PBO Pts Research Articles

Bimekizumab in Patients with Moderate to Severe Plaque Psoriasis: Analysis of Mental Health and Associated Disorders

Introduction: Patients (pts) with psoriasis have a greater risk of depression and suicidality than the general population.1 Here, we report Week (Wk)16 and longer-term depression and suicidal ideation and behavior (SIB) data in bimekizumab (BKZ)-treated pts with moderate to severe plaque psoriasis.
 Procedure/study: The Patient Health Questionnaire (PHQ)-9, scored 0–27, measured depression severity monthly to Wk16 (regular intervals during BE BRIGHT open-label extension);2,3 higher scores indicate worse depression. PHQ-9 data were pooled from Wk0–16 of BE VIVID/BE READY (BKZ 320mg every 4 weeks [Q4W] vs. placebo [PBO]);4,5 3-year BE BRIGHT data are also reported.3 An independent Neuropsychiatric Adjudication Committee evaluated potential SIB treatment-emergent adverse events (TEAEs) and elevated PHQ-9 scores. Adjudicated SIB (suicide completion/attempt/ideation) incidence/100 pt-years (yrs; PY) was pooled from nine BKZ phase 2/3/3b trials in psoriasis, including up to 5 yrs’ exposure.3–11
 Results: At Wk16, mean reduction from baseline in PHQ-9 with BKZ Q4W (N=670) vs. PBO (N=169) was 1.3 vs. 0.3; overall mean Wk16 scores were 1.2 and 2.4 for BKZ and PBO. Low mean BKZ PHQ-9 scores were maintained over 3 yrs of BE BRIGHT following the feeder studies (Wk144: 1.2). At Wk16, 92.9% of BKZ pts scored 0–4 in PHQ-9 (no/minimal depression) vs. 81.1% of PBO pts; 1.3% vs. 6.3% scored ≥10 (moderate–severe depression). Through Wk16, 0.7% BKZ vs. 4.1% PBO pts scored ≥15 (moderately severe–severe) in PHQ-9 at any visit. Over 7,166 PY of BKZ exposure (N=2,480), the rate of adjudicated SIB TEAEs was 0.126/100 PY.
 Conclusion: PHQ-9 scores were low through Wk16 and remained low with longer BKZ exposure. The vast majority of BKZ pts had no/minimal depression at Wk16. The long-term incidence rate of adjudicated SIB with BKZ was low and similar to the general psoriasis population (range: 0.09–0.54/100 PY).1,12
 Funding: UCB Pharma.

517O Overall survival (OS) at 7-year (y) follow-up (f/u) in patients (pts) with newly diagnosed advanced ovarian cancer (OC) and a BRCA mutation (BRCAm) who received maintenance olaparib in the SOLO1/GOG-3004 trial

In the Phase III SOLO1/GOG-3004 trial (NCT01844986), maintenance olaparib provided sustained benefit beyond the end of treatment in pts with newly diagnosed advanced OC and a BRCAm. At 5-y f/u, median progression-free survival was 56.0 months [m] with olaparib vs 13.8m with placebo (pbo) (HR 0.33; 95% CI 0.25–0.43); 48% vs 21% of pts, respectively, were progression-free (KM estimates) (Banerjee et al. Lancet Oncol 2021). Given that most OC deaths occur 5‒10y after diagnosis, we report OS in SOLO1 at 7-y f/u, a clinically relevant timepoint. Pts who were in response to first-line platinum-based chemotherapy received maintenance olaparib tablets 300 mg bid or pbo for up to 2y or until progression. A descriptive analysis of OS, a secondary endpoint, was performed 7y after the last pt was randomized; prespecified final analysis of OS is planned at 60% data maturity. 260 pts were randomized to olaparib and 131 to pbo (median treatment duration 24.6 vs 13.9m, respectively). At OS data maturity of 38.1% (data cut-off 7 Mar 2022), median OS was not reached in olaparib pts vs 75.2m in pbo pts, with an OS HR of 0.55 (95% CI 0.40–0.76; unadjusted for crossover; 44.3% of pbo pts received a PARP inhibitor in a subsequent line of therapy) (Table). At 7y, 45.3% of olaparib pts vs 20.6% of pbo pts were alive and had still not received a first subsequent treatment (KM estimates). The incidence of MDS/AML remained low and new primary malignancies remained balanced between arms (Table).Table: 517OOlaparibPboOSN=260N=131Median f/u, m88.987.4Events, n (%)84 (32.3)65 (49.6)Median OS, mNR75.2HR (95% CI)0.55 (0.40–0.76)P value0.0004*7-y OS rate,† %67.046.5AEs of special interest, n (%)N=260N=130‡MDS/AML4 (1.5)1 (0.8)New primary malignancies14 (5.4)8 (6.2)Pneumonitis5 (1.9)0*P<0.0001 required for statistical significance; †KM estimates; ‡1 pt randomized to pbo did not receive treatment. AE, adverse event; AML, acute myeloid leukaemia; CI, confidence interval; HR, hazard ratio; KM, Kaplan–Meier; MDS, myelodysplastic syndrome; NR, not reached. Open table in a new tab *P<0.0001 required for statistical significance; †KM estimates; ‡1 pt randomized to pbo did not receive treatment. AE, adverse event; AML, acute myeloid leukaemia; CI, confidence interval; HR, hazard ratio; KM, Kaplan–Meier; MDS, myelodysplastic syndrome; NR, not reached. 2y of maintenance olaparib provided a clinically meaningful improvement in OS over pbo in pts with newly diagnosed advanced OC and a BRCAm. At 7y, 67.0% of olaparib pts vs 46.5% of pbo pts were alive; no new safety signals were detected. These data provide the longest f/u for any PARP inhibitor in this setting and support use of maintenance olaparib to achieve long-term remission and enhance the potential for cure.

