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) 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]

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]

PROfound: Efficacy of olaparib (ola) by prior taxane use in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 134-134 ◽  
Author(s):  
Johann S. De Bono ◽  
Karim Fizazi ◽  
Fred Saad ◽  
Neal D. Shore ◽  
Guilhem Roubaud ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Free Survival ◽  
Castration Resistant ◽  
Recombination Repair ◽  
Subgroup Analyses ◽  
Study Population ◽  
Brca1 Brca2 ◽  
Gene Alterations

134 Background: Optimal sequencing of therapies for mCRPC is not established. In the Phase III PROfound study (NCT02987543), ola significantly prolonged radiographic progression-free survival (rPFS) vs physician’s choice of new hormonal agent (pcNHA) in pts with mCRPC and an alteration in genes with a direct or indirect role in HRR. We report exploratory subgroup analyses by prior taxane (yes vs no). Methods: Men with mCRPC that had progressed on prior NHA were randomized to ola (tablets; 300 mg bid) or pcNHA (enzalutamide or abiraterone). Pts had alterations in BRCA1, BRCA2 or ATM (Cohort A) or ≥1 of 12 other prespecified genes with a direct or indirect role in HRR (Cohort B). Stratification factors were prior taxane use and measurable disease. rPFS was assessed by blinded independent central review with RECIST v1.1 + PCWG3. Results: Subgroup analyses of rPFS and overall survival (OS) favored ola vs pcNHA irrespective of prior taxane in Cohort A, Cohorts A+B and pts with a BRCA1 and/or BRCA2 or CDK12 alteration (Table). In the ATM subgroup hazard ratio (HR) point estimates for rPFS and OS were lower in pts who had received prior taxane vs pts who had not, but 95% CIs overlapped and pt numbers were small so data should be interpreted with caution. Conclusions: The benefit of ola over pcNHA in pts with mCRPC and HRR gene alterations was generally independent of prior taxane status in the overall study population. Clinical trial information: NCT02987543. [Table: see text]

Denosumab or zoledronic acid (ZA) therapy on pain interference and cancer-specific quality of life (CSQoL) in patients with castrate-resistant prostate cancer (CRPC) and bone metastases (BM).

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 12-12 ◽  
Author(s):  
Donald Patrick ◽  
Charles S. Cleeland ◽  
Lesley Fallowfield ◽  
Matthew Raymond Smith ◽  
Laurence Klotz ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Prostate Cancer ◽  
Bone Metastases ◽  
Short Form ◽  
Pain Interference ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Mild Pain ◽  
Point Increase

12 Background: Patients with castration-resistant prostate cancer (CRPC) and bone metastases (BM) may experience debilitating pain that impacts daily functioning and diminishes the quality of life. Previous results from a phase III trial demonstrated superiority of denosumab to ZA in delaying or preventing skeletal-related events (pathological fracture, radiation or surgery to the bone, spinal cord compression) in CRPC patients with BM. In this ad-hoc analysis, we present the results of denosumab or ZA therapy on pain interference (PI) and cancer specific quality of life (CSQoL), focusing on the subgroup of CRPC patients with no/mild pain at baseline. Methods: Men with CRPC and BM (no prior IV bisphosphonate use) were randomized to receive either SC denosumab 120 mg+IV placebo or SC placebo+IV ZA 4mg (adjusted for creatinine clearance) every four weeks. Patients were instructed to take calcium and vitamin D supplements. The Brief Pain Inventory–Short Form (BPI-SF) was used to assess PI. The pre-specified clinically meaningful time of a greater than or equal to two point increase from baseline in PI score (overall, physical, and emotional subdomains) was determined for CRPC patients receiving denosumab or ZA therapy. Patients also completed the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire at baseline and each monthly visit to determine CSQoL scores. Declining FACT-G scores points to worsening CSQoL, where a greater than or equal to five point decrease is clinically meaningful. Results: Of the 1,901 patients enrolled (n=950, denosumab; n=951, ZA), 1,045 (55%) had no/mild pain at baseline. Compared with ZA, denosumab therapy delayed the time to a greater than or equal to two point increase from baseline in PI for the overall score (HR=0.83 [0.71, 0.98]; P=0.023), physical (HR=0.87 [0.75, 1.02]; P=0.077) and emotional (HR=0.83 [0.71, 0.97]; P=0.020) subdomains. Over a period of 18 months, more ZA-treated patients than denosumab-treated patients experienced a greater than or equal to five point decrease in FACT-G total scores (average relative difference=6.8%, range -9.4 to 14.6%) or worsening of CSQoL. Conclusions: Denosumab therapy significantly delayed the time to worsening of pain interference and maintained a higher overall CSQoL (FACT-G) compared to ZA in CRPC patients with BM. Clinical trial information: NCT00321620.

