Efficacy and safety of radium-223 dichloride (Ra-223) in castration-resistant prostate cancer (CRPC) patients with bone metastases who did or did not receive prior docetaxel (D) in the phase III ALSYMPCA trial.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 5068-5068
Author(s):  
Nicholas J. Vogelzang ◽  
Svein Inge Helle ◽  
Dag Clement Johannessen ◽  
Joe M. O'Sullivan ◽  
Jose E. Garcia-Vargas ◽  
...  
Keyword(s):  
Bone Metastases ◽  
Survival Data ◽  
Safety Profile ◽  
Phase Iii ◽  
Rank Test ◽  
Efficacy And Safety ◽  
Castration Resistant Prostate Cancer ◽  
Favorable Safety Profile ◽  
Radium 223 ◽  
Favorable Safety

5068 Background: Ra-223, a first-in-class α-emitter, significantly improved median overall survival (OS) by 3.6 mo vs placebo (Pbo) in CRPC patients (pts) with bone metastases (mets) receiving best standard of care (BSoC) in the ALSYMPCA study (HR = 0.695; 95% CI, 0.581-0.832; p = 0.00007), and had a highly favorable safety profile in the updated ALSYMPCA analysis (Parker et al. ASCO 2012). This predefined subgroup analysis assessed efficacy and safety of Ra-223 in pts who did or did not receive prior D (pD). Methods: Eligible pts had progressive, symptomatic CRPC with ≥ 2 bone mets; had no known visceral mets; were receiving BSoC; and had received pD, or were unfit for or declined D (npD). Pts were randomized 2:1 to 6 injections of Ra-223 (50 kBq/kg IV) q4wk or matching Pbo and stratified by prior D use, baseline alkaline phosphatase level, and current bisphosphonate use. Survival data were compared using a log-rank test. Results: 395/921 (43%) randomized pts had npD (Ra-223, n = 262; Pbo, n = 133); 526/921 (57%) received pD (Ra-223, n = 352; Pbo, n = 174). Median ages were 74 y (npD) and 69 y (pD). In pts with npD, median OS was 16.1 mo in the Ra-223 group vs 11.5 mo in the Pbo group (HR = 0.745; 95% CI, 0.562-0.987; p = 0.039). In pts with pD, median OS was 14.4 mo vs 11.3 mo in the Ra-223 and Pbo groups, respectively (HR = 0.710; 95% CI, 0.565-0.891; p = 0.003). Overall, there was a low incidence of myelosuppression. Incidences of neutropenia and thrombocytopenia were higher in pts with pD vs pts with npD. Conclusions: Ra-223 significantly prolonged OS and had a highly favorable safety profile in CRPC pts with bone mets, regardless of whether they had pD or npD. pD pts had a slightly increased rate of grade 3 and 4 bone marrow suppression with Ra-223. Clinical trial information: NCT00699751. [Table: see text]

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.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 8-8 ◽  
Author(s):  
Chris Parker ◽  
Daniel Heinrich ◽  
Joe M. O'Sullivan ◽  
Sophie D. Fossa ◽  
Ales Chodacki ◽  
...  
Keyword(s):  
Overall Survival ◽  
Bone Metastases ◽  
Survival Data ◽  
Safety Profile ◽  
Standard Of Care ◽  
High Energy ◽  
Phase Iii ◽  
Rank Test ◽  
Data Set ◽  
Radium 223

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. Methods: Eligible 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. Results: 922 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). Conclusions: Ra-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]

Safety of darolutamide (DARO) for nonmetastatic castration-resistant prostate cancer (nmCRPC) from extended follow-up in the phase III ARAMIS trial.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 239-239
Author(s):  
Matthew Raymond Smith ◽  
Karim Fizazi ◽  
Teuvo L. J. Tammela ◽  
Felipe Melo Cruz ◽  
Luke T. Nordquist ◽  
...  
Keyword(s):  
Safety Profile ◽  
Safety Data ◽  
Final Analysis ◽  
Phase Iii ◽  
Prolonged Treatment ◽  
Fracture Rate ◽  
Castration Resistant Prostate Cancer ◽  
Favorable Safety Profile ◽  
Risk Of Death ◽  
Favorable Safety