OP30 Upadacitinib modulates inflammatory pathways in gut tissue in patients with Ulcerative Colitis: Transcriptomic profiling from the Phase 2b study, U-ACHIEVE

Abstract Background Upadacitinib (UPA), an oral, reversible, Janus kinase (JAK)-1 selective inhibitor can induce clinical and endoscopic remission after 8 weeks in patients (pts) with moderately to severely active Ulcerative Colitis (UC). To provide mechanistic insights into downstream effects of UPA in the intestinal mucosa, we evaluated pharmacodynamic modulation of gene expression in colon biopsies from pts with UC in the Phase 2b study, U-ACHIEVE (NCT02819635). These analyses aimed to link molecular changes to clinical endpoints. Methods Transcriptomic data were collected from rectosigmoid biopsies at baseline (BL) and Week (Wk) 8 in a subset of pts in sub-study 1 of U-ACHIEVE (N=88: placebo [PBO], n=15; pooled UPA 15, 30 &amp; 45 mg, n=73). Samples underwent bulk RNA sequencing and differentially expressed genes (DEG) (false discovery rate [FDR]&amp;lt;0.05 &amp; |log fold change [FC]|&amp;gt;1) from BL to Wk 8 were identified with linear mixed-effect models. DEG were analysed with KEGG and GO pathway enrichment and clinical endpoint responder analysis. Cellular profiling with gut cell deconvolution based on defined cell types was undertaken.1 Results At Wk 8, expression of 695 gut genes was modulated (FDR&amp;lt;0.05 &amp; |logFC|&amp;gt;1) from BL after UPA treatment compared with no DEG in PBO pts (including responders). Of these genes, ~70% (n=492) were downregulated and enriched in inflammatory pathways including T- and B-cell effector responses, neutrophil-mediated immunity, and leukocyte chemotaxis. Also, irrespective of directionality, most DEG from BL to Wk 8 in UPA-treated pts were associated with clinical response and remission, and histologic and endoscopic improvement. At Wk 8, deconvoluted cell fractions associated with adaptive but also innate inflammatory cells in the gut of UPA responders were decreased compared with non-responders; in contrast, fractions associated with enterocyte, secretory goblet cell and myofibroblast cells were increased in responder gut tissue (Fig 1). Modulation of genes associated with UC disease activity (OSM &amp; S100A8/9 [calprotectin]), Th1 (TBX21, IFNG), Th2 (GATA3, IL5RA, IL13RA2), Th9 (SPI1), Th17 (IL17A, IL23A, IL21R), B-cell responses (BTK, CD40), barrier function (ESPN, VIL1, CLDN23, OCLN, MUC1/2/12/16/20) and wound repair (ANXA1/6/13, MMP7/9) were associated with clinical improvement at Wk 8 (Fig 2). Conclusion JAK inhibition with UPA is associated with transcriptional changes in colonic mucosa that are seen with UC disease pathophysiology. Clinical benefit mediated by UPA is associated with modulation of molecular biomarkers of UC disease activity, T-helper-cell differentiation, B-cell-mediated responses, gut barrier function and wound healing. Reference 1. Menden K, et al. Sci Adv 2020;6:eaba2619

DOP83 Efficacy and Safety of Ustekinumab for Ulcerative Colitis Through 3 Years: UNIFI Long-term Extension

Abstract Background Ustekinumab (UST) is an IL-12/23p40 antagonist used to treat pts with moderate-to-severe ulcerative colitis (UC). The ongoing UNIFI long-term extension (LTE) evaluates subcutaneous (SC) 90mg UST maintenance therapy, with efficacy (wk152) and safety (wk156) results reported here. Methods 523 intravenous UST induction responders were randomized to SC maintenance therapy (175 SC placebo [PBO]; 172 UST 90mg every 12 weeks [q12w]; 176 UST 90mg q8w). 284 UST pts who completed wk44 entered the LTE. PBO pts were discontinued after wk44 unblinding. Starting at wk56, randomized pts with UC worsening could adjust to q8w. Symptomatic remission (Mayo stool frequency subscore of 0 or 1 and a rectal bleeding subscore of 0) was evaluated in randomized pts. Safety was evaluated for all 588 pts treated in the LTE, including the randomized and nonrandomized populations; 188 received PBO and 457 received UST. The nonrandomized population included responders to PBO induction and UST induction nonresponders at wk8 who received SC UST, responded 8 wks later and received UST 90mg q8w. Results Among all pts randomized to UST at maintenance baseline (intent-to-treat population with nonresponder imputation for missing data and treatment failure criteria), 55.2% were in symptomatic remission at wk152 (biologic naïve, 66.1%; biologic failures, 43.5%; Table 1); 96.4% (185/192) of pts in symptomatic remission at wk152 were corticosteroid-free. Overall, 20.1% (39/149 biologic failure, 16/149 biologic naïve) of pts who were randomized to UST and treated in the LTE discontinued treatment between wks44 and 156. Among randomized pts treated with UST in the LTE, 67.6% were in symptomatic remission at wk152; 76.4% of those in clinical remission at wk44 were in symptomatic remission at wk152; and 84.1% of pts with observed data at wk152 were in symptomatic remission. From maintenance wk0-156, combined UST and PBO pts had 1281.6 and 425.0 pt-years of follow-up, respectively; and safety events per 100 pt-years of follow-up for combined UST vs PBO were AEs: 235.81 vs 204.48, SAEs: 7.73 vs 7.53, and serious infections: 2.34 vs 2.35 (Table 2). From wks96-156, there were no reported deaths or major adverse cardiovascular events. One UST-treated pt with fair skin and a prior history of basal cell carcinoma (BCC) reported 2 BCC. One 90 mg q8w UST pt receiving concomitant 6-MP reported SAEs of neutropenic sepsis and oral herpes SAE; the latter events were considered potential opportunistic infections. The dose of 6-MP was reduced, pt recovered and continued UST. Conclusion The efficacy of UST in pts with UC was sustained through 3 years. No new safety signals were observed.

