Post hoc analysis of a phase III study to test the association between circulating methylated glutathione s transferase (mGSTP1) DNA levels and response to docetaxel (DTX) in metastatic castration resistant prostate cancer (mCRPC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 5014-5014
Author(s):  
Kate Lynette Mahon ◽  
Wenjia Qu ◽  
Hui-Ming Lin ◽  
Calan Spielman ◽  
Daniel Cain ◽  
...  
Keyword(s):  
Cpg Island ◽  
Multivariable Analysis ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Serum Samples ◽  
Full Cohort ◽  
Post Hoc Analysis ◽  
Time Points ◽  
Phase Iii Study ◽  
Post Hoc

5014 Background: GSTP1 inactivation is associated with CpG island hypermethylation in > 99% prostate cancers. Detection of circulating mGSTP1 DNA predicts response to DTX and overall survival (OS) in phase I/II mCRPC cohorts. This post hoc analysis of a phase III study aims to test the association between circulating mGSTP1 DNA levels and outcomes. Methods: The phase III SYNERGY study tested DTX +/- custirsen as 1st line chemotherapy in mCRPC (n = 1022) with no OS benefit in the experimental arm. Serum samples were taken at baseline (BL) and preC3 of DTX +/- custirsen from 600 patients (pts) enrolled on the SYNERGY study. mGSTP1levels in free DNA were measured using a sensitive methylation specific PCR assay and correlated with PSA response, time to PSA progression (TTP) and OS. Results: On interim analysis of 300 pts, serum mGSTP1 was detectable at BL in 80% and preC3 in 44%. Undetectable preC3 mGSTP1 correlated with a ≥30% fall in PSA within 3m of starting DTX (p < 0.001). Detectable BL and preC3 mGSTP1 predicted shorter TTP after DTX (BL; HR 1.6 95%CI 1.1-2.3; p = 0.01 and preC3 HR 2.2 95%CI 1.6-2.9; p < 0.001). Detectable mGSTP1 at both time points predicted shorter OS (BL; median OS 18.4 vs 33.1m, HR 2.4 95%CI 1.6-3.7; p < 0.001 and preC3; median OS 13.9 vs 29m, HR 2.7 95%CI 2.0-3.6; p < 0.001). In those with detectable BL mGSTP1, 50% had undetectable preC3 mGSTP1 predicting > 30% fall in PSA within 3m (p < 0.001), improved TTP (HR 0.40 95%CI 0.29-0.57; p < 0.001) and improved OS (25.2 vs 13.9 m HR 0.38 95%CI 0.28-0.51; p < 0.001). On multivariable analysis including Hb, Karnofsky PS, LDH, PSA and visceral metastases, detectable preC3 mGSTP1 independently predicted shorter TTP (HR 1.9 95%CI 1.4-2.6; p < 0.001). Detectable mGSTP1at both time points independently predicted OS (BL; HR1.8 95%CI 1.2-2.8; p = 0.006 and preC3; HR 2.2 95%CI 1.6-3.0; p < 0.001). Results from the full cohort of 600 pts will be available for presentation at the meeting. Conclusions: This study should validate circulating mGSTP1 DNA as a marker of therapeutic benefit and prognosis in men with mCRPC receiving DTX and could be utilized for clinical management.

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.

Understanding the Prognostic Value of Primary Tumor Location and KRAS in Metastatic Colorectal Cancer: A Post Hoc Analysis of the OPTIMOX3 DREAM Phase III Study

2020 ◽  
Vol 19 (3) ◽  
pp. 200-208.e1 ◽  
Author(s):  
Benoist Chibaudel ◽  
Thierry André ◽  
Christophe Tournigand ◽  
Christophe Louvet ◽  
Magdalena Benetkiewicz ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Primary Tumor ◽  
Prognostic Value ◽  
Tumor Location ◽  
Phase Iii ◽  
Primary Tumor Location ◽  
Post Hoc Analysis ◽  
Phase Iii Study ◽  
Post Hoc

Impact of on-study corticosteroid use on efficacy and safety in the phase III AFFIRM study of enzalutamide (ENZA), an androgen receptor inhibitor.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 6-6 ◽  
Author(s):  
Howard I. Scher ◽  
Karim Fizazi ◽  
Fred Saad ◽  
Kim N. Chi ◽  
Mary-Ellen Taplin ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Post Hoc Analysis ◽  
Castration Resistant ◽  
Study Results ◽  
Psa Progression ◽  
Grade 3 ◽  
Post Hoc ◽  
The Impact