scholarly journals Pain Progression at Initiation of Cabazitaxel in Metastatic Castration-Resistant Prostate Cancer (mCRPC): A Post Hoc Analysis of the PROSELICA Study

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1284
Author(s):  
Nicolas Delanoy ◽  
Debbie Robbrecht ◽  
Mario Eisenberger ◽  
Oliver Sartor ◽  
Ronald de Wit ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Radiological Progression ◽  
Post Hoc Analysis ◽  
Psa Response ◽  
Phase Iii Study ◽  
Psa Progression ◽  
Previously Treated ◽  
Post Hoc

Background: In the PROSELICA phase III trial (NCT01308580), cabazitaxel 20 mg/m2 (CABA20) was non-inferior to cabazitaxel 25 mg/m2 (CABA25) in mCRPC patients previously treated with docetaxel (DOC). The present post hoc analysis evaluates how the type of progression at randomization affected outcomes. Methods: Progression type at randomization was defined as follows: PSA progression only (PSA-p; no radiological progression (RADIO-p), no pain), RADIO-p (±PSA-p, no pain), or pain progression (PAIN-p, ±PSA-p, ±RADIO-p). Relationships between progression type and overall survival (OS), radiological progression-free survival (rPFS), and PSA response (confirmed PSA decrease ≥ 50%) were analyzed. Results: All randomized patients (n = 1200) had received prior DOC, and 25.7% had received prior abiraterone or enzalutamide. Progression type at randomization was evaluable in 1075 patients (PSA-p = 24.4%, RADIO-p = 20.8%, PAIN-p = 54.8%). Pain progression was associated with clinical and biological features of aggressive disease. Median OS from CABA initiation or date of mCRPC diagnosis, all arms combined, was shorter in the PAIN-p group than in the RADIO-p or the PSA-p groups (12.0 versus 16.8 and 18.4 months, respectively, p < 0.001). In multivariate analysis, all arms combined, PAIN-p was an independent predictor of poor OS (HR = 1.44, p < 0.001). PSA response, rPFS, and OS were numerically higher with CABA25 versus CABA20 in patients with PAIN-p. Conclusions: This post hoc analysis of the PROSELICA phase III study shows that pain progression at initiation of CABA in mCRPC patients previously treated with DOC is associated with a poor prognosis. Disease progression should be carefully monitored, even in the absence of PSA rise.

CASPAR (Alliance A031902): A randomized, phase III trial of enzalutamide (ENZ) with rucaparib (RUCA)/placebo (PBO) as a novel therapy in first-line metastatic castration-resistant prostate cancer (mCRPC).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. TPS181-TPS181
Author(s):  
Arpit Rao ◽  
Charles J. Ryan ◽  
David James VanderWeele ◽  
Glenn Heller ◽  
Lionel D Lewis ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Radiographic Progression ◽  
Synthetic Lethality ◽  
Short Form ◽  
Parp Inhibitor ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Dna Breaks ◽  
Phase 3 ◽  
Logrank Test

