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.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5542-5542
Author(s):  
Celestia S. Higano ◽  
Lauren C Harshman ◽  
Sabina Dizdarevic ◽  
John Logue ◽  
Timothy Richardson ◽  
...  

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]

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 5042-5042 ◽  
Author(s):  
Celestia S. Higano ◽  
Shawn H. Zimberg ◽  
Sabina Dizdarevic ◽  
Lauren Christine Harshman ◽  
John Logue ◽  
...  

5042 Background: Ra-223, a targeted alpha therapy, prolonged survival with good safety in metastatic castration-resistant prostate cancer (mCRPC) in the phase 3 ALSYMPCA trial. REASSURE will evaluate Ra-223 short- and long-term safety in routine clinical practice settings. This is the first planned interim analysis (median 7 mo observation). Methods: This global, prospective, single-arm, observational study enrolled pts with mCRPC with bone metastases (mets) for whom Ra-223 therapy was planned. Follow-up will continue up to 7 years after last Ra-223 dose. Results: 1106 pts (437 N. America, 665 Europe, 4 not recorded) enrolled from 2 Sep 2014 to 22 Sep 2016. Baseline data are available from 583 pts receiving 1st- (1L), 2nd- (2L), or ≥3rd-line (≥3L) Ra-223 for mCRPC(Table). The majority of pts (n=369, 63%) completed 5–6 doses (1L, 70%; 2L, 64%; ≥3L, 49%); median 6 doses (1L,6; 2L, 6; ≥3L, 4). Treatment-emergent drug-related AEs occurred in 215 pts (37%). Post-treatment grade 3/4 thrombocytopenia occurred in 14 pts (2.4%) and anemia in 45 (7.7%). Conclusions: In routine clinical practice, Ra-223 was associated with no short-term safety concerns and appeared to be used in pts with less advanced mCRPC than in ALSYMPCA. The majority of pts on 1L/2L Ra-223 therapy received 5–6 doses. Ra-223 was often used with abiraterone or enzalutamide, but not chemotherapy. The next interim analysis in 2019 will report long-term safety and outcomes on all pts. Clinical trial information: NCT02141438. [Table: see text]


2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e17592-e17592
Author(s):  
A. Oliver Sartor ◽  
Christian la Fougère ◽  
Markus Essler ◽  
Samer Ezziddin ◽  
Gero Kramer ◽  
...  

e17592 Background: Ra-223, a targeted alpha therapy, showed an overall survival (OS) benefit and favorable safety profile in mCRPC pts in a phase 3 trial. 177Lu-PSMA radioligand is an investigational agent for mCRPC. REASSURE (NCT02141438) is a global, prospective, observational study investigating Ra-223 safety in routine clinical practice over 7 years’ follow-up in mCRPC pts. Data from the second prespecified interim analysis (IA) were used to investigate safety and outcomes of pts who received 177Lu-PSMA after Ra-223 therapy. Methods: Data cut-off for the second prespecified IA was March 2019, and included pts who had subsequent 177Lu-PSMA after the last Ra-223 dose. Disease characteristics, adverse events (AEs) after last Ra-223 dose, and OS are described. Results: Of 1465 pts overall, 26 received 177Lu-PSMA subsequent to Ra-223. In this subgroup, pts received multiple anticancer therapies prior to 177Lu-PSMA. 13 pts (50%) received Ra-223 as combination therapy at second line (metastatic setting). Pts received a median of six Ra-223 doses. After Ra-223 treatment ended, 3 pts (12%) had drug-related serious AEs, 9 pts (35%) had grade 3/4 bone marrow suppression-relevant hematologic AEs. Median duration of 177Lu-PSMA treatment was 3.5 months. 19 pts (73%) received 177Lu-PSMA as fourth-line therapy or onwards. OS was 28.0 months from start of Ra-223 and 13.2 months from start of 177Lu-PSMA. Conclusions: In this select population receiving a sequence of multiple lines of therapy with different modes of action, grade 3/4 hematologic AEs after Ra-223 were low. Treatment with subsequent 177Lu-PSMA seems feasible, based on duration of 177Lu-PSMA and survival. Clinical trial information: NCT02141438 . [Table: see text]


Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5592-5592
Author(s):  
Jing Li ◽  
Li Bao ◽  
Zhong-jun Xia ◽  
Kaiyang Ding ◽  
Bingzong Li ◽  
...  