239 Background: DARO is a structurally distinct androgen receptor inhibitor (ARI) approved for treating nmCRPC. In ARAMIS, DARO significantly reduced the risk of death by 31% (HR = 0.69; 95% CI: 0.53-0.88; p = 0.003) and prolonged median metastasis-free survival vs placebo (PBO; 40.4 months vs 18.4 months; HR = 0.41; 95% CI: 0.34-0.50; p < 0.001). Adverse events (AEs) of interest commonly associated with ARI therapy, such as fatigue, falls, fractures, rash, mental impairment, and hypertension, as well as interactions between ARIs and concomitantly administered drugs, can impact patient daily life. In the final analysis of the double-blind (DB) period of the ARAMIS trial, DARO had a favorable safety profile, showing ≤2% difference vs PBO for most AEs of interest. Fatigue was the only AE with > 10% incidence with DARO. The incidence of permanent discontinuation due to AEs was also similar between DARO and PBO (8.9% vs 8.7%). Here we present safety data for prolonged treatment with DARO from the final analysis of the DB + open-label (OL) period of ARAMIS. Methods: Patients (pts) with nmCRPC (N = 1509) were randomized 2:1 to DARO or matched PBO while continuing androgen deprivation therapy. The data cut-off for the primary analysis of the DB period was September 3, 2018. Study unblinding occurred on November 30, 2018, after which pts in the DARO arm still receiving study treatment continued with OL DARO. The data cut-off for final analysis of the DB+OL period was November 15, 2019. Results: At the final analysis, the median treatment duration for pts randomized to DARO was 18.5 months for the DB period and 25.8 months for the DB+OL period. At the final cut-off date, 48.8% of patients in the DARO DB+OL group were still receiving DARO treatment. The increase in the incidence of any-grade AEs (85.7% vs 89.8%) and serious AEs (26.1% vs 32.1%) between the DB and DB+OL period was small. Between the DB and DB+OL periods, only minor numerical changes for ARI-associated AEs were observed. When the incidences were corrected for exposure, there were minimal differences between the DB and DB+OL period, e.g., the fracture rate was 3.4 vs 4.0 per 100 patient-years for the DB vs DB+OL periods, respectively. Fatigue was the only ARI-associated AE of interest that exhibited > 10% incidence in the DARO arm during the DB+OL period. The incidence of permanent discontinuation of DARO due to AEs increased slightly from 8.9% during the DB period to 10.5% during the DB+OL period; the incidence of discontinuation of PBO due to AEs during the DB period was 8.7%. Conclusions: With longer treatment exposure, DARO remained well-tolerated. In the DB+OL period, no new safety signals were observed. The expected increases in incidence of AEs between the DB and DB+OL periods largely disappeared when adjusted for the longer exposure, confirming the favorable safety profile of DARO with prolonged treatment. Clinical trial information: NCT02200614.

Radium-223 chloride impact on skeletal-related events in patients with castration-resistant prostate cancer (CRPC) with bone metastases: A phase III randomized trial (ALSYMPCA).

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 9-9 ◽  
Author(s):  
A. Oliver Sartor ◽  
Daniel Heinrich ◽  
Svein Inge Helle ◽  
Joe M. O'Sullivan ◽  
Sophie D. Fossa ◽  
...  
Keyword(s):  
Bone Metastases ◽  
Standard Of Care ◽  
High Energy ◽  
Alpha Particles ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Double Blind ◽  
Radium 223 ◽  
Skeletal Related Events ◽  
Favorable Safety

