Health-related quality of life (HRQoL) in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with olaparib in combination with abiraterone.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 234-234 ◽  
Author(s):  
Noel W. Clarke ◽  
Antoine Thiery-Vuillemin ◽  
Pawel J. Wiechno ◽  
Boris Alekseev ◽  
Nuria Sala ◽  
...  
Keyword(s):  
Repeated Measures ◽  
Mixed Model ◽  
Short Form ◽  
Progression Free Survival ◽  
Brief Pain Inventory ◽  
Phase Iii ◽  
Rank Test ◽  
Castration Resistant Prostate Cancer ◽  
Double Blind ◽  
The Impact

234 Background: A Phase II trial showed that addition of olaparib (O) to abiraterone (A) led to significant radiographic progression-free survival benefit for patients (pts) with mCRPC vs placebo (P) + A (hazard ratio [HR] 0.65, 95% confidence interval [CI] 0.44–0.97). We report predefined exploratory HRQoL analyses. Methods: This randomized, double-blind trial enrolled pts with mCRPC, post-docetaxel. Pts were randomized (71 per arm) to receive either O (300 mg bd, tablets) + A (1000 mg od) or P + A; all received prednisone (5 mg bd). Pts completed Functional Assessment of Cancer Therapy-Prostate (FACT-P total score [TS]; range 0–156, higher score = better HRQoL), Brief Pain Inventory–Short Form (BPI-SF) and worst bone pain (wbp) questionnaires (both range 0–10, higher score = more severe pain). Adjusted mean change from baseline was analysed using a mixed model for repeated measures, improvement by logistic regression and deterioration by log-rank test. Results: Overall compliance rates (O + A vs P + A) were 97% vs 96%, 92% vs 85%, and 96% vs 92% for FACT-P, BPI-SF and wbp, respectively. Best FACT-P TS response of ‘improved’ (increase ≥6 points from baseline at two consecutive visits) was reported by 22/67 (33%) evaluable pts in the O + A vs 18/64 (28%) pts in the P + A arm; the odds ratio (1.32; 95% CI 0.64–2.78) favored the O + A arm. Best FACT-P TS response of ‘worsened’ (decrease ≥6 points from baseline) was reported by 15 (22%) vs 22 (34%) pts. Adjusted mean change from baseline in FACT-P TS across all visits was -0.60 vs -2.09 in the O + A and P + A arms, respectively (difference 1.48; 95% CI -3.96–6.92). Time to deterioration (TTD) results are shown in the table. Clinical trial information: NCT01972217. Conclusions: Whilst not statistically significant, in this study a higher percentage of pts treated with O + A vs P + A had improved HRQoL, with fewer pts negatively affected. Ongoing phase III studies will help elucidate the impact of O on HRQoL in pts with mCRPC. (NCT01972217)[Table: see text]

Impact of olaparib vs physician’s choice of new hormonal agent (pcNHA) on burden of pain in metastatic castration-resistant prostate cancer (mCRPC): PROfound.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5538-5538
Author(s):  
Fred Saad ◽  
Guilhem Roubaud ◽  
Giuseppe Procopio ◽  
Neal D. Shore ◽  
Karim Fizazi ◽  
...  
Keyword(s):  
Repeated Measures ◽  
Mixed Model ◽  
Short Form ◽  
Progression Free Survival ◽  
Pain Severity ◽  
Pain Interference ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Opiate Use ◽  
Gene Alterations