DOP86 Corticosteroid-sparing effects of ustekinumab therapy for Ulcerative Colitis through 3 years: UNIFI long-term extension

Abstract Background Ustekinumab (UST) is an IL12/23 blocker approved for use in Crohn’s disease and ulcerative colitis (UC). In the UNIFI maintenance study of patients (pts) with moderate-severe UC, &amp;gt;90% of the pts who achieved clinical response or remission at week (wk) 44 were able to eliminate corticosteroids, an important goal of therapy. In this analysis, we describe the corticosteroid-sparing effects of UST treatment through 3 years among pts who were treated in the UNIFI long-term extension (LTE). Methods 523 intravenous UST induction responders were randomized to SC maintenance therapy (SC placebo [PBO], n=175; UST 90mg every 12 wks [q12w], n=172; or UST 90mg q8w, n=176). 284 UST pts who completed wk44 entered the LTE. PBO pts were discontinued after wk44 unblinding. Based on the investigator’s clinical judgement of their UC disease activity, pts in the LTE were eligible to receive dose adjustment starting at wk56: PBO to q8w, q12w to q8w, and q8w to q8w (sham adjustment). Pts in PBO or q8w groups were only eligible for dose adjustment or sham dose adjustment before unblinding. Efficacy was evaluated in randomized pts using symptomatic remission (Mayo stool frequency subscore of 0 or 1 and a rectal bleeding subscore of 0). During the maintenance study, all pts receiving corticosteroids at maintenance baseline were required to initiate tapering. Through wk152 of the LTE, symptomatic remission endpoints were calculated with treatment failure and missing data nonresponder imputation, and dose adjustment was not considered to be a treatment failure. Missing corticosteroid dose data was managed using last observation carried forward. Results Of the 284 pts in the randomized population who were treated with UST in the LTE, 139 were receiving corticosteroids at maintenance baseline. Of these, 91.4% (n=127) were no longer receiving corticosteroids at wk152. The average prednisone-equivalent corticosteroid dose among pts receiving corticosteroids at maintenance baseline in the q8w group was 15.4 mg/day at maintenance baseline and 1.7 mg/day at wks44 &amp; 152. In the q12w group, average prednisone-equivalent doses were 15.4, 1.0, and 4.6 mg/day, respectively (Table 1). Corticosteroid-free symptomatic remission rates through wk152 are summarized in Table 2. Results were similar for the q8w and q12w maintenance doses. Of the UST-treated pts who were in symptomatic remission at wk152, 94.6% (88/93) in the q12w group and 98.0% (97/99) in the q8w group were corticosteroid-free. Conclusion UST maintenance therapy, with both q8w and q12w dosing regimens, was effective in reducing and eliminating the use of corticosteroids in pts with UC through 3 years. Through 3 years of treatment with UST, the majority of pts in symptomatic remission were corticosteroid free.

S0779 Effect of Ustekinumab Maintenance Therapy on Stool Frequency and Rectal Bleeding Through 2 Years in the UNIFI Phase 3 Study in Ulcerative Colitis

INTRODUCTION: The UNIFI randomized-withdrawal maintenance study evaluated the safety & efficacy of subcutaneous (SC) ustekinumab (UST) in patients (pts) with moderately to severely active ulcerative colitis (UC) who had responded to intravenous (IV) UST induction. Pts who completed the maintenance study could enter a long-term extension (LTE) through 220 weeks (wks). We evaluated the effect of UST maintenance therapy on stool frequency & rectal bleeding through 92wks in pts who were treated in the LTE. METHODS: All pts who completed Wk44 were eligible to enter & continue in the LTE at the investigator’s discretion. PBO pts were discontinued from the LTE after maintenance study unblinding. During the LTE, pts were eligible to receive dose adjustment (PBO to q8w or q12w to q8w or q8w to q8w [sham dose adjustment]) starting at Wk56 based on investigator assessment of pts’ UC disease activity. Dose adjustment was considered part of the treatment experience & not considered a treatment failure for these analyses. Pts recorded the number of stools & rectal bleeding symptoms for 7 days before each visit. The proportions of pts with Mayo stool frequency subscores of 0 (normal number of stools) or 1 (1 to 2 stools more than normal) or rectal bleeding subscores of 0 (no blood seen) were evaluated. Absolute stool number was also summarized. RESULTS: Pts who were randomized & treated in the LTE were included in these analyses (UST 90 mg q12w: n = 141; UST 90 mg q8w: n = 143). Absolute stool numbers in the UST q12w and q8w groups were 6.6 and 6.5 stools per day, respectively, at induction baseline (BL) & decreased to 2.8 and 2.7, respectively, by maintenance BL. Reductions achieved at maintenance BL were maintained at Wk92 (2.7 & 2.2, respectively). At induction BL, only 12.8% & 18.2% of pts, respectively, had Mayo stool frequency subscores of 0 or 1. By maintenance BL, 80.9% & 80.4%, respectively, had Mayo stool frequency subscores of 0 or 1, & these percentages were maintained through Wk92 (79.4% & 86.7% at Wk92, respectively). At induction BL, 9.2% & 7.0%, respectively, had no blood seen in the stool. By maintenance BL, 87.2% & 84.6%, respectively, had no blood seen in the stool, & these percentages were maintained through Wk92 (86.5% & 88.8%). CONCLUSION: Among pts who were treated in the LTE, reductions in stool frequency & rectal bleeding that had been achieved after IV UST induction were maintained through 2 yrs of UST SC maintenance. These data support the durability of response to UST in UC.Table 1

Updated results from BELLINI, a phase III study of venetoclax or placebo in combination with bortezomib and dexamethasone in relapsed/refractory multiple myeloma.

