Pamiparib, an investigational PARP inhibitor, in patients with metastatic castration-resistant prostate cancer (mCRPC) and a circulating tumor cell (CTC) homologous recombination deficiency (HRD) phenotype or BRCA defects: A trial in progress.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS5086-TPS5086 ◽  
Author(s):  
Simon Chowdhury ◽  
Joaquin Mateo ◽  
Mitchell Gross ◽  
Andrew J. Armstrong ◽  
Marcia Cruz-Correa ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Metastatic Disease ◽  
Parp Inhibitor ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
Disease Status ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Measurable Disease ◽  
Psa Response

TPS5086 Background: Men with mCRPC who have a BRCA1/2 mutation ( BRCA1/2mut) or mutations in other genes resulting in HRD have a poor prognosis. A novel liquid biopsy test (EPIC Sciences) identifies CTCs with an HRD phenotype. Preliminary studies showed that these men may respond to treatment with a PARP inhibitor. Pamiparib, an investigational PARP1/2 inhibitor, has shown brain penetration and potent PARP–DNA complex trapping in nonclinical studies. In early phase clinical studies (NCT02361723; NCT03333915), pamiparib was generally well tolerated and showed preliminary antitumor activity; 60 mg orally twice daily (BID) was established as the recommended investigational dose. Methods: This open-label, global, phase 2 study (NCT03712930) evaluates the antitumor activity and safety/tolerability of pamiparib in mCRPC patients (pts) with CTC-HRD, assessed by the CTC-HRD assay, or deleterious germline/somatic mutations in BRCA1/2. Patients must have progressed on/after ≥1 androgen receptor-targeted therapy, received ≥1 taxane-based therapy, and have prostate-specific antigen (PSA) progression per PCWG3 criteria. Four cohorts of pts will receive pamiparib 60 mg BID in 28-day cycles. Cohort 1 will include ~50 pts with CTC-HRD+ +/- BRCA1/2mut mCRPC with measurable metastatic disease; Cohort 2 will include ~30 pts with CTC-HRD+ +/- BRCA1/2mut mCRPC with bone-only disease; Cohorts 3 & 4 will include ~20 pts with CTC-HRD-/unk + BRCA1/2mut mCRPC with measurable metastatic disease (Cohort 3), or bone-only disease (Cohort 4). Disease status will be assessed every 8 wks for 24 wks, then every 12 wks; PSA levels will be tested every 4 wks. Co-primary endpoints are radiographic ORR assessed by IRC (pts with measurable disease) and confirmed PSA response rate per PCWG3 criteria (pts +/- measurable disease). Secondary endpoints include ORR, time to PSA response/progression, duration of PSA response, time to symptomatic skeletal event, radiographic progression-free survival, overall survival, and safety. As of 05 December 2018, this study is actively enrolling. Clinical trial information: NCT03712930.

A phase II trial in progress: Pamiparib, an investigational PARP inhibitor, in patients with metastatic castration-resistant prostate cancer and a circulating tumor cell homologous recombination deficiency (HRD) phenotype or BRCA defects.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. TPS328-TPS328
Author(s):  
Simon Chowdhury ◽  
Joaquin Mateo ◽  
Mitchell Gross ◽  
Andrew J. Armstrong ◽  
Marcia Cruz-Correa ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Antitumor Activity ◽  
Metastatic Disease ◽  
Parp Inhibitor ◽  
Specific Antigen ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Castration Resistant ◽  
Measurable Disease ◽  
Psa Response