5538 Background: In the Phase III PROfound study (NCT02987543) olaparib significantly improved radiographic progression-free survival (primary endpoint) vs pcNHA (enzalutamide or abiraterone) in patients (pts) with mCRPC and homologous recombination repair (HRR) gene alterations. In pts with alterations in BRCA1, BRCA2 and/or ATM (cohort A), time to pain progression was also significantly improved by olaparib vs pcNHA. We report additional pain analyses evaluated in the overall study population (cohort A and B). Methods: Pts were randomized to olaparib tablets (300 mg bid; n=256) or pcNHA (n=131). Pts completed the Brief Pain Inventory-Short Form (BPI–SF) questionnaire (electronic administration) every 4 weeks up to 6 months after progression or treatment crossover. Responses were analysed to determine time to progression to worst pain, pain severity and first opiate use for cancer-related pain (Kaplan-Meier), and also pain interference in daily activity (mixed model for repeated measures). Results: 85% and 76% of olaparib pts were free of pain progression (worst pain item) compared with 75% and 51% in the pcNHA arm, respectively at 6 and 12 months. The proportion of pts without pain progression (overall pain severity) also favoured olaparib (Table). Median time to first opiate use was significantly prolonged in olaparib arm compared with pcNHA arm; 18 months for olaparib vs 9 months for pcNHA (Table). BPI-SF pain interference scores were also more favourable for olaparib than pcNHA; difference in overall adjusted mean change from baseline score −0.75 (95% CI: −1.14, −0.36) P=0.0002. Further pain burden results for cohort A will also be presented. Conclusions: Olaparib reduced the burden of pain and time to first opiate use in pts with mCRPC and HRR gene alterations vs pcNHA, demonstrating a clinical and symptomatic patient benefit. Clinical trial information: NCT02987543 . [Table: see text]

Health-related quality of life (HRQoL) and pain progression with enzalutamide (ENZ) in metastatic hormone-sensitive prostate cancer (mHSPC) from the ARCHES study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5044-5044
Author(s):  
Arnulf Stenzl ◽  
Curtis Dunshee ◽  
Ugo De Giorgi ◽  
Boris Alekseev ◽  
Taro Iguchi ◽  
...  
Keyword(s):  
Repeated Measures ◽  
Mixed Model ◽  
Proportional Hazards ◽  
Short Form ◽  
Progression Free Survival ◽  
Brief Pain Inventory ◽  
Cox Proportional Hazards ◽  
Pain Severity ◽  
Significant Difference ◽  
Patient Reported

5044 Background: The Phase 3 ARCHES trial (NCT02677896) evaluated the efficacy and safety of ENZ + androgen deprivation therapy (ADT) vs placebo (PBO) + ADT in 1150 men with mHSPC. Here we report patient-reported outcome (PRO) data using Functional Assessment of Cancer Therapy-Prostate (FACT-P) and Brief Pain Inventory Short Form (BPI-SF). Methods: FACT-P and BPI-SF were assessed at baseline (BL), week (wk) 13, and then every 12 wks until disease progression. Longitudinal changes were assessed using mean scores and mixed-model repeated measures; lower BPI-SF scores represent less pain/interference; higher FACT-P scores represent better HRQoL. Time from BL to first deterioration in PRO score was assessed by Kaplan-Meier estimates and Cox proportional hazards models. Clinically meaningful difference was defined by change from baseline ≥10 for FACT-P total and ≥2 for worst pain/severity. Results: PRO instrument completion rates were high (88−96%) up to wk 73. At BL, men in both arms were generally asymptomatic and reported good HRQoL (FACT-P total: ENZ + ADT, 113.9; PBO + ADT, 112.7) and low pain (worst pain [item 3]: ENZ + ADT, 1.80; PBO + ADT, 1.77). HRQoL and pain scores remained stable over time and there were no clinically meaningful differences between groups in change from BL to wk 73. The proportion of men with no change or improvement in PRO scores (67–88%) was similar in both groups at all time points up to wk 73. There was no significant difference between arms for time to deterioration in FACT-P total (HR 0.90 [95% CI] (0.74, 1.09); p = 0.2998). ENZ + ADT significantly delayed time to pain progression for worst pain (HR 0.82 [0.69, 0.98]; p = 0.0322) and pain severity (HR 0.79 [0.65, 0.97]; p = 0.0209) vs PBO + ADT. Conclusions: Men with mHSPC were generally asymptomatic and had high levels of HRQoL and low levels of pain at BL, likely due to most men initiating ADT several months prior to study entry. No clinically meaningful differences in HRQoL were observed between ENZ and PBO. The prolongation in radiographic progression-free survival observed with ENZ + ADT was accompanied by a significantly prolonged time to progression of worst pain and pain severity vs PBO + ADT. Clinical trial information: NCT02677896.