8509 Background: Venetoclax (Ven) is a selective, potent, oral BCL-2 inhibitor. In the Phase 3 BELLINI trial, addition of Ven to bortezomib (B) + dexamethasone (d) significantly improved response rates and progression-free survival (PFS) vs placebo (Pbo) and showed significant efficacy in patients (pts) with either t(11;14) or BCL2high gene expression. Here we present updated safety and efficacy data from the prespecified second interim overall survival (OS) analysis. Methods: In this multicenter, randomized, double-blind study (NCT02755597), pts with relapsed/refractory multiple myeloma (RRMM) with 1-3 prior lines of therapy were randomized 2:1 to Ven (800 mg) or Pbo in combination with B (1.3 mg/m2) and d (20 mg). The primary endpoint was PFS; key secondary endpoints included overall response and overall survival (OS). Results: 291 pts were randomized; 194 to Ven, 97 to Pbo. Pt characteristics were well balanced among arms. In the Ven arm, median age was 66, 17% had high-risk cytogenetics, 11% had t(11;14), and 34% had BCL2high gene expression. As of 13 Sept 2019, 59 pts were still on study, 45 (23%) Ven vs 14 (14%) Pbo. At a median follow-up of 28.6 months, there were 64 (33%) deaths in the Ven arm vs 24 (25%) in Pbo. At the initial data cutoff (26 Nov 2018), PFS HR was 0.63 (0.44,0.90) and OS HR was 2.03 (1.04,3.95). Table shows updated PFS and OS. Most common treatment-emergent adverse events (TEAEs) with Ven were diarrhea (59%), nausea (37%), and constipation (35%). Most common grade 3/4 AEs (Ven/Pbo) were neutropenia (21%/8%), thrombocytopenia (15%/30%), anemia (16%/15%), diarrhea (15%/12%), and pneumonia (18%/13%). Serious AEs occurred in 54% Ven and 52% Pbo pts. 24% discontinued Ven due to AEs vs 12% Pbo. There were 14 treatment-emergent deaths in the Ven arm and 1 in Pbo. Conclusions: The addition of Ven to Bd significantly improves PFS but resulted in increased mortality vs Pbo in the total population. Greatest PFS improvement with Ven was observed in pts with t(11;14) or BCL2high gene expression, where Ven shows a favorable benefit-risk profile. The study continues for final OS analysis. Clinical trial information: NCT02755597 . [Table: see text]

LBA10 - Phase III PAOLA-1/ENGOT-ov25 trial: Olaparib plus bevacizumab (bev) as maintenance therapy in patients (pts) with newly diagnosed, advanced ovarian cancer (OC) treated with platinum-based chemotherapy (PCh) plus bev

LBA10 - Phase III PAOLA-1/ENGOT-ov25 trial: Olaparib plus bevacizumab (bev) as maintenance therapy in patients (pts) with newly diagnosed, advanced ovarian cancer (OC) treated with platinum-based chemotherapy (PCh) plus bev

LBA10_PR - ClarIDHy: A global, phase III, randomized, double-blind study of ivosidenib (IVO) vs placebo in patients with advanced cholangiocarcinoma (CC) with an isocitrate dehydrogenase 1 (IDH1) mutation

LBA10_PR - ClarIDHy: A global, phase III, randomized, double-blind study of ivosidenib (IVO) vs placebo in patients with advanced cholangiocarcinoma (CC) with an isocitrate dehydrogenase 1 (IDH1) mutation

995PD - Time to second progression (PFS2) and second subsequent therapy (TSST) for patients (pts) with newly diagnosed, advanced ovarian cancer (OC) and a BRCA mutation (BRCAm) treated with maintenance (mt) olaparib (ola): Phase III SOLO1 trial

995PD - Time to second progression (PFS2) and second subsequent therapy (TSST) for patients (pts) with newly diagnosed, advanced ovarian cancer (OC) and a BRCA mutation (BRCAm) treated with maintenance (mt) olaparib (ola): Phase III SOLO1 trial

Efficacy of apalutamide (APA) plus ongoing androgen deprivation therapy (ADT) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC) and baseline (BL) comorbidities (CM).

5023 Background: The addition of APA to ongoing ADT in pts with nmCRPC significantly prolonged metastasis-free survival (MFS), time to symptomatic progression (SymProg), and second progression-free survival (PFS2) in SPARTAN. We assessed the impact of APA on these end points in pts with or without BL CM. Methods: Using Cox proportional hazards models, treatment effect of APA was evaluated in SPARTAN pts with CM at BL, stratifying by the presence of BL diabetes/hyperglycemia (D/H), cardiovascular disease (CVD), hypertension (HTN), and renal insufficiency (RI). Results: Of 1207 SPARTAN pts, 1062 (88%) had ≥ 1 BL CM, including 703/806 (87%) APA pts and 359/401 (90%) PBO pts. A total of 226 (19%), 398 (33%), 798 (66%), and 774 (64%) pts had D/H, CVD, HTN, and RI, respectively; 323 (27%), 412 (34%), 259 (21%), and 68 (6%) pts had 1, 2, 3, and 4 CM, respectively. Incidence of CM was balanced between arms. Pts with CM were older than pts with no CM (median age, 75 vs 69 yrs, APA; 74 vs 69 yrs, PBO). MFS, SymProg, and PFS2 benefit with APA was significant in all CM subgroups, except PFS2 for pts with D/H (Table) and regardless of the number of CM. The incidence of any treatment-emergent AE was balanced between pts with and without CM. AEs with APA were not affected by any CM. Clinical trial information: NCT01946204. Conclusions: The benefit of APA + ongoing ADT in pts with nmCRPC was maintained in pts with D/H, CVD, HTN, and RI. The safety profile of APA was not affected by any CM.[Table: see text]

PD26-10 ONABOTULINUMTOXINA PROVIDES EARLY AND CONSISTENT IMPROVEMENTS IN OVERACTIVE BLADDER SYMPTOMS AND QUALITY OF LIFE OUTCOMES IN PATIENTS WITH OVERACTIVE BLADDER

