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.

Overall survival (OS) results of phase III ARAMIS study of darolutamide (DARO) added to androgen deprivation therapy (ADT) for nonmetastatic castration-resistant prostate cancer (nmCRPC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5514-5514 ◽  
Author(s):  
Karim Fizazi ◽  
Neal D. Shore ◽  
Teuvo Tammela ◽  
Albertas Ulys ◽  
Egils Vjaters ◽  
...  
Keyword(s):  
Safety Profile ◽  
Final Analysis ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Primary Analysis ◽  
Risk Of Death ◽  
Castration Resistant ◽  
Secondary Endpoints ◽  
Favorable Safety

5514 Background: DARO is a structurally distinct androgen receptor inhibitor with a favorable safety profile, approved for treating men with nmCRPC after demonstrating significantly prolonged metastasis-free survival, compared with placebo (PBO), in the phase III ARAMIS trial: median 40.4 vs 18.4 months, respectively (HR 0.41; 95% CI 0.34–0.50; P<0.0001). We report final analyses of OS and prospectively collected, patient-relevant secondary endpoints, and updated safety results. Methods: 1509 patients (pts) with nmCRPC were randomized 2:1 to DARO 600 mg twice daily (n=955) or PBO (n=554) while continuing ADT. Secondary endpoints included OS, and times to pain progression, first cytotoxic chemotherapy, and first symptomatic skeletal event. The OS analysis was planned to occur after approximately 240 deaths. Secondary endpoints were evaluated in a hierarchical order. Results: Final analysis was conducted after 254 deaths were observed (15.5% of DARO and 19.1% of PBO patients). After unblinding at the primary analysis, 170 pts crossed over from PBO to DARO. DARO showed a statistically significant OS benefit corresponding to a 31% reduction in the risk of death compared with placebo. All other secondary endpoints were significantly prolonged by DARO (Table), regardless of the effect of crossover and subsequent therapies on survival benefit. Incidences of treatment-emergent adverse events (AEs) with ≥5% frequency were generally comparable between DARO and PBO, similar to the safety profile observed at the primary analysis. Incidences of AEs of interest (including falls, CNS effects, and hypertension) were not increased with DARO compared with PBO when adjusted for treatment exposure. AEs in the crossover group were consistent with those for the DARO treatment arm. Conclusions: DARO showed a statistically significant OS benefit for men with nmCRPC. In addition, DARO delayed onset of cancer-related symptoms and subsequent chemotherapy, compared with PBO. With extended follow-up, safety and tolerability were favorable and consistent with the primary ARAMIS analysis (Fizazi et al, N Engl J Med 2019;380:1235-46). Clinical trial information: NCT02200614 .[Table: see text]

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]

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.

IMpower110: Clinical safety in a phase III study of atezolizumab (atezo) monotherapy (mono) vs platinum-based chemotherapy (chemo) in first-line non-small cell lung cancer (NSCLC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21623-e21623 ◽  
Author(s):  
Jacek Jassem ◽  
Roy S. Herbst ◽  
Filippo de Marinis ◽  
Jacques Cadranel ◽  
Tibor Csőszi ◽  
...  
Keyword(s):  
Safety Profile ◽  
Safety Data ◽  
Stage Iv ◽  
Phase Iii ◽  
Low Grade ◽  
Clinical Safety ◽  
Meaningful Improvement ◽  
Platinum Based Chemotherapy ◽  
Ecog Ps ◽  
Favorable Safety