Pancreatic cancer (PaC)-specific health-related quality of life (HRQoL) with maintenance olaparib (O) in patients (pts) with metastatic (m) PaC and a germline BRCA mutation (gBRCAm): Phase III POLO trial.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 648-648
Author(s):  
Michael J. Hall ◽  
Talia Golan ◽  
Pascal Hammel ◽  
Michele Reni ◽  
Eric Van Cutsem ◽  
...  
Keyword(s):  
Repeated Measures ◽  
Mixed Model ◽  
Brca Mutation ◽  
Symptom Burden ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Rank Test ◽  
Point Change ◽  
Symptom Scores ◽  
Over Time

648 Background: In POLO (NCT02184195), maintenance O significantly improved progression-free survival vs placebo (P) in pts with a gBRCAm and mPaC without compromising HRQoL (Hammel Ann Oncol 2019). We report additional predefined exploratory HRQoL data from the PaC-specific EORTC QLQ-PAN26 questionnaire. Methods: Pts were randomized to O (300 mg bid; tablets) or P. QLQ-PAN26 was completed at baseline (BL), after 1, 2, 3 + 4 weeks (wk) of treatment, every 4 wks until progression, at discontinuation, and 30 days after last dose. Scale range = 1–100 (higher score = greater symptoms); a 10-point change was predefined as clinically meaningful. Adjusted mean change from BL (CFBL) was analyzed by mixed model for repeated measures; time to sustained clinically meaningful deterioration (TSCMD) by log-rank test. Results: Analyses included the 89/92 O- and 58/62 P-arm pts with BL data (overall compliance: 97.8% vs 98.3%). Symptom scores were well balanced in both groups at BL and remained low and stable over time (Table). There were no clinically meaningful between-group differences in adjusted mean CFBL symptom scores. TSCMD in symptoms were not significantly different with O vs P. Conclusions: HRQoL was preserved with maintenance O, as shown by a low and stable PaC symptom burden over time, with no difference vs P. These data support the clinical benefit of O in pts with a gBRCAm and mPaC. Clinical trial information: NCT02184195 . [Table: see text]

An international, randomized, placebo-controlled, double-blind phase III study (MONET1) of motesanib plus carboplatin/paclitaxel (C/P) in patients with advanced nonsquamous non-small cell lung cancer (NSCLC).

2011 ◽  
Vol 29 (18_suppl) ◽  
pp. LBA7512-LBA7512 ◽  
Author(s):  
G. Scagliotti ◽  
I. Vynnychenko ◽  
Y. Ichinose ◽  
K. Park ◽  
K. Kubota ◽  
...  
Keyword(s):  
Cox Model ◽  
Objective Response ◽  
Stage Iv ◽  
Progression Free Survival ◽  
High Rate ◽  
Phase Iii ◽  
Rank Test ◽  
Double Blind ◽  
Grade 3 ◽  
Nonsquamous Nsclc

LBA7512 Background: This study evaluated whether motesanib (a selective oral inhibitor of VEGFR 1, 2 and 3; PDGFR and Kit) plus C/P improved overall survival (OS) compared with placebo + C/P in patients (pts) with nonsquamous NSCLC and in a subset of pts with adenocarcinoma. Methods: Pts had stage IIIB/IV or recurrent nonsquamous NSCLC and no prior systemic therapy for advanced NSCLC. The study initially enrolled all histologies but was amended to exclude pts with squamous NSCLC owing to a high rate of hemoptysis. Pts were randomized 1:1 to receive up to six 3-wk cycles of C (AUC 6 mg/mL·min) and P (200 mg/m2) with either motesanib 125 mg QD (Arm A) or placebo QD (Arm B) orally continuously. The primary endpoint was OS; secondary endpoints included progression-free survival (PFS), adverse events (AEs), objective response rate (ORR) and association between placental growth factor (PLGF) change and OS. OS was evaluated using a stratified Cox model and 2-sided log-rank test (α=0.03 for nonsquamous pts and α=0.02 for adenocarcinoma pts). Results: 1090 pts with nonsquamous NSCLC were randomized (Arm A/B, n=541/549); 890 had adenocarcinoma (n=448/442). 61% were men; median age was 60 years (range 21–87); 83% had stage IV disease. At the time of analysis, 753 pts had died (608 pts with adenocarcinoma). Median follow-up was 10.6 mo. OS was not significantly improved in Arm A compared with Arm B (Table). In Arm A, PLGF analysis did not show an association with OS. The incidence of grade ≥3 AEs in Arms A/B was 73/59%. Grade ≥3 AEs occurring more frequently in Arm A than B included neutropenia (22/15%), diarrhea (9/1%), hypertension (7/1%) and cholecystitis (3/0%). The incidence of grade 5 AEs was 14/9% in Arms A/B. Conclusions: In pts with advanced nonsquamous NSCLC, treatment with motesanib + C/P did not significantly improve OS compared with C/P alone. [Table: see text]