You have accessJournal of UrologyUrodynamics/Lower Urinary Tract Dysfunction/Female Pelvic Medicine: Non-neurogenic Voiding Dysfunction II1 Apr 2017PD26-10 ONABOTULINUMTOXINA PROVIDES EARLY AND CONSISTENT IMPROVEMENTS IN OVERACTIVE BLADDER SYMPTOMS AND QUALITY OF LIFE OUTCOMES IN PATIENTS WITH OVERACTIVE BLADDER Kurt McCammon, Alfred Kohan, Jed Kaminetsky, Angelo Gousse, Jennifer Gruenenfelder, Amelia Orejudos, Tamer Aboushwareb, and Scott MacDiarmid Kurt McCammonKurt McCammon More articles by this author , Alfred KohanAlfred Kohan More articles by this author , Jed KaminetskyJed Kaminetsky More articles by this author , Angelo GousseAngelo Gousse More articles by this author , Jennifer GruenenfelderJennifer Gruenenfelder More articles by this author , Amelia OrejudosAmelia Orejudos More articles by this author , Tamer AboushwarebTamer Aboushwareb More articles by this author , and Scott MacDiarmidScott MacDiarmid More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.1218AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES OnabotulinumtoxinA (onabotA) 100U was shown to significantly reduce urinary incontinence (UI) and improve quality of life (QOL) at week (wk) 12 after treatment (tx) in overactive bladder (OAB) patients (pts) in 2 large, placebo (pbo)-controlled phase 3 trials. The earliest time for tx response was not assessed in the phase 3 trials. Here we present an interim analysis of an ongoing post-marketing study of onabotA tx response and QOL outcomes as early as wk 1 postinjection in OAB pts with UI. METHODS OAB pts were randomized 1:1 to receive their 1st tx with onabotA 100U (n=129) or pbo (n=125). Pts could receive an additional tx with open-label onabotA 100U after fulfilling prespecified criteria. This interim analysis presents data up to wk 12 after tx 1. Assessments at wks 1, 2, 6 and 12 (primary timepoint) postinjection included the proportions of pts who achieved 100% UI reduction (ie, ″dry″; co-primary endpoint) and ≥75% and ≥50% UI reduction, mean change from baseline in daily episodes of urgency UI, micturition, nocturia, and in the Incontinence-QOL (I-QOL) total score. Adverse events (AEs) were also assessed. RESULTS Baseline mean UI episodes/day were 5.4 (onabotA) and 6.0 (pbo). As early as wk 1 after onabotA, significantly higher proportion of pts achieved 100% UI reduction vs pbo (24.0% vs 4.8%) and continued through wk 2 (25.6% vs 5.6%), wk 6 (32.6% vs 8.0%) and wk 12 (31.8% vs 7.2%) (P<.001 for all timepoints). Similarly, a significantly higher proportion of onabotA-treated vs pbo pts achieved ≥75% and ≥50% UI reduction as early as wk 1 (45.0% vs 20.8%, and 58.9% vs 36.0%, respectively; P<.001 for both) which continued through wk 12. Decreases were noted with onabotA vs pbo in other urinary symptoms as early as wk 1 and continued through wk 12. The early onset of onabotA response was also evidenced by the significantly greater improvements in I-QOL score at wk 1 (14.3 vs 5.6; P<.001) that were ~1.5x the minimally important difference (MID; +10 points). At wks 2-12 after onabotA, improvements in I-QOL score were consistently ~2-3x the MID and significantly greater than pbo (P<.001 for all timepoints). OnabotA was well tolerated; urinary tract infection was the most common AE (21.1% vs 6.4%). CONCLUSIONS This interim analysis showed a significant and consistent tx response with onabotA vs pbo in OAB pts as early as wk 1 postinjection, with significant reductions in UI episodes and improvements in OAB symptoms and QOL outcomes which continued through wk 12. OnabotA was well tolerated. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e510 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Kurt McCammon More articles by this author Alfred Kohan More articles by this author Jed Kaminetsky More articles by this author Angelo Gousse More articles by this author Jennifer Gruenenfelder More articles by this author Amelia Orejudos More articles by this author Tamer Aboushwareb More articles by this author Scott MacDiarmid More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Updated analysis of CALGB/ECOG/BMT CTN 100104: Lenalidomide (Len) vs. placebo (PBO) maintenance therapy after single autologous stem cell transplant (ASCT) for multiple myeloma (MM).

8523 Background: CALGB 100104 studied Len vs. PBO maintenance following ASCT for newly diagnosed MM patients (pts), demonstrating improved time to progression (TTP), overall survival (OS) and increase in second primary malignancies (SPM) for Len at 34 months (mos) median follow-up. This is an updated intent-to-treat analysis of TTP, OS, and SPM at 65 mos median follow-up for OS. Methods: 460 pts age < 70 years with stable disease or better 100 days post ASCT were randomly assigned to Len (n = 231) vs. PBO (n = 229). Starting dose was 10 mg daily and was escalated to 15 mg daily after 3 mos. Primary endpoint was TTP (time of progressive disease (PD) or death from any cause). After several interim analyses, the study was unblinded at 18 mos median follow-up and 86/128 PBO pts without PD chose to cross over to Len. Results: SPMs diagnosed after randomization but before PD included 14 hematologic and 11 solid tumor SPMs in the Len arm vs. 3 hematologic and 7 solid tumor SPMs in the PBO arm (Table 1). Estimate...

3-year safety follow-up of radium-223 dichloride (Ra-223) in patients (Pts) with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases (Mets) from ALSYMPCA.

195 Background: In ALSYMPCA, the first-in-class α-emitter Ra-223 had a highly favorable safety profile and was well tolerated. Safety monitoring of Ra-223 is essential for a complete safety profile. Here are final safety data including long-term follow-up safety 3 years after last pt’s first injection (inj). Methods: Pts received 6 inj and entered designated follow-up from 4 wks after their last inj to 3 years after first inj. Pts were to be evaluated during tx period and 9 follow-up visits. All adverse events (AEs) were collected until 12 wks after last inj; thereafter, only AEs deemed tx-related were collected. Additional long-term safety data were assessed by specific diseases including acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), aplastic anemia, and new primary cancer in bone or other organs. Results: Safety population (pts receiving ≥ 1 inj) included 901 pts (Ra-223, n = 600; placebo [pbo], n = 301); 572 pts (Ra-223, n = 405; pbo, n = 167) entered follow-up. 60 pts (Ra-223, n = 49; pbo, n = 11) completed all follow-up visits. Overall, 564 (94%) Ra-223 and 292 (97%) pbo pts had ≥ 1 tx-emergent AE (Table). During long-term follow-up, there were no reports of AML, MDS, or new primary bone cancer. New primary cancers in other organs were reported: 2 Ra-223 (1 bladder, 1 lymph node mets), 3 pbo (2 skin, 1 adenocarcinoma rectum and sigmoideum), and 2 pbo cross-over pts (1 skin, 1 meningioma). Aplastic anemia was reported in 1 Ra-223 pt. Conclusions: Ra-223 remained safe and well tolerated 3 years after the last pt’s first inj. No major safety issues were identified during the ALSYMPCA 3-year long-term follow-up. Clinical trial information: NCT00699751. [Table: see text]

Effect of radium-223 dichloride (Ra-223) on risk for and duration of hospitalization in ALSYMPCA by docetaxel (D) subgroup.