J Li, L Bao, ZJ Xia and KY Ding contributed equally to this study. Background: Based on the promising results shown in the phase 3 trial (TOURMALINE-MM1, NCT01564537) and the China Continuation Study of MM1, the oral proteasome inhibitor (PI) ixazomib (ixa) was approved in China in April of 2018, in combination with lenalidomide (len) and dexamethasone (dex) (IRd), for patients (pts) with relapsed/refractory multiple myeloma (RRMM). Data on the efficacy and safety of ixa-based therapy in Chinese pts with MM in real-life practice is rather limited. A large national, multi-center, real-world study involving 14 centers from different areas of China was performed to investigate the current status of ixa usage in China and to evaluate the efficacy and safety in routine clinical practice. A total of 246 ixa-treated MM pts was enrolled, with 163 (66.3%) RRMM, 60 (24.4%) newly diagnosed MM and 23 (9.4%) pts received ixa as maintenance. Herein, we reported the data of RRMM in this study. Methods: Medical records, including demographics, disease characteristics, treatment regimen and duration, response rate, adverse events (AEs) and survival, of ixa-treated (at least one cycle completed with response evaluation result) RRMM pts were analyzed. Results: A total of 149 evaluable pts (out of 163 RRMM pts) treated from April 2018, to July 2019 were included in analysis. Baseline features and prior treatment are summarized in Table 1. Patients were categorized into MM1 trial-eligible/-ineligible groups according to the inclusion and exclusion criteria of MM1 study. Median age was 62 years (range 33 - 87) with 52 (34.9%) ≥65 years. Most pts (75.2%) had ISS stage II-III disease. High-risk cytogenetic abnormalities (including del 17p, t (4;14), and/or t (14;16)) were detected in 19 patients (21.1%, among 90 patients with FISH results). Fifty-two (34.9%) pts had a ECOG PS ≥2. Overall, ixa-based regimens were used as the 2nd/3rd/4th/≥5th-line therapy in 29.7%, 33.1%, 16.2% and 17.4% of the pts, respectively. Prior treatment included bortezomib (91.9%), len (52.0%) and thalidomide (58.8%). More than half pts (54.7%) were refractory to previous bortezomib treatment, and 32.2% pts were len-refractory. MM-1 trial-ineligible pts had more advanced ISS stage, higher ECOG PS, more severe anemia, more lines of prior therapy and more refractory diseases. Treatment, outcome and survival were listed in Table 2. Ixa-based regimens included IRd in 70 (47.0%) patients, ixa-dex (Id) in 31 (20.8%) patients and Id plus chemotherapeutics/other agents (44, 29.5%; including cyclophosphamide in 14 pts, thalidomide in 12 pts, adriamycin in 6 pts, melphalan in 5 pts and daratumumab in 3 pts) in 20 (33.3%). (Table 2). One patient received stem cell transplantation (SCT) during follow-up. The best confirmed ORR (≥PR) for all 149 patients was 53.7% (80/149), including 28.2% of patients with ≥VGPR and 7.4% with a CR, with a median time to response of 41.5 days. Surprisingly, ixa-based regimens demonstrated efficacy in pts with PI/len refractory diseases, with an ORR and ≥VGPR rate of 44.4% and 19.9% for PI-refractory pts, and an ORR and ≥VGPR rate of 30.6% and 12.2% for len-refractory pts. Pts eligible for MM1 study shown comparable ORR (76.7%) with that reported in MM1 (ORR 78%). No significant difference in response between different ixa-based regimens was observed. The median PFS of the whole cohort, pts with standard/high cytogenetic risks, pts refractory to bortezomib/len and pts eligible/ineligible for MM1 trial was 8.2, 8.2, 6.8, 6.7, 5.9months, not reached and 6.6months respectively. The median overall survival (OS) of the whole cohort and every subgroup was not reached. Adverse events (AEs) of grade 3/4, reported in 40 (27.2%) patients, included 10.1% thrombocytopenia, 5.4% anemia, 3.4% diarrhea and 6.0% pneumonia. Only 3 (2.01%) pts had a grade 3/4 peripheral neuropathy during follow-up. Discussion and conclusion: Our results show that ixa-based therapy demonstrated good efficacy with limited toxicity for pts with RRMM in real-life clinical practice. Moreover, in pts with PIs- or len- refractory diseases, ixa-based therapy still showed acceptable effectiveness (ORR: 44.4% and 30.6%; mPFS: 6.7 months and 5.9 months). Although 70.5% pts in our real-life cohort were ineligible for MM1 trial, the efficacy and safety profile is similar to that reported in MM1 China Continuation Study. Ixa-based therapy is a reasonable choice for Chinese RRMM pts. Disclosures No relevant conflicts of interest to declare.


