease (HR 0.47; 95% CI 0.33-0.65; p = 0.001) as significant predictors of OS. Notably, timing of ALP decrease before or after cycle 3 (HR 0.76; 95% CI 0.57-1.02; p = .066) was not significantly associated with survival. We analyzed PSA and ALP dynamics in the largest reported series of patients receiving Ra-223 based on real-world data. We identified baseline ALP and PSA values, presence of an ALP decrease, and presence of a PSA decrease as predictors of OS. Approximately one-third of patients will have a delayed ALP response after cycle 3; however, timing of ALP response was not significantly associated with OS.

Utilization of Radium-223 in Metastatic Prostate Cancer Patients and Novel Prognostic Indicators In Radium-223 Patients

Radium-223 (R-223) is a radiopharmaceutical treatment approved for patients with metastatic castration resistant prostate cancer with symptomatic bony metastases. We sought to examine the utilization and patterns of care of this treatment at a large NCCN and NCI comprehensive cancer center. We also looked to examine predictors of survival after radium treatment in our dataset. A professionally curated, prospectively gathered institutional database was queried for prostate cancer patients treated with R-223 from 2013 to 2019. We analyzed this cohort for patterns of care including the time from initiation of systemic treatment to the initiation of R-223, the number and type of treatment courses prior to R-223 and the number of treatments following R-223. Kaplan Meier analyses and Cox proportional hazards modeling was used to examine an endpoint of overall survival (OS) from the time of administration of R-223 in sub-groups including those who received R-223 early in their treatment course, as well as those with high and low hemoglobin levels prior to R-223 administration. We identified 74 unique patients who were treated with R-223 over the study period at a single institution. The median OS for all patients following R-223 administration was 537 days. On average Radium-223 was initiated over four years following the initiation of the first systemic therapy (1508 days, range 183-6820 days). On average R-223 was the 5th systemic therapy course these patients received (range 2-11). We found that patients who received R-223 later in their treatment course, defined as the 4th systemic therapy or later, had an increased risk of death compared to those who received R-223 as an earlier line (HR 4.59 95% CI 1.36-15.42). Patients received an average of 0.64 systemic treatments following R-223 (range 0-5). For the majority of patients (n = 41, 55%) R-223 was the last treatment received. The most common treatments following R-223 were taxane chemotherapies (docetaxel, cabazitaxel) and antiandrogens (abiraterone, enzalutamide). We stratified patients based on pre-treatment hemoglobin levels and found that those with hemoglobin levels below the mean had a statistically increased risk of death (HR 1.99 95% CI 1.02-3.86). In our analysis of patterns of utilization of R-223 at a single NCCN and NCI member institution we found that R-223 tends to be utilized as a later line agent for patients with metastatic prostate cancer and is often one of the last treatments they receive. We also found that early receipt of R-223 and higher pre-treatment hemoglobin levels were correlated with better survival outcomes. Given these findings, and the favorable side-effect profile of radium-223 reported on the ALSYMPCA trial relative to the placebo group, consideration should be given to using R-223 early in the course of therapy for patients with metastatic prostate cancer with bone disease.

Review of Radium-223 and Metastatic Castration-Sensitive Prostate Cancer.

Background: Radium-223 is approved for treatment of bone metastases in metastatic castration-resistant prostate cancer (mCRPC). After the ALSYMPCA trial showed overall survival benefit with the addition of radium-223 to standard of care in mCRPC in 2013, there have been numerous publications and trials using radium-223 in mCRPC. Recently, there has been interest in using radium-223 earlier in the metastatic prostate cancer timeline, in metastatic castrate-sensitive prostate cancer (mCSPC); however, currently, radium-223 in mCSPC treatment is investigational. Aim: A literature search was conducted to review the use of radium-223 in mCSPC treatment from 1980 to 2019. A review of both radium-223 articles and abstracts was performed. Search terms included metastatic prostate cancer and radium-223, mCSPC, hormone-sensitive metastatic prostate cancer, radium-223, and oligometastatic disease. The results were limited to studies involving multiple patients with mCSPC. Conclusion: There are a limited number of studies of radium-223 in mCSPC treatment and the authors report on these studies (two published studies and four ongoing trials). Trials are currently underway to assess if radium-223 could be used in mCSPC as a treatment for bone metastases and micrometastases. Future data from these trials will be informative as to the benefit of radium-223 in mCSPC treatment and may change treatment paradigms for mCSPC. This review will focus on trials assessing the role of radium-223 in mCSPC.