254 Background: In ALSYMPCA, the first-in-class alpha-emitting radiopharmaceutical Ra-223 significantly improved overall survival vs placebo (pbo) and was well tolerated in patients (pts) with castration-resistant prostate cancer (CRPC) with symptomatic bone metastases and no visceral metastases regardless of prior D use. To understand whether treatment (tx) benefit in prior and no prior D subgroups relates to differences in health care resource utilization, hospitalization and other resource use were evaluated. Methods: Hospitalization, nursing home visit, home health care and adult day care services use, and physician visit data were captured. To account for differences in observation time due to differing survival, resource use was annualized for each pt. Mean number and duration of encounters/year were compared using t-tests. To compare tx groups based on rate of use/year, incidence rates and ratios were calculated using a generalized estimating equation regression model with covariates. Results: For prior D pts, hospitalization incidence rates for Ra-223 vs pbo were 1.18 vs 1.70 (incidence rate ratio = 0.69; 95% CI, 0.53-0.90; P = 0.006) and mean hospitalization days/year were 8.53 vs 16.51 (P = 0.001). Among prior D pts with ≥1 hospitalization, mean hospitalization days/year for Ra-223 vs pbo were 19.65 vs 33.02 (P = 0.003). For no prior D pts, hospitalization incidence rates for Ra-223 vs pbo were 1.02 vs 1.10 (incidence rate ratio = 0.92; 95% CI, 0.66-1.29; P = 0.643) and mean hospitalization days/year were 7.53 vs 12.11 (P = 0.027). Among no prior D pts with ≥1 hospitalization, mean hospitalization days/year for Ra-223 vs pbo pts were 19.12 vs 26.61 (P = 0.063). The only other tx differences were nursing home days/year and day care services/year in the no prior D subgroup, but t-test and regression results were inconsistent. Conclusions: In the prior D subgroup, Ra-223 pts experienced 8.0 fewer hospitalization days/pt/year, driven by a 31% reduction in hospitalization and shorter duration among pts hospitalized. In the no prior D subgroup, Ra-223 pts experienced 4.6 fewer hospitalization days/pt/year, primarily driven by a shorter duration among pts hospitalized. Clinical trial information: NCT00699751.

Effects of radium-223 dichloride (Ra-223) on risk for hospitalization and health care resource use in the phase 3 ALSYMPCA trial.

21 Background: Ra-223 is a first-in-class alpha-emitter approved for treatment (tx) of patients (pts) with castration-resistant prostate cancer and symptomatic bone metastases. In ALSYMPCA, Ra-223 significantly improved overall survival by 3.6 months vs placebo (pbo) (HR = 0.70; 95% CI, 0.58-0.83; P &lt; 0.001) and was well tolerated. To understand whether the tx benefit corresponds to differences in utilization, hospitalization and other types of health care resource use were evaluated. Methods: Data on hospitalization, nursing home visits, home health care and adult day care services use, and physician visits were captured for each pt. Tx groups were compared, based on percentage needing each type of health care resource, using Fisher’s exact test. To account for differences in each pt resource use in ALSYMPCA, the number of encounters (eg, office visits) and duration of encounters (eg, days hospitalized) were divided by observation time. The mean number and duration of encounters were compared using analysis of variance. To compare tx groups based on the rate of use per year, incidence rates and ratios were calculated using a generalized estimating equation (GEE) regression model. Results: The mean follow-up time in months for Ra-223 vs pbo was 10.0 vs 8.6. The incidence rate for Ra-223 vs pbo was 1.1 vs 1.4 (incidence rate ratio = 0.77; 95% CI, 0.62-0.95; P = 0.013). The mean number of hospitalizations and hospitalization days per year for Ra-223 vs pbo were 1.3 vs 1.7 (P = 0.020) and 8.1 vs 14.6 (P &lt; 0.001), respectively. The percentage of pts that required hospitalization was nominally lower for Ra-223 vs pbo (42.3% vs 49.0%, P = 0.062). Among pts who experienced at least one hospitalization, the mean number of hospitalization days per year for Ra-223 vs pbo pts was 19.4 vs 30.4 (P &lt; 0.001). No significant differences were found between tx groups in terms of visits or durations of time in nursing homes per year, amount of adult day care and home health care services utilized per year, and number of physician visits per year. Conclusions: Compared with pbo, Ra-223 tx resulted in a 23% reduction in incidence of hospitalizations per year and about 6.5 fewer hospitalization days per pt per year. Clinical trial information: NCT00699751.

769P - 1.5-Year Posttreatment Follow-Up of Radium-223 Dichloride (Ra-223) Safety in Patients (Pts) with Castration-Resistant Prostate Cancer (Crpc) and Symptomatic Bone Metastases from Alsympca: Characterization of Hematologic Safety Profiles