6 Background: ENZA increased median overall survival (OS) by 4.8 mo (P <0.001, HR 0.63) vs placebo (PBO) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) post-docetaxel in AFFIRM (HI Scher et al, NEJM 2012). Corticosteroids (CS) can activate AR signaling in nonclinical models (J Richards, Can Res 2012). In a multivariate model of AFFIRM data baseline CS use was associated with reduced OS (HI Scher et al. ESMO 2012 abstract 899PD). The impact of CS use during study treatment in AFFIRM was evaluated to test if concomitant CS use is also associated with inferior outcomes. Methods: Pts were randomized 2:1 to ENZA 160 mg/d or PBO. Pts were allowed but not required to take CS. OS was the primary endpoint. In a post-hoc analysis On-study CS use was defined as oral CS user for ≥ 1 day on study. Results: On study CS use was 48% in ENZA and 45% in PBO pts. Prognostic factors were slightly better in the no CS group compared to the CS group. Use of CS regardless of treatment was associated median OS of 11.5 mo (95% CI: 10.5, 13.0) for CS pts vs median OS NM (NM, NM) for no CS pts (HR=0.40; 95% CI: 0.33, 0.48). ENZA was consistently superior to PBO for OS, radiographic progression free survival (rPFS) and time to PSA progression (TTPP), regardless of CS use (Table). Pts on CS had higher rates of grade 3 - 4 adverse events (AE) compared to no CS pts: 63.3% vs 34.4% respectively. Conclusions: In this post-hoc analysis, on study CS use was associated with reduced OS and higher rates of grade 3 -4 AEs in mCRPC pts post-docetaxel. While CS pts had worse outcomes, ENZA was consistently superior to PBO regardless of on study CS use. The inferior outcomes in CS pts may be due to unmeasured confounders or the biologic properties of CS use itself. Clinical trial information: NCT00974311. [Table: see text]

Exploratory analysis of survival benefit and prior docetaxel (D) treatment in COU-AA-301, a phase III study of abiraterone acetate (AA) plus prednisone (P) in metastatic castration-resistant prostate cancer (mCRPC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4558-4558 ◽  
Author(s):  
Oscar B. Goodman ◽  
Kim N. Chi ◽  
Arturo Molina ◽  
Christopher Logothetis ◽  
Robert J. Jones ◽  
...  
Keyword(s):  
Abiraterone Acetate ◽  
Phase Iii ◽  
Double Blind Study ◽  
Castration Resistant Prostate Cancer ◽  
Double Blind ◽  
Survival Result ◽  
Castration Resistant ◽  
Phase Iii Study ◽  
Previously Treated ◽  
Post Hoc

4558 Background: AA, a selective androgen biosynthesis inhibitor, blocks the action of CYP17, thereby inhibiting adrenal and intratumoral androgen production. AA has demonstrated improved overall survival (OS) by 4.6 months (mos) vs placebo (HR=0.74) in patients (pts) previously treated with D. Methods: COU-AA-301 is a randomized double blind study of AA (1 g) + P (5 mg po BID) vs placebo + P administered to mCRPC pts post-D with a primary endpoint of OS. To further evaluate primary survival result robustness, we performed post hoc exploratory analyses to assess whether the timing of first and last dose of D and reason for D discontinuation impacted OS. Results: At randomization, treatment arms were balanced with respect to baseline characteristics, prior D use, and reasons for discontinuation. In both arms, almost half (45%) discontinued D due to progressive disease (PD); remainder discontinued D after completing all planned cycles (37%), due to toxicity (12%), or for other reasons (5%) per investigator. Median OS from first and last dose of D were longer with AA vs placebo (Table). Median OS was longer with AA vs placebo in pts who discontinued D for PD, or for all other reasons. Conclusions: These exploratory analyses suggest that the OS benefit of AA in mCRPC was maintained when calculated from first or last dose of prior D, and whether or not pts discontinued D for PD. Pts in AA arm of this study had a prolonged median OS of > 32 mos from time of initial D therapy. Congruity among these analyses and lack of dependence on D timing demonstrate robustness of the primary survival result. [Table: see text]

Exploratory analysis of survival benefit and prior docetaxel (D) treatment in COU-AA-301, a phase III study of abiraterone acetate (AA) plus prednisone (P) in metastatic castration-resistant prostate cancer (mCRPC).

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 15-15 ◽  
Author(s):  
Kim N. Chi ◽  
Howard I. Scher ◽  
Arturo Molina ◽  
Christopher Logothetis ◽  
Robert J. Jones ◽  
...  
Keyword(s):  
Survival Benefit ◽  
Abiraterone Acetate ◽  
Phase Iii ◽  
Double Blind Study ◽  
Castration Resistant Prostate Cancer ◽  
Double Blind ◽  
Androgen Synthesis ◽  
Survival Result ◽  
Phase Iii Study ◽  
Post Hoc

15 Background: AA, a selective androgen biosynthesis inhibitor, blocks the action of CYP17, thereby inhibiting adrenal and intratumoral androgen synthesis. AA has demonstrated improved overall survival (OS) by 4.6 months (mos) vs placebo (HR=0.74) in patients (pts) previously treated with D. Methods: COU-AA-301 is a randomized double-blind study of AA (1 g) + P (5 mg po BID) vs placebo + P administered to mCRPC pts post-D with a primary endpoint of OS. To evaluate the robustness of the primary survival results, we performed post hoc exploratory analyses to assess whether the timing of first and last dose of D and reason for D discontinuation impacted OS. Results: At the time of randomization, treatment arms were balanced with respect to baseline characteristics, prior D use, and reasons for discontinuation. In both arms, almost half (45%) discontinued D due to progressive disease (PD); the remainder discontinued D as part of planned treatment (37%), toxicity (12%), or for other reasons (5%) per investigator reporting. Median OS from first and last dose of D were longer with AA vs placebo (Table). Median OS was longer with AA vs placebo in pts who discontinued D for PD or for all other reasons. Conclusions: These exploratory analyses suggest that the survival benefit of AA in mCRPC was maintained when calculated from first or last dose of prior D, and whether or not pts discontinued D for PD. Pts in the AA arm of this study had a prolonged median OS of > 32 mos from the time of initial D therapy. Congruity among these analyses demonstrates the robustness of the primary survival result. [Table: see text]

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