Endocrine ◽  
2020 ◽  
Vol 70 (2) ◽  
pp. 280-291
Author(s):  
Alfredo Campennì ◽  
Daniele Barbaro ◽  
Marco Guzzo ◽  
Francesca Capoccetti ◽  
Luca Giovanella

Abstract Purpose The standard of care for differentiated thyroid carcinoma (DTC) includes surgery, risk-adapted postoperative radioiodine therapy (RaIT), individualized thyroid hormone therapy, and follow-up for detection of patients with persistent or recurrent disease. In 2019, the nine Martinique Principles for managing thyroid cancer were developed by the American Thyroid Association, European Association of Nuclear Medicine, Society of Nuclear Medicine and Molecular Imaging, and European Thyroid Association. In this review, we present our clinical practice recommendations with regard to implementing these principles in the diagnosis, treatment, and long-term follow-up of patients with DTC. Methods A multidisciplinary panel of five thyroid cancer experts addressed the implementation of the Martinique Principles in routine clinical practice based on clinical experience and evidence from the literature. Results We provide a suggested approach for the assessment and diagnosis of DTC in routine clinical practice, including the use of neck ultrasound, measurement of serum thyroid-stimulating hormone and calcitonin, fine-needle aspiration, cytology, and molecular imaging. Recommendations for the use of surgery (lobectomy vs. total thyroidectomy) and postoperative RaIT are also provided. Long-term follow-up with neck ultrasound and measurement of serum anti-thyroglobulin antibody and basal/stimulated thyroglobulin is standard, with 123/131I radioiodine diagnostic whole-body scans and 18F-fluoro-2-deoxyglucose positron emission tomography/computed tomography suggested in selected patients. Management of metastatic DTC should involve a multidisciplinary team. Conclusions In routine clinical practice, the Martinique Principles should be implemented in order to optimize clinical management/outcomes of patients with DTC.


2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5002-5002
Author(s):  
Silke Gillessen ◽  
Ananya Choudhury ◽  
Alejo Rodriguez-Vida ◽  
Franco Nole ◽  
Enrique Gallardo Diaz ◽  
...  