TPS181 Background: Treatment with novel antiandrogens (NAA) and androgen deprivation therapy prolongs life in men with mCRPC but approximately 40% patients (pts) have radiographic progression within the first year. Inhibition of androgen receptor signaling results in increased double-strand DNA breaks and genomic instability. NAA+PARP inhibitor (PARPi) combinations have shown induction of synthetic lethality by this mechanism in multiple preclinical studies. Homologous recombination repair (HRR) gene aberrations do not appear to be necessary for this synergy and an NAA+PARPi combination has shown improved radiographic progression-free survival (rPFS) in HRR-wild-type pts compared with NAA alone. Methods: CASPAR (A031902) is a randomized phase 3 study in which 984 pts will be randomized on a 1:1 basis to ENZ plus RUCA/PBO. A PK substudy will precede the phase 3 portion and enroll 6-18 pts to various doses of ENZ plus RUCA to establish safety and evaluate any clinically-significant drug-drug interactions (S-DDI). Treatment will be continued until disease progression and cross-over is not allowed. Co-primary endpoints are rPFS and overall survival (OS). The OS analysis will be undertaken as a primary endpoint if the rPFS endpoint is met. For a one-sided logrank test with a type 1 error rate equal to 0.025, the study has 90% power to detect a hazard ratio (HR) of 0.71 in rPFS (median rPFS of 15 and 21 months in control and combination arms, respectively), and 80% power to detect an HR of 0.80 in OS (median OS of 32 and 40 months, respectively). Key secondary endpoints are rPFS and OS in pts with vs without pathogenic BRCA1, BRCA2, or PALB2 mutations; and differences in adverse events and quality of life (QOL) outcomes between the treatment arms. QOL assessments include Functional Assessment of Cancer Therapy–Prostate (FACT-P), Brief Pain Inventory Short Form (BPI-SF), and EQ-5D-5L. A key correlative endpoint is the concordance between tissue and plasma ctDNA-based HRR testing. Key eligibility criteria are age ≥ 18 years, ECOG PS 0-2, biopsy-proven prostate adenocarcinoma, progressive (PSA or radiographic) disease per Prostate Cancer Working Group 3 guidelines, measurable or non-measurable disease per RECIST 1.1, no prior treatment for mCRPC (prior abiraterone, darolutamide, or apalutamide in non-mCRPC setting is allowed), no significant uncontrolled comorbidity, and no medications with S-DDI with ENZ/RUCA. HRR gene aberration is not required for enrollment. All pts will undergo next-generation targeted-exome sequencing from archival tumor tissue (new biopsy only required if no archival tissue available). CASPAR is available for participation to all US-NCTN sites starting in October 2020 with a projected enrollment of 3 years. Support: U10CA180821, U10CA180882; acknowledgments.alliancefound.org. Clinical trial information: NCT04455750.

Role of detection of metastatic disease as a leading cause of screening failure in an ongoing phase III trial of zibotentan versus placebo in patients with nonmetastatic castration-resistant prostate cancer (CRPC).

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 135-135 ◽  
Author(s):  
E. Y. Yu ◽  
F. E. Nathan ◽  
C. S. Higano
Keyword(s):  
Prostate Cancer ◽  
Metastatic Disease ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Asymptomatic Patients ◽  
Primary Endpoints ◽  
Number Of Patients ◽  
Definitive Therapy ◽  
Patients Experience

135 Background: Many patients with biochemical relapse after definitive therapy for prostate cancer receive androgen deprivation therapy. Although most patients experience a decline in PSA, PSA eventually rises despite a castrate level of testosterone. Many of these patients have non-metastatic disease and do not develop metastases for a median of 30 mos (Smith MR. JCO, 2005). However, there is no standard therapy for asymptomatic patients with non-metastatic CRPC. ENTHUSE M0 (Study 15) is an ongoing global phase III study comparing zibotentan 10 mg (an oral specific endothelin A receptor antagonist) vs placebo in non-metastatic CRPC patients. Co-primary endpoints are overall survival and progression-free survival; secondary endpoints are safety, PSA, quality of life, and time to symptomatic progression. Eligible patients are screened for metastases by bone and CT/MRI scan and other parameters. An unexpectedly high number of patients failed screening, prompting this analysis. Methods: All patients who were screened were included in the analysis. Reasons for exclusion were recorded. Results: As of June 3, 2010, 1,756 patients completed screening. Of these patients, 960 (55%) were randomized and 796 (45%) failed screening. The leading causes of screen failures are listed in the table. Exclusion rates by investigator specialty and country will be reported. Conclusions: As 30% of patients had metastatic disease on screening and were excluded, these data suggest that the frequency of asymptomatic metastases is high in men thought to have non-metastatic CRPC. These findings stress the value of periodic staging studies in men progressing from hormone sensitive to non-metastatic CRPC as metastatic CRPC patients may benefit from standard treatments or research treatments on other protocols. [Table: see text] [Table: see text]

Comparison of two doses of cabazitaxel plus prednisone in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) previously treated with a docetaxel (D)-containing regimen.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS4692-TPS4692 ◽  
Author(s):  
Mario A. Eisenberger ◽  
Anne-Claire Hardy-Bessard ◽  
Loic Mourey ◽  
Paul N. Mainwaring ◽  
Daniel Ford ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Hematologic Toxicity ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Measurable Disease ◽  
Previously Treated ◽  
Grade 3 ◽  
Ecog Ps