Sensitivity analyses for progression-free survival (PFS) and radiographic PFS (rPFS) from the phase II STRIVE trial comparing enzalutamide (ENZA) with bicalutamide (BIC) in men with castration-resistant prostate cancer (CRPC).

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 169-169 ◽  
Author(s):  
David F. Penson ◽  
Andrew J. Armstrong ◽  
Raoul S. Concepcion ◽  
Kenneth Wu ◽  
Fong Wang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Progression Free Survival ◽  
Sensitivity Analyses ◽  
Castration Resistant Prostate Cancer ◽  
Double Blind ◽  
Treatment Benefit ◽  
Objective Evidence ◽  
Original Definition ◽  
The Impact

169 Background: STRIVE was arandomized, double-blind, phase 2 trial comparing ENZA vs BIC in nonmetastatic (M0) or metastatic (M1) CRPC. In this study, ENZA significantly reduced the risk of prostate cancer progression or death compared with BIC in patients with M0 or M1 CRPC. Methods: 396 men with M0 (n = 139) or M1 (n = 257) CRPC were randomized to ENZA 160 mg/day or BIC 50 mg/day. The primary endpoint of PFS was defined as the time from randomization to radiographic progression, PSA progression, or death from any cause, whichever occurred first. rPFS was defined as the time from randomization to death or the first objective evidence of radiographic disease progression in soft-tissue disease per RECIST v1.1 or in bone per PCWG2 guidelines. Sensitivity analyses were prespecified to assess the impact of alternative definitions for PFS in all patients and were performed post hoc for the key secondary endpoint of rPFS in patients with M1 disease only (table). Results: Consistent with the primary analyses of PFS and rPFS, the results from all sensitivity analyses favored ENZA over BIC (table). Conclusions: PFS and rPFS sensitivity analyses in STRIVE demonstrated a consistent and robust treatment benefit with ENZA compared with BIC by any variation of the original definition of PFS. Clinical trial information: NCT01664923. [Table: see text]

Personalized peptide vaccination for castration-resistant prostate cancer progressing after docetaxel chemotherapy: A randomized, double-blind, placebo-controlled, phase III trial.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5033-5033 ◽  
Author(s):  
Masanori Noguchi ◽  
Kiyohide Fujimoto ◽  
Gaku Arai ◽  
Hiroji Uemura ◽  
Katsuyoshi Hashine ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Human Leukocyte ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Peptide Vaccination ◽  
Double Blind ◽  
Castration Resistant ◽  
New Treatment ◽  
Docetaxel Chemotherapy