Radium 223 treatment in metastatic prostate cancer: Exploring use of clinical factors for prognostication in routine practice.

e17550 Background: Skeletal metastases are seen in over 90% of metastatic castrate resistant prostate cancer (mCRPC) patients during the course of their disease and is a major cause for significant morbidity and mortality in them. Radium 223 (Ra-223) is a bone seeking calcium mimetic alpha emitter that has demonstrated significant improvement in survival and reduction in skeletal related events (ALSYMPCA trial). Ra-223 treatment was well tolerated and showed benefit before or after chemotherapy. In this study we aimed to assess efficacy of Ra-223 in mCRPC patients treated in our centre and their survival in relation to some common clinical variables that may assist patient selection in routine clinical practice. Methods: We conducted a retrospective audit of mCRPC patients treated with Ra-223 from June 2015 – December 2019. We analysed treatment outcomes and use of Haemoglobin (Hb), Albumin (Alb) and Alkaline Phosphatase (ALP) as potential prognostic factors. Results: There were 46 patients in total with a median age of 76 years (range; 56-90) and 26% were ≥80 years of age. The median follow-up was 10 months (range; 2-38 months). Median baseline PSA was 103.7 (range; 7.2 - 2534) and median baseline ALP was 188 U/L (range; 51 - 2262). Ra-223 was given as 1st or 2nd line treatment in 65% of our patients. Median number of cycles of Ra-223 administered was 4 and 41% of patients completed 6 cycles of treatment. Biochemical response (drop in PSA &gt; 50%) was only seen in 11% of patients but good response in ALP levels (drop in ALP &gt; 50%) was seen in 35%. Median overall survival (OS) was 10 months. Median OS for patients who received Ra-223 as 1st or 2nd line vs subsequent line was 13 and 8.5 months respectively. Median OS for patients with Haemoglobin (Hb) ≥12gm/dl) and lower Hb were 11 and 7 months respectively. Patients with normal albumin at baseline had median OS of 15 months compared to 6 months for those with low albumin. Favourable prognostic group patients (Normal Hb, Normal albumin at baseline and normal ALP after treatment) had a median OS of 31 months compared to 9 months for those in less favourable group. Patients who completed at least 5 cycles had a better survival (13 vs 8.5 months). Fractures were reported in 3 patients (6.5%). Conclusions: Ra-223 treated patients in our centre had a reasonable survival despite having a larger proportion of elderly population compared to the registration trial. Ra-223 treatment seems to be more effective when given at earlier lines in mCRPC setting. Pre-treatment Albumin lower than normal seems to be a predictor for poor overall survival.

Safety and overall survival (OS) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) treated with radium-223 (Ra-223) plus subsequent taxane therapy.

5542 Background: Ra-223, a targeted alpha therapy, showed a survival benefit and favorable safety profile over 3 years’ (yrs) follow-up in mCRPC pts (ALSYMPCA trial). REASSURE (NCT02141438) is a global, prospective, single-arm, observational study of long-term Ra-223 safety in routine clinical practice in mCRPC pts (planned 7-yr follow-up). Methods: This analysis, based on the second prespecified interim analysis (data cutoff 3-20-2019) of REASSURE (N = 1465), evaluated safety/OS in the pt subset that was chemotherapy-naïve at Ra-223 administration but received subsequent taxane therapy any time after Ra-223 completion. Results: 182 pts received taxane therapy after Ra-223. Most (58%) had unresected primary tumors, 69% had ≥6 metastases, 99% received prior systemic anticancer therapy (Table). 143 (79%) completed 5 or 6 Ra-223 injections. Subsequent anticancer therapies included docetaxel (95%), enzalutamide (25%), cabazitaxel (24%), abiraterone (12%), lutetium-177-prostate-specific membrane antigen (4%), and sipuleucel-T (1%). During/up to 30 days after taxane therapy, 15 pts (8%) had grade 3/4 hematologic adverse events: anemia (erythropenia) (n = 11, 6%), neutropenia (n = 3, 2%), and thrombocytopenia (n = 2, 1%). Median OS was 24.3 (95% CI: 20.9–27.5) months from Ra-223 initiation and 11.8 (95% CI: 10.6–14.1) months from subsequent taxane initiation. Conclusions: In this cohort where Ra-223 was integrated prior to taxane therapy, most pts received multiple subsequent anticancer therapies. It appears that sequencing of multiple treatment modalities with different mechanisms of action may contribute to improved OS. Taxane therapy in routine clinical practice in pts previously treated with Ra-223 had acceptable hematologic safety/tolerability profiles. Clinical trial information: NCT02141438 . [Table: see text]

Clinical outcomes and patient (pt) profiles in REASSURE: An observational study of radium-223 (Ra-223) in metastatic castration-resistant prostate cancer (mCRPC).