TPS328 Background: Men with metastatic castration-resistant prostate cancer (mCRPC) who have a BRCA1/2 mutation ( BRCA1/2mut) or mutations in other HRD genes have a poor prognosis. The EPIC liquid biopsy test is a novel assay that can identify circulating tumor cells (CTC) with HRD associated phenotypes. Preliminary studies have shown that these men may respond to treatment with a PARP inhibitor. Pamiparib is an investigational PARP1/2 inhibitor that has shown brain penetration and potent PARP–DNA complex trapping in nonclinical studies. In early phase clinical studies (NCT02361723; NCT03333915), pamiparib was generally well tolerated and showed preliminary antitumor activity; 60 mg orally twice daily (BID) was established as the recommended investigational dose. Methods: This open-label, global, phase 2 study (NCT03712930) will evaluate antitumor activity and safety of pamiparib in mCRPC pts with CTC-HRD, assessed by the EPIC CTC-HRD assay, or deleterious germline/somatic BRCA1/2mut status. Patients must have progressed on/after ≥1 androgen receptor-targeted therapy, have received ≥1 taxane-based therapy, and have prostate-specific antigen (PSA) progression per PCWG3 criteria. Four cohorts of patients will receive pamiparib 60 mg BID in 28-day cycles. Cohort 1 will include ~50 pts with CTC-HRD+ +/- BRCA1/2mut mCRPC with measurable metastatic disease; Cohort 2 will include ~30 pts with CTC-HRD+ +/- BRCA1/2mut mCRPC with bone-only disease; Cohorts 3 & 4 will include ~20 pts with CTC-HRD-/unknown + BRCA1/2mut mCRPC with measurable metastatic disease (Cohort 3), or bone-only disease (Cohort 4). Disease status will be assessed every 8 wks for 24 wks, then every 12 wks; PSA levels will be tested every 4 wks. Co-primary endpoints are radiographic ORR assessed by IRC (pts with measurable disease) and confirmed PSA response rate per PCWG3 criteria (pts +/- measurable disease). Secondary endpoints include ORR, time to PSA response/progression, duration of PSA response, time to symptomatic skeletal event, radiographic progression-free survival, overall survival, and safety. Clinical trial information: NCT03712930.

TALAPRO-1: Phase II study of talazoparib (TALA) in patients (pts) with DNA damage repair alterations (DDRm) and metastatic castration-resistant prostate cancer (mCRPC).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 93-93
Author(s):  
Johann S. De Bono ◽  
Niven Mehra ◽  
Celestia S. Higano ◽  
Fred Saad ◽  
Consuelo Buttigliero ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Radiographic Progression ◽  
Parp Inhibitor ◽  
Objective Response ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
Response Duration ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Measurable Disease

93 Background: Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) show antitumor activity in mCRPC/DDRm pts treated with novel hormonal therapy (NHT). TALAPRO-1 is an open-label study evaluating TALA (a potent PARP inhibitor/trapper) in men with mCRPC/DDRm. We report a planned interim analysis (IA; Dec 2019). Updated results at a Sep 4 2020 cut-off, available in November 2020, will be presented at the meeting. Methods: TALAPRO-1 (NCT03148795) is enrolling pts (N ≈ 100) with measurable soft tissue disease, progressive mCRPC, and DDRm likely to sensitize to PARPi ( ATM, ATR, BRCA1/2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C), who received 1–2 chemotherapy regimens (≥1 taxane-based) for metastatic disease and progressed on ≥1 NHT (enzalutamide/abiraterone acetate) given for mCRPC. DDRm are defined as known/likely pathogenic variants or homozygous deletions. Pts receive oral TALA 1 mg/day (moderate renal impairment 0.75 mg/day) until radiographic progression, unacceptable toxicity, consent withdrawal, or death. Primary endpoint is objective response rate (ORR). Secondary endpoints: time to objective response; response duration; prostate-specific antigen (PSA) decrease ≥50%; circulating tumor cell (CTC) count conversion (to CTC = 0 and <5 per 7.5 mL blood); time to PSA progression; radiographic progression-free survival (rPFS); overall survival; safety. A planned efficacy/safety IA was done when 60 pts with DDRm and measurable disease completed ≥6 months of TALA/no longer followed. Radiographic responses are based on investigator assessments. Results: 113 pts received TALA (cut-off Dec 12 2019); 75 pts were evaluable for IA, with DDRm, had measurable disease, received ≥16 weeks’ treatment, and were assessed for ORR (54.7% BRCA1/2, 4.0% PALB2, 22.7% ATM; 18.7% other DDRm).All pts evaluable for IA had prior docetaxel; 45.3% cabazitaxel. Confirmed ORR, rPFS, and composite response (investigator-assessed) in pts who received TALA for ≥16 weeks are in the table. Most common treatment-emergent adverse events: anemia (42.5%); nausea (32.7%). Conclusions: TALA monotherapy has encouraging antitumor activity in docetaxel-pretreated mCRPC pts with BRCA1/2 alterations and was generally well tolerated. Funding: Pfizer Inc. Clinical trial information: NCT03148795. [Table: see text]