ABSTRACT Aim: In ALSYMPCA, the first-in-class alpha-emitter Ra-223 had a highly favorable safety profile and was well tolerated (Parker et al. NEJM 2013). Safety monitoring of Ra-223 is essential for a complete safety profile. Reported here are safety results of a post hoc analysis from an interim review of ∼1.5 years after the last pt's last injection. Methods: Pts were to enter designated follow-up starting 4 weeks after their last injection until 3 years after first injection. Pts were to be evaluated at 9 follow-up visits. Only adverse events (AEs) considered treatment (tx) related were reported. Long-term safety was assessed by specific diseases (acute myelogenous leukemia [AML], myelodysplastic syndrome [MDS], aplastic anemia [AA], new primary bone cancer, and new primary cancer in other organs). Results: Of 921 pts (Ra-223, n = 614; placebo [pbo], n = 307), 574 entered follow-up (Ra-223, n = 406; pbo, n = 168). Median follow-up time was 10.4 months with Ra-223 and 7.6 months with pbo. In the safety population, 25/404 (6%) Ra-223 pts and 8/167 (5%) pbo pts had 37 tx-related AEs. Overall, myelosuppression incidence was ≤ 3%. Leukopenia, neutropenia, or thrombocytopenia occurred in 7 Ra-223 pts (Table). As shown, 6 had prior docetaxel and 4 had extent of disease (EOD) grade 3; 2 completed long-term follow-up, 4 did not due to death or disease progression. Grade 3/4 anemia occurred in 5 Ra-223 pts and 1 pbo pt; their data will be presented. To date, no pts had AML, MDS, or primary bone cancer; 1 Ra-223 pt had AA; 5 pts had primary cancer in other organs (Ra-223, n = 2; pbo, n = 3). Pt Data and Characteristics for the 7 Ra-223 Pts With Either Leukopenia, Neutropenia, or Thrombocytopenia Parameter Pt 1 Pt 2 Pt 3 Pt 4 Pt 5 Pt 6 Pt 7 Hematologic AE Thrombo- cytopenia (grade 1) Leukopenia/ Neutropenia (grade 3) Leukopenia (grade 4) Thrombo- cytopenia (grade 2) Thrombo- cytopenia (grade 2) Neutropenia (grade 3) Thrombo- cytopenia (grade 1) Age 65 68 74 61 64 79 72 Baseline ECOG score: 0 = fully active; 1 = physical strenuous activity restricted 1 1 1 0 1 0 1 WHO ladder for cancer pain:1 = mild, no opioids; 2 = moderate, occasional opioids; 3 = severe, regular daily opioids 3 1 1 1 3 3 2 EOD (grades): 1 = 20 mets 3 3 3 2 1 1 3 Prior docetaxel yes yes yes yes yes no yes Concomitant cancer tx Luteinizing hormone– releasing hormone analogue (LHRHa) Zoledronic acid LHRHa Zoledronic acid LHRHa Prednisolone LHRHa LHRHa Dexamethasone Diethylstilbestrol Zoledronic acid LHRHa Zoledronic acid LHRHa Prednisone No. of Ra-223 inj received 6 6 5 6 6 5 6 Status of follow-up Completed Withdrew (pt request) Withdrew (death) Completed Withdrew (death) Withdrew (death) Withdrew (disease progression) Conclusions: Long-term follow-up of ∼1.5 years after last pt's last injection showed no major hematologic safety issues. Hematologic toxicity appeared to be associated with prior docetaxel and EOD grade 3, and did not affect number of Ra-223 injections received. Disclosure: C. Parker: has had a consultant or advisory relationship with Algeta, Bayer, and BNIT, and has received honoraria from Amgen, Astellas, Bayer, Janssen, Sanofi-Aventis, and Takeda; N. Vogelzang: has had a consultant or advisory relationship with Bayer, Algeta, Janssen, and Medivation, and has received honoraria from Bayer.v; . Sartor: has had a consultant or advisory relationship with and has received research funding from Algeta and Bayer; R.E. Coleman: has served as a consultant for Bayer, has received honoraria from Bayer and Amgen, and has provided expert testimony for Novartis; I. Skjorestad: is employed by and has an ownership interest in Algeta ASA (Bayer); A. Aksnes: is employed by Algeta ASA (Bayer); M. Wahba: is employed by Bayer HealthCare; S. Nilsson: has had a consultant or advisory relationship with Algeta and has received remuneration from Bayer for travel costs and accommodations for study and writing meetings. All other authors have declared no conflicts of interest.

770P - Reasons for Patients (Pts) Discontinuing Study Treatment (Tx) in the Phase 3 Alsympca Trial of Radium-223 Dichloride (Ra-223) in Castration-Resistant Prostate Cancer (Crpc) with Bone Metastases (Mets)

