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]

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.

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]

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: A phase II study of talazoparib (TALA) in men with DNA damage repair mutations (DDRmut) and metastatic castration-resistant prostate cancer (mCRPC)—First interim analysis (IA).

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 119-119 ◽  
Author(s):  
Johann S. De Bono ◽  
Niven Mehra ◽  
Celestia S. Higano ◽  
Fred Saad ◽  
Consuelo Buttigliero ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Primary Endpoint ◽  
Radiographic Progression ◽  
Objective Response ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
Circulating Tumor Cell ◽  
Abiraterone Acetate ◽  
Phase 2 ◽  
Castration Resistant Prostate Cancer

119 Background: Phase 2 and 3 studies with poly(ADP-ribose) polymerase inhibitors (PARPi) have demonstrated antitumor activity in patients (pts) with mCRPC with DDRmut who were previously treated with novel hormonal therapy (NHT). We report the first IA of a Phase 2 study of TALA, a potent inhibitor and trapper of PARP. Methods: TALAPRO-1 (NCT03148795) is enrolling pts (N ≈ 100) with measurable soft tissue disease, progressive mCRPC, and DDRmut likely to sensitize to PARPi (including ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C), who received 1–2 chemotherapy regimens (≥1 taxane-based) and progressed on ≥1 NHT (enzalutamide/abiraterone acetate). Pts receive oral TALA 1 mg/d (moderate renal impairment, 0.75 mg/d) until radiographic progression, unacceptable toxicity, or consent withdrawal. Primary endpoint is objective response rate (ORR; blinded independent review). Secondary endpoints are time to OR, duration of response, prostate-specific antigen (PSA) decrease ≥50%, circulating tumor cell (CTC) count conversion (to CTC = 0 and <5 per 7.5 mL of blood), time to PSA progression, radiographic progression-free survival (rPFS), overall survival, safety, pt-reported outcomes, and pharmacokinetics. A planned IA of safety and efficacy was performed after 20 pts with BRCA1/2 mutations were on treatment for ≥8 wks. Results: 81 pts received TALA as of June 5, 2019; 43 pts enrolled by Feb 12, 2019 were evaluable for the primary endpoint (20 BRCA1/2, 2 PALB2, 14 ATM, 7 other). All had received docetaxel and 49% prior cabazitaxel. Overall ORR (95% CI) was 25.6% (13.5–41.2), ORRBRCA1/2 50.0% (27.2–72.8), ORRATM 7.1% (0.2–33.9). Overall median (95% CI) rPFS was 5.6 months (mo) (3.5–8.2), rPFSBRCA1/2 8.2 mo (5.6–NE), rPFSATM 3.5 mo (1.7–8.1). Most common treatment-emergent adverse events (≥20%) were anemia, nausea, asthenia, decreased appetite, constipation, and platelet count decreased. Conclusions: TALA monotherapy demonstrates encouraging antitumor activity in docetaxel-pretreated mCRPC pts, especially those with BRCA1/2mut, and was generally well tolerated. This study was sponsored by Pfizer Inc. Clinical trial information: NCT03148795.

Randomized phase II study of olaparib with or without cediranib in men with metastatic castration-resistant prostate cancer (mCRPC).

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 111-111 ◽  
Author(s):  
Joseph W. Kim ◽  
Rana R. McKay ◽  
Mary-Ellen Taplin ◽  
Nancy B. Davis ◽  
Paul Monk ◽  
...  
Keyword(s):  
Dna Repair ◽  
Radiographic Progression ◽  
Kinase Inhibitor ◽  
Parp Inhibitor ◽  
Objective Response ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Castration Resistant Prostate Cancer ◽  
Tumor Biopsy

111 Background: Cediranib, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, suppresses expression of BRCA1, BRCA2, and RAD51 and increases sensitivity of tumors to poly (ADP-ribose) polymerase (PARP) inhibitors in vitro. Olaparib, a PARP inhibitor, demonstrates clinical efficacy in men with DNA repair deficient, mCRPC. We therefore performed a randomized phase 2 trial comparing olaparib with or without cediranib in men with mCRPC. Methods: Men with a minimum of one prior line of systemic therapy for mCRPC were randomized 1:1 to receive cediranib 30mg po daily plus olaparib 200mg po BID (Arm A) or olaparib 300mg BID alone (Arm B). At radiographic progression, patients (pts) in Arm B could crossover to Arm A. The primary endpoint was radiographic progression-free survival (rPFS). Secondary endpoints were objective response rate (ORR) and PSA50 decline rate (PSA50). Tumor biopsy specimens were obtained for biomarker analyses pre- and on-treatment. Results: Baseline characteristics of the 90 pts enrolled are summarized below. The median rPFS was 11.1 versus 4.0 months in Arm A and Arm B, respectively (Hazard Ratio 0.54, 95% CI 0.317, 0.928, p=0.026). Trends toward a higher ORR (19% and 12%), Disease Control Rate (Stable Disease + Partial Response) (77% and 64%,) and PSA50 (29% and 17%) were observed in Arm A compared to Arm B, respectively. Thirteen pts in Arm B crossed over to Arm A. One pt had a PR after crossover. Grade 3/4 adverse events (G3/4 AEs), irrespective of attribution, occurred in 77% and 58% of Arm A and Arm B pts, respectively. G3/4 AEs occurring in >10% of pts were hypertension (32%), fatigue (23%) and diarrhea (11%) in Arm A, and anemia (16%) and lymphopenia (11%) in Arm B. Conclusions: The cediranib/olaparib combination significantly improves rPFS in unselected, mCRPC pts. AEs were manageable. Analyses of mutation status in homologous recombination DNA repair genes are pending and will be key in interpreting the data. Clinical trial information: NCT02893917. [Table: see text]