Phase 1b/2 keynote-365 trial: Pembrolizumab (pembro) combination therapy in metastatic castration-resistant prostate cancer (mCRPC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS5089-TPS5089 ◽  
Author(s):  
Evan Y. Yu ◽  
Haiyan Wu ◽  
Charles Schloss
Keyword(s):  
Response Rate ◽  
Parp Inhibitor ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
Abiraterone Acetate ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Eligibility Criteria ◽  
End Points ◽  
Phase 1B

TPS5089 Background: Approved treatments for mCRPC (eg, enzalutamide and docetaxel) may increase programmed death ligand 1 (PD-L1) expression and facilitate neoantigen release. In phase 1b and 1/2 trials, pembro, an anti–PD-1 antibody, has produced antitumor responses in previously treated mCRPC as monotherapy and in combination with enzalutamide. Olaparib, a PARP inhibitor, has shown activity in mCRPC with DNA-repair defects. The nonrandomized, multicohort, open-label KEYNOTE-365 study (NCT02861573) will evaluate the safety and efficacy of pembro with olaparib (cohort A), docetaxel + prednisone (cohort B), or enzalutamide (cohort C) in mCRPC. Methods: Cohort allocation depends upon prior treatment: cohort A requires prior docetaxel (treatment with 1 other chemotherapy and ≤2 second-generation hormonal manipulations is allowed); cohort B requires prior abiraterone acetate or enzalutamide (but not both); cohort C requires prior abiraterone acetate. Additional eligibility criteria include confirmed prostate adenocarcinoma, disease progression (PD) ≤6 months before screening, ongoing androgen deprivation (serum testosterone < 50 ng/dL), and provision of nonirradiated tumor sample. Pembro 200 mg will be given every 3 weeks (Q3W) with either olaparib 400 mg twice daily (cohort A), docetaxel 75 mg/m2 Q3W + prednisone 5 mg twice daily (cohort B), or enzalutamide 160 mg once daily (cohort C). Pembro treatment will continue for up to 35 cycles or until PD or unacceptable adverse events (AEs). Patients in cohort B may receive a maximum of 10 cycles of docetaxel + prednisone. Patients who discontinue 1 of 2 drugs in a combination because of a treatment-related AE may continue to receive the other drug until PD. Response will be evaluated by prostate-specific antigen (PSA) levels Q3W and by imaging Q9W for the first year and Q12W thereafter. Primary end points are safety and PSA response rate (decline of ≥50% from baseline twice ≥3 weeks apart). Secondary end points include time to PSA progression, progression-free survival, overall survival, and overall response rate. Enrollment will continue until 70 patients are enrolled for each cohort. Clinical trial information: NCT02861573.

TALAPRO-1: Phase II study of talazoparib (TALA) in patients (pts) with DNA damage repair alterations (DDRm) and metastatic castration-resistant prostate cancer (mCRPC) – updated interim analysis (IA).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5566-5566 ◽  
Author(s):  
Johann S. De Bono ◽  
Niven Mehra ◽  
Celestia S. Higano ◽  
Fred Saad ◽  
Consuelo Buttigliero ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Parp Inhibitor ◽  
Objective Response ◽  
Response Duration ◽  
Circulating Tumor Cell ◽  
Parp Inhibitors ◽  
Abiraterone Acetate ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Measurable Disease