5033 Background: To develop a new treatment modality, we conducted a phase III randomized trial of personalized peptide vaccination (PPV) for human leukocyte antigen (HLA) -A24 positive patients with castration-resistant prostate cancer (CRPC) who failed docetaxel chemotherapy. Methods: Patients were randomly assigned in a 2:1 ratio to receive PPV or placebo. Four of 12 warehouse peptides selected based on preexisting peptide-specific immunoglobulin G levels or the corresponding placebo were subcutaneously injected 6 doses weekly followed the maximum of 30 doses bi-weekly until disease progression. The primary end point was overall survival (OS), and secondary end points were progression-free survival (PFS) and immune responses. Results: From August 2013 to April 2016, 310 patients were randomly assigned (207 to PPV and 103 to placebo), and 306 patients were analyzed by the full analysis set (204 to PPV and 102 to placebo). Baseline characteristics were balanced between groups. Estimated median OS was 16.1 months (95% CI, 13 to 18.2) with PPV and 16.9 months (95% CI, 13.1 to 20.4) with placebo (HR, 1.04; 95%CI, 0.79 to 1.37; P = 0.77). Median PFS was also not significantly different among them. Median Grade ≥ 3 adverse events were observed in 41% in both groups. The analysis of treatment arm effects among various subgroups revealed a lower HR for OS in favor of the PPV arm in patients with a < 64% neutrophil proportion (HR, 0.55; 95%CI, 0.33 to 0.93), with a significant interaction test ( P = 0.003). Conclusions: PPV did not prolong either OS or PFS in HLA-A24 positive patients with CRPC progressing after docetaxel chemotherapy. Clinical trial information: 0000113088.

Phase III study of androgen deprivation therapy (ADT) with enzalutamide (ENZA) or placebo (PBO) in metastatic hormone-sensitive prostate cancer (mHSPC): The ARCHES trial.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 687-687 ◽  
Author(s):  
Andrew J. Armstrong ◽  
Russell Zelig Szmulewitz ◽  
Daniel Peter Petrylak ◽  
Arnauld Villers ◽  
Arun Azad ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
High Volume ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Double Blind ◽  
Secondary Endpoints ◽  
Phase Iii Study ◽  
Grade 3

687 Background: ENZA, a potent androgen receptor inhibitor, has demonstrated benefit in men with metastatic and nonmetastatic castration-resistant prostate cancer (CRPC). Efficacy of ENZA with ADT in men with mHSPC is unknown. Methods: ARCHES is a multinational, double-blind, phase 3 study (NCT02677896). Patients (pts) with mHSPC were randomized 1:1 to ENZA (160 mg/day) + ADT or PBO + ADT, stratified by disease volume (CHAARTED criteria) and prior docetaxel therapy. Primary endpoint was radiographic progression-free survival (rPFS) assessed centrally or death within 24 weeks of treatment discontinuation. Secondary endpoints included time to prostate-specific antigen (PSA) progression, PSA and radiographic responses and overall survival (OS). Treatment continued until disease progression or unacceptable toxicity. Results: 1150 men were randomized to ENZA (n=574) or PBO (n=576); baseline characteristics were balanced between groups. Overall, 67% had distant metastasis at initial diagnosis; 63% had high volume disease, 18% had prior docetaxel. Median follow-up was 14.4 mo. ENZA + ADT significantly improved rPFS (Table); similar significant improvements in rPFS were reported in prespecified subgroups of disease volume, pattern of spread, region and prior docetaxel (HRs 0.24–0.53). Secondary endpoints improved with ENZA + ADT (Table); OS data are immature. Grade 3–4 adverse events (AEs) were reported in 23.6% of ENZA pts vs 24.7% of PBO pts with no unexpected AEs. Conclusions: ENZA + ADT significantly improved rPFS and other efficacy endpoints vs PBO + ADT in men with mHSPC, with a preliminary safety analysis that appears consistent with the safety profile of ENZA in previous CRPC clinical trials. Acknowledgements: Medical writing and editing assistance was provided by Stephanie Rippon, MBio, and Lauren Smith from Complete HealthVizion, funded by the study sponsors. This study was funded by Astellas Pharma Inc. and Medivation LLC, a Pfizer Company, the co-developers of enzalutamide. Clinical trial information: NCT02677896. [Table: see text]