9 Background: Radium-223 chloride (Ra-223) is a 1st-in-class alpha-pharmaceutical targeting 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 (pbo) plus BSC in patients (pts) with bone mets in CRPC. The primary endpoint was OS; secondary endpoints included skeletal-related events (SREs). Methods: Eligible 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 pbo and stratified by prior docetaxel use, baseline alkaline phosphatase level, and current bisphosphonate use. Results: 922 pts (Ra-223, n = 615; pbo, n = 307) were randomized from 6/2008-2/2011. Based on data from a planned interim analysis (n = 809), unblinded June 2011, Ra-223 significantly improved OS in pts with CRPC with bone mets vs pbo (median OS 14.0 vs 11.2 mo, respectively; two-sided P = 0.00185; HR = 0.695; 95% CI, 0.552-0.875). SREs were lower in the Ra-223 vs pbo group, and time to 1st SRE was significantly delayed (median time to SRE 13.6 mo vs 8.4 mo, respectively; P = .00046; HR = .610; 95% CI, .461-.807). Conclusions: Ra-223 significantly delayed time to 1st SRE and SRE components, except surgical intervention. These reductions in SREs, particularly SCC, are noteworthy. Ra-223 is an effective therapy with a highly favorable safety profile and may provide a new standard of care for treatment of CRPC pts with bone mets. [Table: see text]

Efficacy and safety of zoledronic acid in men with castration-sensitive prostate cancer and bone metastases: Results of CALGB 90202 (Alliance).

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 27-27 ◽  
Author(s):  
Matthew Raymond Smith ◽  
Susan Halabi ◽  
Charles J. Ryan ◽  
Walter Michael Stadler ◽  
Arif Hussain ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Zoledronic Acid ◽  
Bone Metastases ◽  
Statistical Power ◽  
Phase Iii ◽  
Rank Test ◽  
Rank Statistic ◽  
Type I ◽  
Efficacy And Safety ◽  
Castration Resistant Prostate Cancer

27 Background: Zoledronic acid (ZA) decreases risk of skeletal-related events (SREs) in men with castration-resistant prostate cancer (CRPC) and bone metastases. This phase III study evaluated efficacy and safety of earlier treatment with ZA in men with castration-sensitive metastatic prostate cancer. Methods: CALGB 90202 was a randomized, double-blinded, placebo-controlled phase III trial in men with castration-sensitive prostate cancer and bone metastases who had initiated androgen deprivation therapy within six months of study entry. Subjects were randomized 1:1 in blinded manner to receive ZA (4 mg intravenously every 4 weeks) or placebo (P). After progression to CRPC, all patients crossed over to open-label ZA. The primary endpoint was time to first SRE. Target sample size was 680. Time to SRE was defined as interval between date of randomization and date of first SRE (radiation to bone, or clinical fracture, or surgery to bone, or death due to prostate cancer). With 470 SRE events, the log-rank test has 88% power to detect a 23% decrease in hazard rate of SRE event assuming a one-sided type I error rate of 0.05. The study was discontinued prematurely after the corporate supporter withdrew study drug supply. Primary analysis was based on the stratified log-rank statistic adjusting on the stratification factors following observation of 284 SREs (60% of total events). Results: Between June 2004 and April 2012, 645 patients were randomly assigned to ZA or P. Median time to first SRE was 32.5 months in the ZA group and 29.8 months in the P group (hazard ratio (HR) 0.96 [0.76-1.22]; stratified log-rank P=0.74). A total of 271 deaths were observed; median follow-up time for surviving patients was 24.4 months (20.6, 28.3). Overall survival was similar between groups (HR= 0.89 [0.70-1.14]; stratified P=0.34). Rates of grade 3 or higher adverse events were similar between groups (15% vs. 12% in ZA and P). Conclusions: In men with castration-sensitive prostate cancer and bone metastases, early treatment with zoledronic acid was not associated with lower risk for SREs or death. Early termination limited statistical power of the study. Clinical trial information: NCT00079001.