5566 Background: PARP inhibitors (PARPi) show antitumor activity in mCRPC/DDRm pts treated with novel hormonal therapy (NHT). TALAPRO-1 is an open-label study evaluating TALA (potent PARP inhibitor/trapper) in men with mCRPC/DDRm. We report a planned IA (Dec 2019). Methods: TALAPRO-1 (NCT03148795) is enrolling pts (N ≈ 100) with measurable soft tissue disease, progressive mCRPC, and DDRm likely to sensitize to PARPi ( ATM, ATR, BRCA1/2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C), who received 1–2 chemotherapy regimens (≥1 taxane-based) for metastatic disease and progressed on ≥1 NHT (enzalutamide/abiraterone acetate) given for mCRPC. DDRm are defined as known/likely pathogenic variants or homozygous deletions. Pts receive oral TALA 1 mg/day (moderate renal impairment 0.75 mg/day) until radiographic progression, unacceptable toxicity, consent withdrawal or death. Primary endpoint is objective response rate (ORR). Secondary endpoints: time to OR; response duration; PSA decrease ≥50%; circulating tumor cell (CTC) count conversion (to CTC = 0 and <5 per 7.5 mL blood); time to PSA progression; radiographic PFS (rPFS); overall survival; safety. A planned efficacy/safety IA was done when 60 pts with DDRm and measurable disease completed ≥6 months of TALA/no longer followed (DDR population [DDRp]). Radiographic responses are based on investigator assessments. Results: 113 pts received TALA (cutoff Dec 12, 2019); 75 pts were DDRp, had measurable disease, received ≥16 wk treatment, and were evaluable for ORR (54.7% BRCA1/2, 4.0% PALB2, 22.7% ATM; 18.7% other DDRm).All DDRp pts had prior docetaxel; 45.3% cabazitaxel. Confirmed ORR, rPFS, and composite response (investigator-assessed) in pts who received TALA for ≥16 weeks are in the table. Most common treatment-emergent adverse events: anemia (42.5%); nausea (32.7%). Conclusions: TALA monotherapy has encouraging antitumor activity in docetaxel-pretreated mCRPC pts with BRCA1/2 alterations and was generally well tolerated. Clinical trial information: NCT03148795 . [Table: see text]

scholarly journals Combined CTLA-4 and PD-L1 blockade in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer is associated with increased myeloid and neutrophil immune subsets in the bone microenvironment

2021 ◽  
Vol 9 (10) ◽  
pp. e002919
Author(s):  
Sumit K Subudhi ◽  
Bilal A Siddiqui ◽  
Ana M Aparicio ◽  
Shalini S Yadav ◽  
Sreyashi Basu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Adverse Events ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
Immune Checkpoints ◽  
Castration Resistant Prostate Cancer ◽  
Bone Microenvironment ◽  
Castration Resistant ◽  
Number Of Patients ◽  
Measurable Disease

BackgroundImmune checkpoint therapy (ICT) has low response rates in patients with metastatic castration-resistant prostate cancer (mCRPC), in part due to few T cells in the tumor microenvironment (TME). Anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) promotes intratumoral T cell infiltration but induces upregulation of PD-1 and programmed death ligand-1 (PD-L1) within the prostate TME. Combined anti-CTLA-4 plus anti-PD-1 can partly overcome this adaptive resistance and was recently shown to augment responses in patients with mCRPC with measurable disease. Although bone is the most common site of metastasis in prostate cancer, patients with bone-predominant disease are frequently excluded from trials because they lack measurable disease, which limits assessment of disease progression and tissue sampling. We therefore designed this study to investigate combined ICT in mCRPC to bone.HypothesisCombined anti-CTLA-4 (tremelimumab) plus anti-PD-L1 (durvalumab) is safe and well tolerated in patients with chemotherapy-naïve mCRPC to bone.Patients and methodsIn this single-arm pilot study, men with chemotherapy-naïve mCRPC to bone received tremelimumab (75 mg intravenous) plus durvalumab (1500 mg intravenous) every 4 weeks (up to four doses), followed by durvalumab (1500 mg intravenous) maintenance every 4 weeks (up to nine doses). The primary endpoint was incidence of adverse events. Secondary endpoints included serum prostate-specific antigen (PSA), progression-free survival (PFS), radiographic PFS (rPFS), and maximal PSA decline.ResultsTwenty-six patients were treated between August 8, 2017 and March 28, 2019. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 11 patients (42%), with no grade 4 or 5 events. TRAEs leading to discontinuation occurred in three patients (12%). PSA decline ≥50% occurred in three patients (12%). Six patients (24%) achieved stable disease for >6 months. At a median follow-up of 43.6 months, median rPFS was 3.7 months (95% CI: 1.9 to 5.7), and median overall survival was 28.1 months (95% CI: 14.5 to 37.3). Post-treatment evaluation of the bone microenvironment revealed transcriptional upregulation in myeloid and neutrophil immune subset signatures and increased expression of inhibitory immune checkpoints.ConclusionsTremelimumab plus durvalumab was safe and well tolerated in patients with chemotherapy-naïve mCRPC to bone, with potential activity in a small number of patients as measured by rPFS. Combination of CTLA-4 and PD-L1 blockade with therapies targeting the myeloid compartment or other inhibitory immune receptors may be necessary to overcome mechanisms of resistance within prostate bone microenvironment.Trial registration numberNCT03204812.