Single nucleotide polymorphisms (SNPs) as predictors of efficacy of cabazitaxel in patients with metastatic castration-resistant prostate cancer (mCRPC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e17582-e17582
Author(s):  
Daniel Herrero Rivera ◽  
Ignacio Duran ◽  
Laura Marcos Kovandzic ◽  
Javier Puente ◽  
Begona Mellado ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Gleason Score ◽  
Univariate Analysis ◽  
Progression Free Survival ◽  
Rank Test ◽  
Genetic Constitution ◽  
Castration Resistant Prostate Cancer ◽  
Free Survival ◽  
The Impact

e17582 Background: Cabazitaxel is a semi-synthetic derivative of a natural taxoid approved for the treatment of mCRPC patients (pts) after failure to docetaxel. Despite its proven efficacy, there is variability in the response, progression-free survival (PFS) and overall survival (OS) of pts. Changes in the genetic constitution of the individual such as the SNPs could explain this variability. The aim of this study was to evaluate the impact of certain SNPs in cabazitaxel activity. Methods: Clinical data from 67 mCRPC pts treated with cabazitaxel between March 2011 and October 2016 were collected. DNA was isolated from formalin fixed paraffin-embedded tumor samples. 56 SNPs in 5 genes related with metabolism and/or mechanism of action of cabazitaxel (CYP3A4, CYP3A5, ABCB1, TUBB1, CYP2C8) were chosen based on their Minor Allele Frequency, linkage disequilibrium and information from dbSNP and analyzed by TaqMan OpenArray (Lifetech). The presence/absence of mutant alleles of the selected SNPs was correlated with clinical features, progression free survival (PFS) and overall survival (OS) of prostate cancer. Chi-square test and Kaplan-Meier with log-rank test were used for statistical analyses. Results: The median age was 61 years (range 44-82). 56.7% (n = 38) had a Gleason score ≥8 and 94% had received docetaxel in first line. Type of response to cabazitaxel was associated with median OS (Partial response = 24.35 months, Stable disease = 11.16 months, Progression disease = 5.8 months; p= 0.045). Univariate analysis, showed worsed OS at 1 year for wild type status of SNP rs151352 (OR = 4, 95%CI 1.27-12.58, p= 0.029). In addition, two SNPs (rs11773597, rs1202186) were associated with radiological response to cabazitaxel ( p= 0.031 and p= 0.030 respectively). Other 7 SNPs (rs11773597, rs2235040, rs1045642, rs1419745, rs1202170, rs6949448, rs11572093) were associated ( p<0.05) with Gleason score, pain, PSA doubling time, febrile neutropenia and asthenia. Conclusions: A particular SNP profile could be predictive of efficacy and related with toxicity in mCRPC population treated with cabazitaxel after progression to docetaxel. These outcomes become particularly relevant in patient selection given the recent results of the CARD trial.

TALAPRO-2: A placebo-controlled phase III study of talazoparib (TALA) plus enzalutamide (ENZA) for patients with first-line metastatic castration-resistant prostate cancer (mCRPC).

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. TPS264-TPS264
Author(s):  
Neeraj Agarwal ◽  
Neal D. Shore ◽  
Curtis Dunshee ◽  
Lawrence Ivan Karsh ◽  
Arun Azad ◽  
...  
Keyword(s):  
Parp Inhibitor ◽  
Performance Status ◽  
Dose Finding ◽  
Phase Iii ◽  
Asia Pacific ◽  
Rank Test ◽  
Castration Resistant Prostate Cancer ◽  
Ecog Performance Status ◽  
Double Blind ◽  
Combination Methods