e21623 Background: IMpower110 evaluated atezo mono in PD-L1–selected, chemo-naive patients (pts) with nonsquamous (nsq) or squamous (sq) NSCLC. At the interim analysis, IMpower110 met its primary OS endpoint, with a statistically significant and clinically meaningful improvement for atezo vs chemo in TC3 or IC3 wild-type ( EGFR/ALK-negative) pts. We report on the safety profile of atezo vs chemo in IMpower110. Methods: 572 pts with stage IV nsq or sq NSCLC, PD-L1 expression ≥ 1% on TC or IC and ECOG PS 0-1 were randomized 1:1 to receive atezo (1200 mg IV q3w) or chemo (4 or 6 21-day cycles). In the chemo arm, nsq pts received cisplatin (cis) 75 mg/m2 or carboplatin (carbo) AUC 6 + pemetrexed (pem) 500 mg/m2 IV q3w; sq pts received cis 75 mg/m2 + gemcitabine (gem) 1250 mg/m2 or carbo AUC 5 + gem 1000 mg/m2 IV q3w. Safety was assessed in all treated pts (safety evaluable [SE] population [pop]), regardless of PD-L1 expression or EGFR/ALK status. AEs were summarized per MedDRA v22.0 and severity graded per NCI CTCAE v4.0. Immune-mediated AEs (imAEs) were defined per a sponsor-specified list of terms, regardless of whether the events led to systemic glucocorticoid, endocrine therapy, or other immunosuppressants use. Results: At data cutoff (Sep 10, 2018) within the ITT pop, treatment (tx) was ongoing in 90 (atezo: 31.6%) and 25 (chemo: 8.7%) pts, with 13.7 mo of follow-up. Within the SE pop (atezo: n = 286, chemo: n = 263), atezo pts had longer tx exposure (5.3 mo) vs chemo pts (pem, 3.5 mo; gem, 2.6 mo; carbo, 2.3 mo; cis, 2.1 mo). Atezo had a favorable safety profile vs chemo (table); safety data were consistent with data from a pooled atezo mono pop. imAEs occurred in 40.2% (atezo) and 16.7% (chemo) of pts and were Grade (Gr) 3-4 in 6.6% and 1.5%, respectively. Conclusions: Atezo was better tolerated than chemo and imAEs were generally low grade. Overall, the safety experience with atezo mono in IMpower110 was consistent with its known safety profile; no new safety signals were identified. Clinical trial information: NCT02409342. [Table: see text]

scholarly journals MOD-4023, a long-acting carboxy-terminal peptide-modified human growth hormone: results of a Phase 2 study in growth hormone-deficient adults

2017 ◽  
Vol 176 (3) ◽  
pp. 283-294 ◽  
Author(s):  
Christian J Strasburger ◽  
Peter Vanuga ◽  
Juraj Payer ◽  
Marija Pfeifer ◽  
Vera Popovic ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Safety Profile ◽  
Safety Data ◽  
Human Growth ◽  
Phase 2 ◽  
Pivotal Phase ◽  
Favorable Safety Profile ◽  
Phase 2 Study ◽  
Dosing Regimens ◽  
Favorable Safety

Objective Growth hormone (GH) replacement therapy currently requires daily injections, which may cause distress and low compliance. C-terminal peptide (CTP)-modified growth hormone (MOD-4023) is being developed as a once-weekly dosing regimen in patients with GH deficiency (GHD). This study’s objective is to evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of MOD-4023 administered once-weekly in GHD adults. Design 54 adults with GHD currently treated with daily GH were normalized and randomized into 4 weekly dosing cohorts of MOD-4023 at 18.5%, 37%, 55.5% or 123.4% of individual cumulative weekly molar hGH dose. The study included 2 stages: Stage A assessed the effectiveness and PK/PD profiles of the 4 dosing regimens of MOD-4023. Stage B was an extension period of once-weekly MOD-4023 administration (61.7% molar hGH content) to collect further safety data and confirm the results from Stage A. Results Dose-dependent response was observed for both PK and PD data of weekly MOD-4023 treatment. Insulin-like growth factor I (IGF-I) SDS levels were maintained within normal range. The 18.5% cohort was discontinued due to low efficacy. MOD-4023 was well tolerated and exhibited favorable safety profile in all dose cohorts. The reported adverse events were consistent with known GH-related side effects. Conclusions Once-weekly MOD-4023 administration in GHD adults was found to be clinically effective while maintaining a favorable safety profile and may obviate the need for daily injections. Weekly GH injections may improve compliance and overall outcome. The promising results achieved in this Phase 2 study led to a pivotal Phase 3 trial, which is currently ongoing.

scholarly journals Favorable Safety Profile of Tirbanibulin Ointment 1% for Actinic Keratosis: Pooled Results from Two Phase III Studies

2020 ◽  
Vol 4 (6) ◽  
pp. s120
Author(s):  
Todd Schlesinger ◽  
Neal Bhatia ◽  
Brian Berman ◽  
Ayman Grada ◽  
Albert Torra ◽  
...  
Keyword(s):  
Actinic Keratosis ◽  
Safety Profile ◽  
Phase Iii ◽  
Two Phase ◽  
Favorable Safety Profile ◽  
Favorable Safety ◽  
Phase Iii Studies

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