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.

Safety, efficacy, and pharmacodynamics of the investigational agent orteronel (TAK-700) in metastatic castration-resistant prostate cancer (mCRPC): Updated data from a phase I/II study.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 98-98 ◽  
Author(s):  
David B. Agus ◽  
Walter Michael Stadler ◽  
Daniel H. Shevrin ◽  
Lowell Hart ◽  
Gary R. MacVicar ◽  
...  
Keyword(s):  
Phase 1 ◽  
Specific Antigen ◽  
Response Rates ◽  
Similar Efficacy ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Investigational Agent ◽  
Psa Response

98 Background: The investigational agent orteronel (TAK-700) is a selective 17,20 lyase inhibitor that down regulates androgenic steroid production in vitro and in vivo. Since phase 1 data in patients (pts) with mCRPC were promising, this open-label, multicenter study was expanded to gather additional data on safety and antitumor activity. Methods: The phase 2 portion of this study included four additional dose cohorts. Pts had no prior chemotherapy, and had baseline testosterone <50 ng/dL and prostate-specific antigen (PSA) ≥5 ng/mL. Results: 97 pts received orteronel 300 mg BID (n=23), 400 mg BID + prednisone 5 mg BID (n=24), 600 mg BID + prednisone (n=26), or 600 mg QD (n=24). At data cut-off (23 May 2011), 62% of pts had withdrawn (including 19% due to AEs and 19% for disease progression [PD]). Most common AEs were fatigue (76%), nausea (47%), and constipation (38%); most common grade ≥3 AEs were fatigue (12%) and hypokalaemia (8%). PSA response rates (≥50% decrease) at 12 wks were 63%, 50%, 41%, and 60% in the 300 mg BID, 400 and 600 mg BID + prednisone, and 600 mg QD groups. Of 51 RECIST-evaluable pts, 10 had partial responses (of which 5 confirmed), 22 stable disease, and 15 PD. At 12 wks, median testosterone decreased from baseline in all groups: (ng/dL, 12 wks/baseline) 0.98/8.50 (300 mg BID), 0.30/9.90 (400 mg BID +prednisone), 0.07/7.33 (600 mg BID + prednisone), 0.49/6.31 (600 mg QD). Similarly, at 12 wks, median dehydroepiandrosterone sulfate (DHEA-S) decreased from baseline in all groups: (µg/dL, 12 wks/baseline) 8.65/53.0 (300 mg BID), 0.10/36.3 (400 mg BID + prednisone), 0.10/51.7 (600 mg BID + prednisone), 5.30/31.5 (600 mg QD). Overall, mean circulating tumor cell numbers decreased from 16.6 (per 7.5mL blood) at baseline to 3.9 at 12 wks. Conclusions: Orteronel ≥300 mg BID appears active and well tolerated in pts with mCRPC, with similar efficacy ± prednisone. PSA response rates suggest that testosterone, rather than DHEA, may be a more reliable marker of lyase inhibition efficacy. Preclinical data and changes in pharmacodynamic parameters in this study suggest partially selective 17,20 lyase inhibition. Final data will be reported.