TPS264 Background: TALA is a poly(ADP-ribose) polymerase (PARP) inhibitor that inhibits PARP1/2 and traps PARP on DNA, preventing DNA damage repair (DDR) and causing death of cells with DDR mutations (eg BRCA1/2). TALA is approved in multiple countries for germline BRCA1/2-mutated HER2- advanced breast cancer. ENZA is an established therapy for CRPC. PARP1 activity has been shown to support AR function, suggesting that co-blockade of PARP1 may synergize with AR-directed therapy, regardless of DDR deficiency. A combination of TALA with ENZA in mCRPC may improve clinical outcomes in patients with or without DDR-deficient tumors. TALAPRO-2 (NCT03395197) is a 2-part study to evaluate efficacy, safety, pharmacokinetics, and patient (pt)-reported outcomes (PROs) of the combination. Methods: Enrollment goal is 1037 pts (19 pts, part 1 dose-finding; 1,018 pts, part 2 placebo-controlled). Key eligibility criteria: age ≥18 y, asymptomatic/mildly symptomatic mCRPC, ECOG performance status ≤1, no brain metastases, and no prior life-prolonging systemic therapy in nonmetastatic CRPC or mCRPC state. Prior docetaxel or novel hormonal therapy (excluding novel AR inhibitors) in castration sensitive (CSPC) setting is allowed. The randomized double-blind portion will evaluate safety, efficacy, and PROs of TALA (0.5 mg QD) + ENZA (160 mg QD) vs placebo + ENZA (160 mg QD). Randomization is stratified by prior NHT or docetaxel for CSPC (yes/no) and DDR mutation status (deficient vs nondeficient/unknown). The primary endpoint is radiographic progression-free survival (rPFS), defined as time to progression in soft tissue per RECIST v.1.1 or in bone per PCWG3 criteria or death. The key secondary endpoint is overall survival (OS). Efficacy will be assessed by radiography every 8 weeks up to week 25 and every 8–12 weeks thereafter. rPFS will be compared between two arms by a 1-sided stratified log-rank test. Pt recruitment is ongoing in multiple regions including US, Europe/Eastern Europe, Israel, South America, South Africa, and Asia Pacific region. This study was sponsored by Pfizer Inc. Clinical trial information: NCT03395197.

Everolimus in patients with advanced pancreatic neuroendocrine tumors (pNET): Updated results of a randomized, double-blind, placebo-controlled, multicenter phase III trial (RADIANT-3).

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 158-158 ◽  
Author(s):  
M. H. Shah ◽  
T. Ito ◽  
C. Lombard-Bohas ◽  
E. M. Wolin ◽  
E. Van Cutsem ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Controlled Trial ◽  
Somatostatin Analogs ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Open Label ◽  
Double Blind ◽  
Phase Ii Studies ◽  
The Impact ◽  
Patient Subgroups

158 Background: There is an unmet medical need for effective treatments for patients with advanced pNET. Systemic therapies for advanced pNET are limited both by toxicity and efficacy. Everolimus, an oral mTOR inhibitor, has shown promising antitumor activity in 2 phase II studies, leading to further investigation in the largest phase III randomized controlled trial completed in pNET patients. Methods: Patients with advanced low- or intermediate-grade pNET were randomly assigned to everolimus 10 mg/d orally + best supportive care (BSC; n = 207) or placebo + BSC (n = 203). Long-acting somatostatin analogs (SSAs) were permitted as BSC during the study. The primary endpoint was progression free survival (PFS). At progression (RECIST), patients could be unblinded and those randomly assigned to placebo were offered open-label everolimus. Results: Compared with placebo, everolimus reduced the risk of progression by 65% and increased median PFS by more than 6 months, from 4.6 to 11.0 months (HR = 0.35; 95% CI: 0.27-0.45; p < 0.0001), by investigator review (primary endpoint). Median PFS by central review was consistent (HR = 0.34; 95% CI: 0.26 to 0.44; p < 0.001] in favor of everolimus. Eighteen-month PFS estimates were 34% for everolimus (95% CI: 26-43) vs 9% (95% CI: 4-16) for placebo. Everolimus demonstrated a significant PFS benefit across all patient subgroups according to baseline characteristics and prior SSA use. Prior SSA use was 49% in the everolimus arm and 50% in the placebo arm. Updated analyses of the impact of concomitant SSA will be reported. The most common drug-related adverse events were stomatitis, rash, diarrhea, fatigue, and infections (primarily upper respiratory); most were grade 1 or 2. Stomatitis (6.9% vs 0%), anemia (6% vs 0%), and hyperglycemia (5% vs 2%) were the most common grade 3-4 events. Conclusions: Everolimus significantly prolonged PFS compared with placebo in patients with advanced pNET in this large phase III clinical trial. This benefit was seen across all patient subgroups. Treatment resulted in a significant 6.4-month prolongation in median PFS. Everolimus had an acceptable and predictable safety profile. [Table: see text]

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