Long-term safety and efficacy analysis of abiraterone acetate (AA) plus prednisone (P) in metastatic castration-resistant prostate cancer (mCRPC) without prior chemotherapy (COU-AA-302).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 5009-5009
Author(s):  
Dana E. Rathkopf ◽  
Matthew R. Smith ◽  
Johann Sebastian De Bono ◽  
Christopher Logothetis ◽  
Neal Shore ◽  
...  
Keyword(s):  
Incidence Rate ◽  
Safety Profile ◽  
Castration Resistant Prostate Cancer ◽  
Prior Chemotherapy ◽  
Favorable Safety Profile ◽  
Post Hoc Analysis ◽  
Long Term Treatment ◽  
Favorable Safety ◽  
Post Hoc

5009 Background: AA, a CYP17 inhibitor, prolongs the lives of men with progressive pre- or post-chemotherapy treated mCRPC with a favorable safety profile (Rathkopf et al. ASCO-GU 2013. Abstr 5). This post hoc analysis examines the safety and tolerability of long-term treatment (≥ 24 mos) in study COU-AA-302. Methods: 1,088 pts were randomized 1:1 to AA 1000 mg + P 5 mg po BID vs placebo + P. Co-primary endpoints were radiographic progression-free survival (rPFS) and OS. Median times with 95% CI of the end points were estimated using the Kaplan-Meier (KM) method. Post hoc analysis of adverse events (AEs) was performed at pre-specified interim analysis (IA3) (55% OS events). Results: At a median follow-up = 27.1 mos (IA3): rPFS HR (95% CI) = 0.53 (0.45, 0.62), p < 0.0001 and OS was improved over P [0.79 (0.66, 0.96), p = 0.0151]; the latter did not reach the pre-specified efficacy boundary (p = 0.0035). All secondary endpoints favored the AA arm (Rathkopf et al. ASCO-GU 2013. Abstr 5). The incidence rate of selected AEs by duration of exposure is shown below (Table). There was no clinically relevant increase in the incidence rate of AEs with longer exposure using AA + P versus P alone; although pts on treatment for ≥ 24 mos may have had greater tolerability. The percentage of patients who came off study due to an AE was 8% (AA) versus 6% (P). Conclusions: The updated IA3 of COU-AA-302 in pts without prior chemotherapy confirms the delay in progression and prolongation of life with a favorable safety profile including pts treated for ≥ 24 mos with AA + P or P. Clinical trial information: NCT00887198. [Table: see text]

Larotrectinib efficacy and safety in adult TRK fusion cancer patients.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3122-3122 ◽  
Author(s):  
David S. Hong ◽  
Shivaani Kummar ◽  
Anna F. Farago ◽  
Ulrik Niels Lassen ◽  
Jordan Berlin ◽  
...  
Keyword(s):  
Disease Progression ◽  
Safety Profile ◽  
Safety Data ◽  
Disease Status ◽  
Bone Sarcoma ◽  
Primary Diagnosis ◽  
Efficacy And Safety ◽  
Favorable Safety Profile ◽  
Duration Of Response ◽  
Favorable Safety