First-line use of cabazitaxel in chemotherapy-naive patients with metastatic castration-resistant prostate cancer (mCRPC): A three-arm study in comparison with docetaxel.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS4696-TPS4696
Author(s):  
Stephane Oudard ◽  
Lisa Sengelov ◽  
Paul N. Mainwaring ◽  
Antoine Thiery- Vuillemin ◽  
Christine Theodore ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Standard Of Care ◽  
Phase Iii ◽  
Clinical Activity ◽  
Castration Resistant Prostate Cancer ◽  
First Line ◽  
Current Standard ◽  
Open Label ◽  
Measurable Disease ◽  
Ecog Ps

TPS4696^ Background: Docetaxel (D) in combination with prednisone (P) as first-line (1L) chemotherapy in patients (pts) with mCRPC is the current standard of care. However, treatment is not curative and D-resistant disease typically develops. Cabazitaxel (Cbz) is a novel taxane active in D-sensitive and -resistant tumor models. Clinical activity of Cbz plus P (CbzP) was demonstrated in the Phase III TROPIC study in mCRPC pts previously treated with a D-containing regimen; CbzP showed a significant overall survival (OS) benefit vs mitoxantrone plus prednisone (median OS 15.1 vs 12.7 months; HR 0.70; P < 0.0001). Therefore, it is of interest to determine if CbzP provides an OS advantage vs DP in 1L mCRPC pts. Methods: The phase III FIRSTANA study (NCT01308567) is a randomized, open-label, multinational trial in 1L mCRPC pts, designed to compare the efficacy of Cbz 25 mg/m² IV Q3W (Arm A) and Cbz 20 mg/m² IV Q3W (Arm B) vs D 75 mg/m2 IV Q3W (Arm C). P 10 mg PO QD is to be given concomitantly. Pts are stratified by ECOG PS (0–1 vs 2), measurable disease (yes/no) and region (depending on availability of Cbz as 2L). Pts with ECOG PS ≤ 2, histologically/cytologically confirmed metastatic prostate adenocarcinoma, with no prior chemotherapy and with disease progression following medical or surgical castration are eligible. The primary endpoint is OS. Secondary endpoints include progression-free survival (PFS) (PCWG2 criteria), radiologic PFS, tumor response in measurable disease (RECIST 1.1), PSA response and PSA PFS, pain response and pain PFS, time to occurrence of any skeletal-related events, safety profile and health-related quality of life. Cbz pharmacokinetics and pharmacogenomics will be assessed in pt subgroups. Pts will be treated until progression, unacceptable toxicity or pt request. Planned enrollment is 1,170 pts; study size was calculated to achieve 90% power for OS. Study start was in May 2011; at January 2012, 219 pts were enrolled. The first DMC meeting recommended continuing the study without change.

Prospective evaluation of low-dose ketoconazole plus hydrocortisone (HC) in chemotherapy-pretreated castration-resistant prostate cancer (CRPC) patients.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 227-227
Author(s):  
Ernest N. Lo ◽  
Laurel A. Beckett ◽  
Chong-xian Pan ◽  
Daniel Robles ◽  
Jennifer Marie Suga ◽  
...  
Keyword(s):  
Stable Disease ◽  
Low Dose ◽  
Response Rate ◽  
Randomized Study ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
Published Data ◽  
Castration Resistant Prostate Cancer ◽  
Psa Response ◽  
Grade 3

