J. Garcia-Vargas

Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer

BACKGROUNDnRadium-223 dichloride (radium-223), an alpha emitter, selectively targets bone metastases with alpha particles. We assessed the efficacy and safety of radium-223 as compared with placebo, in addition to the best standard of care, in men with castration-resistant prostate cancer and bone metastases.nnnMETHODSnIn our phase 3, randomized, double-blind, placebo-controlled study, we randomly assigned 921 patients who had received, were not eligible to receive, or declined docetaxel, in a 2:1 ratio, to receive six injections of radium-223 (at a dose of 50 kBq per kilogram of body weight intravenously) or matching placebo; one injection was administered every 4 weeks. In addition, all patients received the best standard of care. The primary end point was overall survival. The main secondary efficacy end points included time to the first symptomatic skeletal event and various biochemical end points. A prespecified interim analysis, conducted when 314 deaths had occurred, assessed the effect of radium-223 versus placebo on survival. An updated analysis, when 528 deaths had occurred, was performed before crossover from placebo to radium-223.nnnRESULTSnAt the interim analysis, which involved 809 patients, radium-223, as compared with placebo, significantly improved overall survival (median, 14.0 months vs. 11.2 months; hazard ratio, 0.70; 95% confidence interval [CI], 0.55 to 0.88; two-sided P=0.002). The updated analysis involving 921 patients confirmed the radium-223 survival benefit (median, 14.9 months vs. 11.3 months; hazard ratio, 0.70; 95% CI, 0.58 to 0.83; P<0.001). Assessments of all main secondary efficacy end points also showed a benefit of radium-233 as compared with placebo. Radium-223 was associated with low myelosuppression rates and fewer adverse events.nnnCONCLUSIONSnIn this study, which was terminated for efficacy at the prespecified interim analysis, radium-223 improved overall survival. (Funded by Algeta and Bayer HealthCare Pharmaceuticals; ALSYMPCA ClinicalTrials.gov number, NCT00699751.).

Overall survival benefit and safety profile of radium-223 chloride, a first-in-class alpha-pharmaceutical: Results from a phase III randomized trial (ALSYMPCA) in patients with castration-resistant prostate cancer (CRPC) with bone metastases.

8 Background: Radium-223 chloride (Ra-223) is a first-in-class alpha-pharmaceutical targeting bone metastases (mets) with high-energy alpha-particles of extremely short range (<100 μm). ALSYMPCA, a phase III, double-blind, randomized, multinational study, compared efficacy, in terms of overall survival (OS), and safety of Ra-223 plus best standard of care (BSC) vs placebo plus BSC in patients (pts) with bone mets in CRPC.nnnMETHODSnEligible pts had progressive, symptomatic CRPC with ≥ 2 bone mets on scintigraphy and no known visceral mets; were receiving BSC; and either previously received docetaxel, were docetaxel ineligible, or refused docetaxel. Pts were randomized 2:1 to receive 6 injections of Ra-223 (50 kBq/kg IV) q4 wks or matching placebo and stratified by prior docetaxel use, baseline alkaline phosphatase level, and current bisphosphonate use. A planned interim analysis (IA) was conducted to assess the effect of Ra-223 on the primary endpoint (OS) using a predefined threshold. Survival data were compared using a stratified log-rank test.nnnRESULTSn922 pts (Ra-223, n = 615; placebo, n = 307) were randomized from 6/2008-2/2011. 445 (58%) of 809 pts in the IA data set received prior treatment with docetaxel. Ra-223 significantly improved OS in pts with CRPC with bone mets vs placebo (two-sided P = 0.00185; HR = 0.695; 95% CI, 0.552-0.875; median OS 14.0 mo vs 11.2 mo, respectively). Safety and tolerability of Ra-223 were highly favorable and showed low incidence of myelosuppression (eg, grades 3/4 neutropenia in 1.8% and 0.8% and thrombocytopenia in 4% and 2% of the Ra-223 and placebo groups, respectively).nnnCONCLUSIONSnRa-223 is an effective therapy that improved OS with a highly favorable safety profile, and may provide a new standard of care for the treatment of CRPC pts with bone mets. [Table: see text].