TPS4692^ Background: The phase III TROPIC study (NCT00417079) reported a significant improvement in overall survival (OS) for cabazitaxel (Cbz) + prednisone (P;CbzP) (25 mg/m2 IV Q3W/10 mg PO QD) vs mitoxantrone (M) + P (MP) (median OS 15.1 vs 12.7 mos; HR 0.70; P < 0.0001) in pts with mCRPC (also known as hormone-refractory prostate cancer) previously treated with a D-containing regimen. CbzP is approved by the FDA, EMA and other health authorities for the treatment of pts with mCRPC that has progressed after a D-containing regimen. Cbz toxicity is consistent with other taxanes; compared with M, more hematologic toxicities are reported (primarily Grade 3–4 neutropenia). Phase I/II studies identified 20 and 25 mg/m2 as recommended doses; 25 mg/m2 was selected for the phase III TROPIC study. As pooled data show Grade 3–4 neutropenia incidence is lower with Cbz < 25 mg/m2 (61%) vs ≥ 25 mg/m2 (74%), it is of interest to assess if reducing the Cbz approved dose in mCRPC lessens hematologic toxicity and is non-inferior in terms of efficacy. Methods: PROSELICA (NCT01308580) is a randomized, open-label, multinational, phase III study comparing 20 mg/m2 and 25 mg/m2 Cbz for efficacy and tolerability. Pts with a life expectancy > 6 mos, ECOG PS ≤ 2, histologically/cytologically confirmed metastatic prostate adenocarcinoma resistant to hormone therapy and previously treated with a D-containing regimen are eligible. Pts are randomized 1:1 to receive Cbz 20 mg/m² or 25 mg/m² IV Q3W + P 10 mg PO QD, treated until disease progression, unacceptable toxicity or withdrawal of consent (max 10 cycles), and stratified according to ECOG PS, measurable disease (yes/no) and region. The primary endpoint is OS (non-inferiority design). Secondary endpoints include safety, progression-free survival (PCWG2 criteria), PSA and pain progression and response, tumor response in pts with measurable disease and health-related quality of life. Cbz PK and pharmacogenomics will be assessed in pt subgroups. Planned enrollment is 1,200 pts. Study start was in May 2011; as of Jan 2012, 270 pts had been enrolled. The first DMC meeting recommended continuing the study without change.

Intergroup study EORTC-1333-GUCG: A randomized multicenter phase III trial comparing enzalutamide vs. a combination of Ra223 and enzalutamide in asymptomatic or mildly symptomatic castration resistant prostate cancer (CRPC) patients metastatic to bone (PEACE III).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. TPS390-TPS390
Author(s):  
Bertrand F. Tombal ◽  
Yohann Loriot ◽  
Fred Saad ◽  
Raymond S. McDermott ◽  
Sandrine Marreaud ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
The United States ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Risk Of Death ◽  
Related Quality ◽  
Favourable Safety Profile ◽  
Health Related

TPS390 Background: α-emitting radiopharmaceutical Ra-223 reduces the risk of death by 30% vs placebo in phase 3 ALSYMPCA (Parker et al. NEJM 2013). Ra-223’s favourable safety profile and lack of significant toxicity support combining it with other agents. The ALSYMPCA trial was developed to add Ra-223 on the contemporary standard of care that did not include last generation AR pathway inhibitors enzalutamide, one of the modern reference treatments for asymptomatic or moderately symptomatic metastatic CRPC (Gillessen et al. Eur Urol. 2017). In addition Ra-223 is registered in symptomatic prostate cancer (PCa), a very late stage of modern patient disease. There is thus a good rationale to combine Ra-223 to modern AR pathway inhibitors and to initiate the treatment in asymptomatic or moderately symptomatic patients. Methods: The EORTC 1333-GUCG study will run in 51 sites (21 activated) across 7 European countries, 4 sites in US and 12 sites in Canada. The study is an intergroup initiative between EORTC (Coordinating Group), UNICANCER; Cancer Trials Ireland (Ireland), ACCRU (The United States), and CUOG (Canada). A total of 560 patients will be randomized in a 1:1 ratio to receive enzalutamide 160 mg q.d. p.o. or enzalutamide at the same dose and Ra223 at 55 kBq/kg i.v. monthly for 6 months. Patients will be stratified by country, pain (BPI 0-1 vs BPI 2-3), prior docetaxel use (no vs yes) and use of bone targeting agents (no vs yes). The main inclusion criteria require asymptomatic or mildly symptomatic (defined as no opioids and BPI-SF question 3 < 4), metastatic to bone with ≥ 2 bone metastases with or without additional lymph node metastases. Visceral metastases are not allowed. The primary endpoint is radiological progression-free survival (rPFS1), according to PCWG3. Secondary endpoints include: overall survival, PCa specific survival, 1st symptomatic skeletal event (SSE), time to initiation of next systemic anti-neoplastic therapy, time to pain progression, health-related quality of life (EQ-5D-5L and BPI). Clinical trial information: NCT02194842.

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