227 Background: Ketoconazole (keto), a known CYP17 inhibitor, is a traditional systemic treatment for CRPC. However, most of the published data has been in the pre-chemo setting; its efficacy in the post-chemo setting has not been as widely reported. Chemo-naive patients treated with attenuated doses of keto (200-300 mg TID) had prostate specific antigen (PSA) response rate (> 50% decline) ranges from 21%-62% and treatment was well tolerated. We hypothesized that low dose keto would likewise possess efficacy and tolerability in the CRPC post-chemo state. Methods: CRPC patients with ECOG PS 0-3, adequate end organ function, who had received at least one chemo were treated with low-dose keto (200 mg PO TID) and HC (20 mg PO q AM and 10 mg PO q PM) until progression, as defined by either RECIST or PSA rise > 50% from nadir or baseline. Primary endpoint was PSA response rate (> 50% reduction from baseline). A Simon minimax design was used. PSA response of > 25% was to be considered promising for further study (versus null rate of < 5%); 25 patients were required. Secondary endpoints included PSA response > 30%, progression-free survival (PFS), duration of stable disease, and evaluation of adverse events (AE). Results: 29 patients were accrued: median age was 71 (range 55-86) and median pretreatment PSA was 76 ng/mL (range 7-11,420 ng/ml); all had prior docetaxel-based chemotherapy. 28 patients were evaluable for response; all were evaluable for toxicity. PSA response of >50% was seen in 48% of patients and 59% of patients had a PSA response of > 30%. Median PFS was 138 days; median duration of stable disease was 123 days. 12 patients had grade 3 or 4 toxicity on treatment. Of the 17 grade 3 AEs, only 3 were considered ‘probably’ or ‘possibly’ related to treatment, while none of the 2 grade 4 AEs were considered related to treatment. Conclusions: In docetaxel pre-treated CRPC patients, low-dose keto + HC is a well-tolerated, relatively inexpensive and clinically active treatment option. PSA response with low-dose keto appears comparable to that of abiraterone in this patient context. A prospective randomized study of available post-chemo options is needed to assess comparative efficacy. Clinical trial information: NCT00895310.

Updated analysis of progression-free survival with first subsequent therapy (PFS2) and safety in the SPARTAN study of apalutamide (APA) in patients (pts) with high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC).

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 144-144 ◽  
Author(s):  
Eric Jay Small ◽  
Fred Saad ◽  
Simon Chowdhury ◽  
Stephane Oudard ◽  
Boris A. Hadaschik ◽  
...  
Keyword(s):  
High Risk ◽  
Distant Metastasis ◽  
Treatment Duration ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
Significant Benefit ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Free Survival

144 Background: In the phase 3 SPARTAN study, compared with placebo (PBO), APA, a next-generation androgen receptor inhibitor, decreased the risk of distant metastasis or death by 72% (hazard ratio [HR], 0.28; p < 0.0001) in men with high-risk nmCRPC. After 1 year of additional follow-up, PFS2 and safety were reevaluated to ensure maintenance of benefit against potential harm. Methods: Pts with nmCRPC and prostate-specific antigen doubling time of ≤ 10 mos were randomized 2:1 to APA (240 mg QD) + androgen deprivation therapy (ADT) or PBO + ADT. All pts who developed distant metastasis, determined by blinded independent central review, were eligible to receive subsequent therapy including open-label treatment with abiraterone acetate + prednisone, provided by the sponsor. The exploratory PFS2 end point (time from randomization to disease progression on subsequent anticancer therapy or death) was evaluated, as was incidence of treatment-emergent adverse events (TEAEs). Results: Median treatment duration with APA was 25.7 mos; with PBO, 11.5 mos (original analysis, mos: APA, 19.2; PBO, 11.2). Pts randomized to APA continued to show significant benefit in PFS2 (HR, 0.5; 95% CI, 0.39-0.63; p < 0.0001) vs PBO (APA median time to PFS2 not reached vs PBO 39.3 mos). At a median follow-up of 32 mos, 51.3% of pts receiving APA, 8% of the 75 pts who crossed over from PBO to APA, and 99.7% of remaining PBO pts had discontinued study treatment. Rates of discontinuations due to progressive disease and AEs were 27.3% and 12.7%, respectively, in the APA group and 73.4% and 8.4% in the PBO group. There was no substantial change in the incidence of TEAEs in the APA group at the 1-year update. With regard to drug specific TEAEs, there were no grade 4 or 5 events; grade 3 TEAEs consisted of rash, 5.2%; falls, 2.4%; fractures, 3.1%; hypothyroidism, 0%; and seizures, 0%. Conclusions: APA was previously shown to result in an improvement in metastasis-free survival and symptomatic progression. With a median APA treatment duration of 25.7 mos, APA continues to show significant benefit in PFS2, and its safety profile remains unchanged. Clinical trial information: NCT01946204.

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