32 Background: Ra-223 is a targeted alpha therapy that showed a survival advantage and favorable safety profile in the phase 3 ALSYMPCA trial in pts with mCRPC. REASSURE (NCT02141438) is evaluating the long-term safety of Ra-223 in routine clinical practice in pts with mCRPC over a 7-year follow-up period. Methods: In this global, prospective, single-arm, observational study, the second prespecified interim analysis (data cut-off March 2019) evaluated safety and clinical outcomes of Ra-223 in pts with mCRPC. Primary outcome measures were incidence of second primary malignancies (SPM), bone marrow suppression and short- and long-term safety in pts who had ≥1 Ra-223 dose. Secondary outcomes included overall survival (OS). Results: For 1465 pts in the safety analysis, median follow up was 11.5 months. Median PSA (n=1053), ALP (n=1048), and LDH (n=555) levels at baseline were 59 ng/mL, 135 U/L, and 269 U/L, respectively. 81% of pts had bone metastases only at baseline; 19% of pts had other metastatic sites, mostly in the lymph nodes. 19% of pts had &lt;6 metastatic sites, 47% had 6–20 sites, 20% had &gt;20 lesions but not a superscan, and 6% had a superscan. 45%, 38%, 37%, 9%, and 8% of pts received prior abiraterone, docetaxel, enzalutamide, cabazitaxel, or sipuleucel-T as prior therapies, respectively. Median number of Ra-223 doses received was 6; 67% of pts had ≥5 doses. SPM occurred in 1% of pts. The most common treatment-emergent drug-related adverse event (AE) of any grade was diarrhea (11%). 10% of pts had a bone-associated event, 5% had fractures, and 15% had a hematological AE. Median OS was 15.6 months (95% CI 14.6–16.5). Conclusions: In REASSURE, there was a low incidence of SPM, bone fractures, and bone marrow suppression after Ra-223 treatment, with no new AEs identified. This study confirms that in routine clinical practice, Ra-223 AE rates were low, and pts generally received ≥5 doses. Clinical trial information: NCT02141438. [Table: see text]

Fracture rates in radium223 (Ra223) treated mCRPC patients (pts): A real-world analysis in 177 pts treated at a single community center 2010-2018.

41 Background: Ra223 was FDA approved 5/15/13 as a life extending therapy in conjunction with Standard of Care (SOC) agents for mCRPC in the ALSYMPCA trial. However, agents such as abiraterone (abi) and enzalutamide (enza) were not part of the SOC regimens allowed during conduct of ALSYMPCA. Phase 2 and expanded access programs (EAPs) suggested enhanced activity when abi or enza were given with Ra223. A phase 3 trial (ERA223 Smith et al. Lancet Oncology 2019) comparing Ra223 +/-abi showed an increased fracture (Fx) rate (29% vs 11%) and no survival advantage for the combo, leading to regulatory restrictions on abi and Ra223 combination therapy. However, only 41% of pts in ERA223 received bone health agents (BHAs). This center participated in ALSYMPCA and in the US EAP and based on those data, BHAs were consistently administered monthly during Ra223. The Fx rate in ERA223 did not mirror our clinical experience and thus our institutional Ra223 database was reviewed. Methods: Cohort analysis of pts who received Ra223 for mCRPC under the supervision of NJV. Follow-up was until date of death or last data entry. Results: 177 pts received Ra223 between 11/2010 and 8/2018. Median age 73 at 1st Ra223 (range 40-93); Median PSA (15.8- at 1st Ra223 (range 0.1-1952); Demographics-AA-10, C-130, Asian-9, unspecified- 28; Median Gleason score 8, Median Alk Phos 95 at 1st Ra233 (range 25-1515). Median mos of prior ADT 23 (range 0-247mos). Pts on concurrent abi + pred + Ra223 69 (39%); abi + Ra223 7 (4%); abi + pred prior to Ra223 54 (31%); abi prior to Ra223 4 (2.3%). Enza + Ra223 51 (29%); enza prior to Ra223 39 (22%). 164 pts (93%) were on BHAs before or during Ra223 (denosumab 86 concurrent vs zoledronic acid 64 concurrent). 10 pts (5.6%) had Fxs reported after the start of Ra223 (4 with concurrent abi, 3 with concurrent enza, 3 on Ra 223 w/o concurrent abi or enza; 8/10 Fxs occurred while on BHA’s). Conclusions: In contrast to the ERA223 study where 11-29% of pts experienced Fxs, this real-world experience with Ra223 in which 164/177 pts (93%) received BHAs before or during Ra223 saw a 5.6% Fx rate. When Ra223 was given concurrently with abi or enza and BHAs, the Fx rate was 6/177 (3.4%).