Updated analysis of the phase III, double-blind, randomized, multinational study of radium-223 chloride in castration-resistant prostate cancer (CRPC) patients with bone metastases (ALSYMPCA)

LBA4512 Background: Radium-223 chloride (Ra-223), a targeted alpha-emitter, targets bone metastases (mets) with high-energy alpha-particles of short range (<100 µm). ALSYMPCA, a phase III double-blind, randomized, multinational study, compared Ra-223 plus best standard of care (BSC) vs placebo plus BSC in CRPC patients (pts) with bone mets. In a planned interim analysis (n = 809), based on 314 events, Ra-223 significantly improved overall survival (OS) vs placebo (median 14.0 mo vs 11.2 mo, respectively; HR = .695; 95% CI, .552-.875; 2-sided p = .00185). Secondary endpoints were met and Ra-223 safety was favorable. An updated analysis was conducted prior to the crossover to further assess the effect of Ra-223 on the primary endpoint (OS), secondary endpoints including skeletal-related events (SREs), and safety.nnnMETHODSnEligible pts had confirmed symptomatic CRPC with ≥ 2 bone mets; no known visceral mets; and were post-docetaxel, unfit for docetaxel, or had declined docetaxel. Pts were randomized 2:1 to receive 6 injections of Ra-223 (50 kBq/kg IV) q4wks or matching placebo. An updated descriptive analysis of OS, based on 528 events, was performed including data from all randomized pts prior to implementing crossover to Ra-223 for placebo pts.nnnRESULTSn921 pts (Ra-223, n = 614; placebo, n = 307) were randomized from 6/2008-2/2011. Ra‑223 significantly improved OS vs placebo (median 14.9 mo vs 11.3 mo, respectively; HR = .695; 95% CI, .581-.832; p = 0.00007), and time to first SRE was significantly prolonged (median 15.6 mo vs 9.8 mo, respectively; HR = 0.658; 95% CI, 0.522-0.830; p = 0.00037). Safety and tolerability of Ra-223 remained favorable, with low myelosuppression (e.g., gr 3/4 neutropenia in 2.2% and 0.7% and gr 3/4 thrombocytopenia in 6.3% and 2% of the Ra-223 and placebo groups, respectively).nnnCONCLUSIONSnOn updated analysis, the median OS benefit for Ra-223 increased from 2.8 to 3.6 months, with a hazard ratio of 0.695 (i.e., 30.5% reduction in risk of death). Ra-223 is an effective therapy that improves OS and time to first SRE with a highly favorable safety profile, and may provide a new standard of care for CRPC pts with bone mets.

Phosphatidylinositol 3-kinase inhibition by Copanlisib in relapsed or refractory indolent lymphoma

Purpose Phosphatidylinositol 3-kinase (PI3K) signaling is critical for the proliferation and survival of malignant B cells. Copanlisib, a pan-class I PI3K inhibitor with predominant activity against PI3K-α and -δ isoforms, has demonstrated efficacy and a manageable safety profile in patients with indolent lymphoma. Patients and Methods In this phase II study, 142 patients with relapsed or refractory indolent lymphoma after two or more lines of therapy were enrolled to receive copanlisib 60 mg intravenously on days 1, 8, and 15 of a 28-day cycle. The primary end point was objective response rate; secondary end points included duration of response, progression-free survival, and overall survival. In addition, safety and gene expression were evaluated. Results Median age was 63 years (range, 25 to 82 years), and patients had received a median of three (range, two to nine) prior regimens. The objective response rate was 59% (84 of 142 patients); 12% of patients achieved a complete response. Median time to response was 53 days. Median duration of response was 22.6 months, median progression-free survival was 11.2 months, and median overall survival had not yet been reached. The most frequent treatment-emergent adverse events were transient hyperglycemia (all grades, 50%; grade 3 or 4, 41%) and transient hypertension (all grades, 30%; grade 3, 24%). Other grade ≥3 events included decreased neutrophil count (24%) and lung infection (15%). High response rates to copanlisib were associated with high expression of PI3K/B-cell receptor signaling pathway genes. Conclusion PI3K-α and -δ inhibition by copanlisib demonstrated significant efficacy and a manageable safety profile in heavily pretreated patients with relapsed or refractory indolent lymphoma.

768PEXTERNAL-BEAM RADIATION THERAPY (EBRT) USE AND SAFETY WITH RADIUM-223 DICHLORIDE (RA) IN PATIENTS (PTS) WITH CASTRATION-RESISTANT PROSTATE CANCER (CRPC) AND SYMPTOMATIC BONE METASTASES (METS) FROM THE ALSYMPCA TRIAL

EXTERNAL-BEAM RADIATION THERAPY (EBRT) USE AND SAFETY WITH RADIUM-223 DICHLORIDE (RA) IN PATIENTS (PTS) WITH CASTRATION-RESISTANT PROSTATE CANCER (CRPC) AND SYMPTOMATIC BONE METASTASES (METS) FROM THE ALSYMPCATRIAL