ABSTRACT Aim: Adherence to prescribed tx is an important factor in determining outcome in advanced CRPC pts, and is often driven by drug tolerability. In ALSYMPCA, the first-in-class a-emitter Ra-223 had a highly favorable safety profile and was well tolerated (Parker et al. NEJM 2013). Here we report results from a post hoc analysis identifying factors associated with ALSYMPCA study tx discontinuation to inform pt management and allow the full course of Ra-223 therapy. Methods: ALSYMPCA pts had progressive, symptomatic CRPC with ≥ 2 bone mets, had no known visceral mets, and had received docetaxel or were unfit for or declined docetaxel. Pts were randomized 2:1 to 6 injections (inj) of Ra-223 (50 kBq/kg IV) q 4 wk or matching placebo (pbo). Pts who did not receive all 6 study inj were considered to have discontinued tx and withdrawn early from the study. A post hoc analysis of these pts was performed. Results: Of the 921 pts enrolled, 901 were treated (Ra-223, n = 600; pbo, n = 301); 209 (35%) Ra-223 and 157 (52%) pbo pts discontinued tx after inj 1-5. Prior vs no prior docetaxel was associated with a greater percentage of pts discontinuing tx in both groups. Adverse events (AEs) were the primary reason for discontinuing tx across all categories (Table on following page). The most common AE was disease progression (Ra-223, 17%; pbo, 16%). Anemia was a more common reason for discontinuing Ra-223 (15% vs 3%), as was general physical health deterioration (9% vs 2%); bone pain was more common with pbo (11% vs 2%), as was fatigue (8% vs 4%). Pts (n) Discontinuing Treatment After Injections 1-5 Pt Group Total Discontinued Reason for Discontinuing Treatment Total, n (%) RA N = 600 Total, n (%) Pbo N = 301 Ra Inj 1 Pbo Inj 1 Ra Inj 2 Pbo Inj 2 Ra Inj 3 Pbo Inj 3 Ra Inj 4 Pbo Inj 4 Ra Inj 5 Pbo Inj 5 All pts 209 (35) 157 (52) 18 21 37 36 48 37 60 34 46 29 AE 92 (44) 59 (38) 7 11 14 12 23 10 27 16 21 10 Death 27 (13) 28 (18) 6 4 5 3 7 8 4 5 4 8 Inv Request 25 (12) 27 (17) 1 0 7 6 3 9 9 7 5 5 Pt Request 40 (19) 22 (14) 4 4 7 6 9 4 8 3 12 5 Other 26 (12) 21 (13) 0 2 4 9 6 6 12 3 4 1 Prior Doce 132 (22) 92 (30) 11 12 17 21 31 20 40 20 33 19 AE 60 (45) 37 (40) 3 8 6 6 13 5 22 11 16 7 Death 12 (9) 12 (13) 5 2 1 2 4 4 1 1 1 3 Inv Request 17 (13) 18 (20) 1 0 5 5 2 4 5 5 4 4 Pt Request 29 (22) 15 (16) 2 1 3 3 7 3 7 3 10 5 Other 14 (11) 10 (12) 0 1 2 5 5 4 5 0 2 0 No Prior Doce 77 (13) 65 (21) 7 9 20 15 17 17 20 14 13 10 AE 32 (42) 22 (35) 4 3 8 6 10 5 5 5 5 3 Death 15 (19) 16 (25) 1 2 4 1 3 4 3 4 3 5 Inv Request 8 (10) 9 (14) 0 0 2 1 1 5 4 2 1 1 Pt Request 11 (14) 7 (11) 2 3 4 3 2 1 1 0 2 0 Other 12 (16) 11 (17) 0 1 2 4 1 2 7 3 2 1 Conclusions: The percentage of pts discontinuing tx before the full course of therapy was smaller with Ra-223 than with pbo, which indicates a positive tx effect and safety profile. Supportive measures to improve the pts' general health and tx of anemia could help achieve the full course of Ra-223 therapy. Disclosure: O. Sartor: has had a consultant or advisory relationship with and has received research funding from Algeta and Bayer; S. Nilsson: has had a consultant or advisory relationship with Algeta and has received remuneration from Bayer for travel costs and accommodations for study and writing meetings; R.E. Coleman: has had a consultant or advisory relationship with Bayer, has received honoraria from Bayer and Amgen, and has provided expert testimony for Novartis; N. James: has had a consultant or advisory relationship with Algeta and Bayer; A. Aksnes: is employed by Algeta ASA (Bayer); M. Wahba: is employed by Bayer HealthCare; C. Parker: has had a consultant or advisory relationship with Algeta, Bayer, and BNIT, and has received honoraria from Amgen, Astellas, Bayer, Janssen, Sanofi-Aventis, and Takeda. All other authors have declared no conflicts of interest.

Effect of Ramipril On Urinary Protein Excretion in Maintenance Renal Transplant Patients Converted to Sirolimus.

Purpose: Evaluate the effect of ramipril on urinary protein excretion in maintenance renal transplant pts converted to sirolimus (SRL). Methods: This placebo (pbo)-controlled, double-blind, multicenter study randomized pts to ramipril or pbo for up to 6 wks preconversion from calcineurin inhibitors to SRL. Pts then received assigned treatment plus SRL for 52 wks. Pts who developed proteinuria (urinary protein:creatinine ratio [U p/c] ≥0.5) were treated with increased doses of assigned treatment; losartan was initiated if proteinuria persisted. Primary endpoint was time to losartan initiation after SRL conversion, presented by Kaplan-Meier curves and analyzed using the log-rank test. Secondary endpoints included change in estimated glomerular filtration rate (eGFR) from baseline to 12, 24, and 52 wks and % of pts with U p/c <0.5 at 24 and 52 wks. Results: 295 pts (mean age 47y; 67% male; 64% white) were randomized and received ≥1 dose of study drug; 264 met criteria for SRL conversion (mITT population; ramipril 138; pbo 126). Cumulative rate of losartan initiation for 52 wks was significantly lower with ramipril vs pbo (6.2% vs 23.2%; HR=0.228; 95% CI: 0.099-0.528; P=.0002). Percentage of pts with U p/c <0.5 was significantly higher with ramipril vs pbo at 24 wks (92% vs 78%; P=.002) and remained numerically higher at 52 wks (83% vs 73%, P=.07). No significant differences in ramipril vs pbo pts in eGFR were observed from baseline to 12, 24, or 52 wks. The 5 most common treatment-emergent AEs included diarrhea, peripheral edema, upper respiratory infection, acne and cough. Biopsy-confirmed acute rejection occurred in 13 ramipril pts and 5 pbo pts (P=.07). No pts experienced graft loss. One pt (pbo group) died due to cerebrovascular accident. One pt in each group experienced angioedema; neither case was considered serious by investigators. Conclusions: This study demonstrated the efficacy of ramipril in preventing proteinuria after SRL conversion. The AEs observed were consistent with the known safety profile of SRL and were not potentiated with the coadministration of ramipril. DISCLOSURE:Mandelbrot, D.: Grant/Research Support, NIH, Employee, Beth Israel Deaconess Medical Center, Other, Harvard Medical School, Honorarium. Alberu, J.: Speaker’s Bureau, Pfizer. Tedesco-Silva, H.: Grant/Research Support, Astellas, Bristol Myers Squibb, Novartis, Pfizer, Roche, and Veloxsis, Other, Novartis, Consultant, Pfizer, Consultant. Flynn, A.: Employee, Pfizer. Healy, C.: Employee, Pfizer. Li, H.: Employee, Pfizer. Tortorici, M.: Employee, Pfizer. Schulman, S.: Employee, Pfizer.

SAT0375 The Distribution of Inflammatory Lesions in the Anterior and Posterior Structures of the Spine in Patients with Active Ankylosing Spondylitis and the Effect of Tnf-Alpha -Blockade

BackgroundMagnetic resonance imaging (MRI) is a key tool for the assessment of inflammatory lesions used for diagnosis and the monitoring of treatment effects in patients (pts) with ankylosing spondylitis (AS).ObjectivesUsing...