5002 Background: The randomized phase III EORTC-1333-GUCG (NCT02194842) trial compares enzalutamide vs. a combination of Radium 223 and enzalutamide in asymptomatic or mildly symptomatic metastatic castration resistant prostate cancer (mCRPC) patients. The premature unblinding of ERA223 (NCT02043678) in Nov 2017 due to a significant increase in the rate of fractures in the combination of abiraterone and Ra223 arm led to the implementation of the mandatory use of bone protecting agents (BPA) in the EORTC-1333-GUCG trial. Skeletal fractures, pathological or not, are a frequent and underestimated adverse event of systemic treatment of advanced prostate cancer. Whether this mandated use of BPA (zoledronic acid or denosumab) would mitigate the risk of fractures in this patient population was unclear. An early safety analysis (Tombal, ASCO, 2019) suggested that the risk of fractures was well controlled in both arms when patients receive BPA. We present here an updated analysis of fracture incidence with longer follow-up. Methods: As of 28/01/2021, a total of 253 patients (134 after making BPA mandatory) were randomized between enzalutamide/Ra223 and enzalutamide. The fracture rate was estimated with the cumulative incidence method in the safety population of 237 (122 after making BPA mandatory) treated patients. Death in absence of fracture was analyzed as competing risk and censoring was applied at last follow-up. Results: Overall, 69.5% of enzalutamide/Ra223 patients (95.2% after making BPA mandatory) and 73.1% of enzalutamide patients (95% after making BPA mandatory) received BPA on treatment: 13.6% in the enzalutamide/Ra223 arm and 21.8% in the enzalutamide arm did not use BPA at registration, but started during protocol treatment and 55.9% and 51.3% respectively, received BPA since entry. At 36.7 months median follow-up in patients without BPA and 23.1 months median follow-up in patients receiving BPA, a total of 39 patients reported a fracture. Among them, 30 patients (20 in enzalutamide/Ra223 arm) did not receive BPA and 9 (4 in the enzalutamide/Ra223 arm) received BPA (see table). Conclusions: The updated safety analysis confirms the early fracture rate results. In the absence of BPA, the risk of fracture is increased when RA223 is added to enzalutamide. Strikingly, in both arms, the risk remains almost abolished by a preventive continuous administration of BPA, thus stressing the importance of complying to international recommendations in terms of giving BPA to mCRPC patients. This study is sponsored by EORTC and supported by Bayer and Astellas. Clinical trial information: NCT02194842. [Table: see text]


2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5042-5042
Author(s):  
Julie N Graff ◽  
Scott T. Tagawa ◽  
Christopher J. Hoimes ◽  
Winald R. Gerritsen ◽  
Ulka N. Vaishampayan ◽  
...  

5042 Background: KEYNOTE-199 (NCT02787005) is a multicohort phase 2 study to evaluate pembrolizumab (pembro) in mCRPC. A previous analysis of patients with RECIST-measurable (cohort 4 [C4]) or bone-predominant nonmeasurable (cohort 5 [C5]) disease who were chemotherapy-naive and had progression while on enzalutamide (enza) found that pembro + enza showed antitumor activity and manageable safety. Long-term outcomes are of interest with immunotherapy; hence, updated efficacy and safety data after an additional 1 year of follow-up are presented. Methods: Pts were eligible if they had resistance to enza after prior response. Prior treatment with abiraterone was allowed. Pts received pembro 200 mg Q3W for up to 35 cycles + enza QD until progression, unacceptable toxicity, or withdrawal. Primary end point was ORR per RECIST v1.1 by blinded independent central review (BICR) in C4. Secondary end points were DOR (C4), and DCR, rPFS, OS and safety (both cohorts). Results: 126 pts (C4, 81; C5, 45) were treated. Median age was 72 years (range 43-92), 32.5% had visceral disease and 87.3% previously received ≥6 mo of enzalutamide; 121 pts (96.0%) discontinued, most because of progressive disease. Median (range) time from enrollment to data cutoff was 31.7 mo (23.1-37.1) in C4 and 35.5 mo (22.9-37.3) in C5. In C4, confirmed ORR was 12.3% (95% CI 6.1-21.5) (2 CRs, 8 PRs); median (range) DOR was 8.1 mo (2.5+ to 15.2), and 62.5% had a response ≥6 mo (Kaplan-Meier estimate). Additional efficacy analyses are outlined in the table. A total of 27.2% and 28.9% of pts in C4 and C5, respectively, experienced grade ≥3 treatment-related adverse events. Two pts in C4 died of immune-related AEs (Miller Fisher syndrome and myasthenia gravis). Incidence of any-grade (34.1%) and grade 3 or 4 (5.6%) rash, regardless of relatedness to treatment, was higher than previously reported for individual agents but manageable with standard-of-care treatments; 2 pts discontinued because of rash. Conclusions: After an additional 1 year of follow-up, pembro + enza continued to show antitumor activity and a manageable safety profile in pts with mCRPC who became resistant to enza. The treatment combination is being further evaluated in the ongoing phase 3 KEYNOTE-641 trial (NCT03834493). Clinical trial information: NCT02787005. [Table: see text]