765PDSAFETY OF RADIUM-223 DICHLORIDE (RA) WITH DOCETAXEL (D) IN PATIENTS (PTS) WITH BONE METASTASES (METS) FROM CASTRATION-RESISTANT PROSTATE CANCER (CRPC): A PHASE 1/2A CLINICAL TRIAL

ABSTRACT Aim: Ra is an approved a-emitter that prolongs survival in pts with CRPC and symptomatic bone mets (Parker et al. NEJM. 2013). D is an approved chemotherapy for CRPC. We conducted a phase 1/2a study of Ra + D in CRPC pts with bone mets to establish safety and a recommended dose of the combination. We previously reported dose escalation data and recommended dose (ASCO 2013). Here we report preliminary data on an expansion cohort studying safety of Ra + D vs D alone. Methods: Eligible pts had progressing CRPC with ≥ 2 bone mets and were candidates for D treatment (tx). Pts were randomized 2:1 to the recommended dose (5 × Ra 50 kBq/kg q 6 wk + 10 × D 60u2003mg/m2 q 3 wk) vs D alone (75u2003mg/m2 q 3 wk with step-down option to 60u2003mg/m2). Adverse events were assessed during tx. Long-term safety data were collected q 3 mo for up to 1 year after start of study tx. Accrual is complete. Results: 46 pts are enrolled (dosed) in the expanded safety cohort. Baseline characteristics in the 2 tx arms are presented below (Table); 33 pts had Ra + D, and 13 had D alone. As of May 2014, 13 (Ra + D) vs 4 (D) pts had all planned study tx doses. To date, febrile neutropenia occurred in 2 pts (both had D alone). There were 1 case of grade 3/4 anemia (Ra + D), 2 cases of grade 1 anemia (both D alone), and no thrombocytopenia. Preliminary data for neutrophils and platelets (Table) indicate a nadir ∼ 1 week after injection, with values similar in the 2 tx arms. 3 of 4 pts receiving D had confirmed dose reductions. A safety review in Nov 2013 raised no concern; recommended Ra + D dose was continued. Patient Data and Characteristics From Expanded Safety Cohort Ra + Docetaxel n = 33 Docetaxel n = 13 No. of patients in treatment 10 4 No. of patients who discontinued study treatment 6 5 No. of patients in follow-up 13 4 No. of patients who completed study 4 0 Age, median (min-max), y 68 (49-82) 67 (55-82) Weight, median (min-max), kg 87 (58-119) 77 (67-131) PSA, median (min-max), mg/L 99 (3-1000) 43 (4-1042) Total ALP, median (min-max), mg/L 167 (62-1016) 284 (74-472) Bone ALP, median (min-max), mg/L 36 (10-331) 43(16-164) LDH, median (min-max), U/L 191 (123-418) 195 (124-328) Mean (min-max) nadir platelet count, thou/cumm, on treatment 261.9 (162-332) 231 (139-314) Mean (min-max) nadir absolute neutrophil count, thou/mL, on treatment 1.4 (0.2-5.5) 0.6 (0.1-1.2) Extent of disease 2-4 metastases 5-9 metastases 10-20 metastases > 20 metastases 3 6 9 11 0 3 4 6 Conclusions: The expanded safety cohort data confirm that Ra + D was well tolerated at 5 × Ra 50 kBq/kg q 6 wk + 10 × D 60u2003mg/m2 q 3 wk in pts who had all planned injections. More pts completed Ra + D tx vs D alone. Expanded safety cohort continues as planned. Disclosure: M.J. Morris: has had a consultant or advisory relationship with and has received research funding from Sanofi-Aventis and Algeta; C. Higano: Consultancy in the past 2-years from Bayer and Johnson & Johnson. Research funding from Algeta, Bayer and Janssen; H.I. Scher: D has had a consultancy relationship with Sanofi; D. Shevrin: Consulted with Astellas on Enzalutamide speakers Bureau for Astellas and Bayer C.J. Ryan: Consultancy: Bayer Adboard, Millenium Adboard Research funding: Algeta ASA (Bayer) Honoraria directly received from Janssen; Y. Loriot: has served as a consultant for Bayer, has received honoraria from Sanofi and Bayer, and has received research funding from Sanofi; K. Fizazi: has served on the speakers bureau or advisory committee for Sanofi and Bayer; J.E. Garcia-Vargas: is employed by Bayer HealthCare; K. Lyseng: M is employed by Algeta ASA (Bayer); M. Bloma: is employed by and has an ownership interest in Algeta ASA (Bayer); A. Aksnes: D is employed by Algeta ASA (Bayer); J.A. Carrasquillo: has had a consultant or advisory relationship with Bayer and has received honoraria and research funding from Algeta. All other authors have declared no conflicts of interest.