3122 Background: A broad range of pediatric and adult malignancies harbor TRK fusions involving the NTRK1, NTRK2, and NTRK3 genes. The highly-selective TRK inhibitor, larotrectinib, has previously shown a high overall response rate (ORR) and a favorable safety profile in patients (pts) with TRK fusion cancer. To better delineate efficacy in adults, as pediatric pts have a particularly high ORR, here we report updated efficacy and safety data from the adult subset of pts with TRK fusion cancer treated with larotrectinib. Methods: Adult pts (aged 18 or older) with TRK fusion cancer detected by local testing in 2 larotrectinib clinical trials (NCT02122913 and NCT02576431) were analyzed. Larotrectinib was administered 100 mg PO BID until disease progression, withdrawal, or unacceptable toxicity. Disease status was assessed by both investigator (INV) and independent assessment (IRC) using RECIST v1.1. Results: As of July 30, 2018, 83 adults (median age: 57 y, range 20–80 y) with TRK fusion cancer had been treated. Cancer types included salivary gland (23%) and thyroid cancer (19%), soft tissue sarcoma (14%), lung cancer (13%), colon cancer and melanoma (7% each), GIST (5%), and bone sarcoma, cholangiocarcinoma, and appendiceal, breast, and pancreas cancer (≤2% each). TRK fusions involved NTRK1 (40%), NTRK2 (2%), and NTRK3 (57%). 77% of pts had received prior systemic therapy (median lines: 2, range 0–10). In 74 pts evaluable per INV, the ORR was 76% with 9% CR, 57% confirmed PR, 9% PR pending confirmation, 12% SD, 11% PD, and 1% not determined; 9 pts were non-evaluable (NE) due to lack of post-baseline assessment. In 65 pts evaluable per IRC, the ORR was 68% with 17% CR, 51% PR, 15% SD, 12% PD, and 5% NE. With a median follow up of 17.2 and 17.5 mo per INV and IRC, respectively, the median duration of response had not been reached (ranges identical: 1.9+ to 38.7+ months). At data cutoff, 63% remained on treatment; 30% had discontinued due to disease progression. Adverse events were mostly grade 1–2. Conclusions: Larotrectinib demonstrated robust tumor-agnostic efficacy and a favorable safety profile in adult pts with TRK fusion cancer. These results support testing for TRK fusion cancer in pts with advanced solid tumors, regardless of site of primary diagnosis. Clinical trial information: NCT02122913 and NCT02576431.

A meta-analysis on individual data of bone-targeting radio-isotopes in men with bone metastases from castration-resistant prostate cancer.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 352-352
Author(s):  
Safae Aarab Terrisse ◽  
Chris C. Parker ◽  
Karamouza Eleni ◽  
A. Oliver Sartor ◽  
Nicholas James ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Metastases ◽  
Meta Analysis ◽  
External Beam Radiotherapy ◽  
Rank Test ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Radium 223 ◽  
Significant Difference ◽  
Radio Isotopes

352 Background: Among bone-targeted radio-isotopes (RI), Radium-223 (an α-emitter) is the only one with clearly demonstrated overall survival (OS) benefit in men with castration-resistant prostate cancer (CRPC). The aim of this meta-analysis is to estimate the OS impact of RI in men with CRPC. Methods: An individual patient data meta-analysis was carried out from randomized trials with inclusion period 1993-2013. Eligible trials included more than 50 patients, mandated bone metastases from CRPC and randomly evaluated RI. Endpoints were OS (primary), symptomatic skeletal events (SSE) and toxicity. A fixed-effect model was used. The log-rank test stratified by trial was used to estimate individual and overall hazard ratios (HR). Subset analyses were performed by the type of radiation (α vs. β emission) and by trial comparison: RI + Chemotherapy (CT) vs. CT, RI+ External beam radiotherapy (EBRT) vs. EBRT, RI vs. EBRT. Results: From 9 identified trials, data from 6 trials comprising 2081 patients (min: 64, max: 921) were collected with 2 trials representing 80% of data. The data from 3 trials (n = 341) were not available. The overall effect on OS favoured RI with HR = 0.86 [0.77-0.95] but high heterogeneity between trials (p < 0.001, I2= 79.6%). The overall effect of α- emitters on OS (HR = 0.70 [0.58; 0.83], 2 trials, n = 985) significantly differed from that of β-emitters (HR = 0.96 [0.84; 1.10], n = 4 trials, n = 1096) (interaction p = 0.0041). The overall effect on SSE favoured RI with HR = 0.81 [0.69-0.93] (4 trials, n = 1806) with marked between trial heterogeneity (p = 0.08, I² = 55.3%) and a significant difference (p = 0.02) by the type of RI (α-emitters: HR = 0.65 [0.52-0.82]-2 trials, β-emitters: HR = 0.93 [0.77-1.13]-2 trials). Conclusions: In men with metastatic CRPC a significant improvement of OS and SSE was obtained with bone targeted α-emitter radio isotopes, but not with β-emitter. However, some between trial heterogeneity of effects on OS need further investigations.

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