The Prostate ◽  
2019 ◽  
Vol 79 (14) ◽  
pp. 1683-1691 ◽  
Author(s):  
Oliver Sartor ◽  
Daniel Heinrich ◽  
Neil Mariados ◽  
Maria José Méndez Vidal ◽  
Daniel Keizman ◽  
...  

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
R De Caterina ◽  
P Kelly ◽  
P Monteiro ◽  
J C Deharo ◽  
C De Asmundis ◽  
...  

Abstract Introduction Edoxaban has been approved for stroke prevention in patients with atrial fibrillation based on its comparable efficacy and superior safety compared to warfarin in the pivotal ENGAGE AF-TIMI 48 trial. ETNA-AF Europe (NCT02944019) was initiated in agreement with the EMA to evaluate benefits and risks of edoxaban treatment in unselected patients in routine clinical practice. Methods 13,980 patients from across 825 hospital and office-based physicians from 10 European countries (Austria, Belgium, Germany, Ireland, Italy, The Netherlands, Portugal, Spain, Switzerland and United Kingdom) were enrolled, and will be followed-up for 4 years. This snapshot analysis includes baseline and first outcome data of 7,672 patients (56.3% of all enrolled patients) that have completed their first 1-year follow-up visit (mean follow-up: 343.5 days). Results The average age of patients was 73.4 years, the mean weight was 81.9 kg (Table 1). Frequent comorbidities include hypertension (77.2%), valvular heart disease (17.4%), congestive heart failure (5.8%) and history of myocardial infarction (4.2%). Patients receiving the 30 mg dose (22.9%) were older, had a lower creatinine clearance and had a higher risk for both stroke and bleeding as compared to those on the 60 mg dose (77.1%). Overall, the incidence of clinical events was low: all-cause mortality: 3.56%/y, major bleeding 0.95%/y, intracranial haemorrhage 0.28%/y, any stroke or systemic embolic events 0.88%/y. Patient characteristics at Year 1 Patient characteristics All patients Edoxaban 60 mg Edoxaban 30 mg [7,672] [5,916 (77.1%)] [1,756 (22.9%)] Age [years] mean (SD) 73.4 (9.26) 71.8 (8.98) 79.1 (7.81) Body weight [kg] mean (SD) 81.9 (17.33) 84.1 (16.80) 74.3 (16.93) CrCl (CG) [mL/min] mean (SD) 75.0 (30.29) 82.5 (29.14) 51.2 (19.75) CHA2DS2-VASc mean (SD) 3.1 (1.38) 2.9 (1.34) 3.8 (1.28) HAS-BLED mean (SD) 2.5 (1.10) 2.4 (1.07) 2.9 (1.08) First occurrence of all-cause mortality (n, %/year) 257 (3.56%) 129 (2.31%) 128 (7.90%) First occurrence of intracranial haemorrhage (n, %/year) 20 (0.28%) 16 (0.29%) 4 (0.25%) First occurrence of major bleeding (n, %/year) 68 (0.95%) 49 (0.88%) 19 (1.18%) First occurrence of stroke/SEE (n, %/year) 63 (0.88%) 45 (0.81%) 18 (1.11%) CG, Cockcroft-Gault; CrCl, creatinine clearance; SD, standard deviation; SEE, systemic embolic events. Conclusions We found low bleeding and stroke rates in 7,672 unselected, mainly elderly AF patients treated with edoxaban in routine clinical practice. These findings were consistent across edoxaban doses and reinforce the effectiveness and safety of NOACs such as edoxaban in routine clinical care in Europe. Acknowledgement/Funding Daiichi Sankyo Europe GmbH, Munich, Germany


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