CheckMate 9KD cohort A1 final analysis: Nivolumab (NIVO) + rucaparib for post-chemotherapy (CT) metastatic castration-resistant prostate cancer (mCRPC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5044-5044
Author(s):  
Russell Kent Pachynski ◽  
Margitta Retz ◽  
Jeffrey C. Goh ◽  
Mauricio Burotto ◽  
Gwenaelle Gravis ◽  
...  
Keyword(s):  
Dna Damage ◽  
Response Rate ◽  
Parp Inhibitor ◽  
Objective Response ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
Parp Inhibition ◽  
Castration Resistant Prostate Cancer ◽  
Immune Priming

5044 Background: CheckMate 9KD is a phase 2 trial of NIVO (anti-PD-1) combined with either rucaparib, docetaxel, or enzalutamide for mCRPC. PARP inhibitors, like rucaparib, increase cellular DNA damage, particularly in tumors with DNA repair defects, leading to genomic instability and cell death. This DNA damage promotes immune priming and adaptive PD-L1 upregulation. Consequently, dual PD-(L)1 and PARP inhibition is a plausible therapeutic strategy for mCRPC. We report final results for cohort A1 (NIVO + rucaparib for post-CT mCRPC) of CheckMate 9KD. Methods: Cohort A1 enrolled patients (pts) with post-CT mCRPC (1–2 prior taxane regimens), ongoing ADT, ≤ 2 prior novel hormonal therapies (abiraterone, enzalutamide, etc) for mCRPC, and no prior PARP inhibitor treatment. Pts received NIVO 480 mg Q4W + rucaparib 600 mg BID until disease progression/unacceptable toxicity (NIVO dosing limited to 2 yrs). Coprimary endpoints: objective response rate (ORR) per PCWG3 criteria and prostate-specific antigen response rate (PSA-RR; ≥ 50% PSA reduction) in all treated pts and pts with homologous recombination deficiency positive (HRD+) tumors, determined before enrollment. Secondary endpoints included radiographic progression-free survival (rPFS), overall survival (OS), and safety. Results: Of 88 treated pts, median age 66 yrs (range, 46–85), 34.1% had visceral metastases and 65.9% had measurable disease. Median follow-up was 11.9 mo. Pts had a median of 4.5 NIVO doses and 3.8 mo of rucaparib. The table summarizes primary and key secondary efficacy results, and shows better outcomes for HRD+ vs HRD–/not evaluable (NE) tumors. In pts with BRCA2 mutations, confirmed ORR was 37.5% (3/8 pts) and confirmed PSA-RR was 45.5% (5/11 pts). Any-grade treatment-related AEs (TRAEs) occurred in 93.2% of pts, most commonly nausea (40.9%) and fatigue (33.0%). Grade ≥ 3 TRAEs occurred in 54.5% of pts, most commonly anemia (20.5%) and neutropenia (10.2%). TRAEs led to discontinuation in 27.3% of pts. One pt had a stroke, considered related to rucaparib by the investigator, after 28 days on rucaparib and 2 NIVO doses and died 2 months later due to post-thrombolysis hematoma. Conclusions: NIVO + rucaparib is active in pts with HRD+ post-CT mCRPC, although the trial design and short follow-up limit assessment of benefits of the combination vs individual components. Pts with HRD– tumors did not appear to benefit from either drug. No new safety signals were observed with NIVO + rucaparib. Additional biomarker analyses are ongoing. Clinical trial information: NCT03338790. [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.

A multicenter, randomized, controlled phase II study: Efficacy and safety of PSMA-targeted radioligand therapy I-131-1095 (1095) plus enzalutamide (enza) in 18F-DCFPyL PSMA scan avid, metastatic castration-resistant prostate cancer (mCRPC) patients post-abiraterone (abi) progression (ARROW).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. TPS187-TPS187
Author(s):  
A. Oliver Sartor ◽  
David Laidley ◽  
Frederic Pouliot ◽  
Stephan Probst ◽  
Robert Sabbagh ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Radiographic Progression ◽  
Objective Response ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Castration Resistant Prostate Cancer ◽  
Radioligand Therapy ◽  
Open Label ◽  
Recist 1.1 ◽  
Modified Recist

TPS187 Background: PSMA is a transmembrane glycoprotein overexpressed in prostate cancer (PC) and further upregulated in castrate resistant disease. 1095 is a novel PSMA-targeted small molecule radioligand therapeutic that binds to the extracellular domain of PSMA selectively with high affinity, internalized, and delivers a targeted lethal radiation dose to PC cells. 18F-DCFPyL is a novel PSMA-targeted PET imaging agent that has shown robust diagnostic performance for detecting recurrent and metastatic PC. In the ARROW study, pts must demonstrate 18F-DCFPyL avidity prior to 1095 treatment. Methods: ARROW is an open-label, randomized (2:1) trial of enza plus 1095 or enza alone in pts with progressive mCRPC who previously received abi. ~120 pts (80: 1095 + enza; 40: enza alone) will be treated at multiple sites in the US and Canada. Eligible male pts must have metastatic disease documented by bone scan or soft tissue lesions measurable per RECIST 1.1 on CT/MRI, be PSMA-avid as determined by 18F-DCFPyL PET/CT, have evidence of biochemical or radiographic progression on abi, and be ineligible for or refuse to receive chemotherapy. Pts will receive enza (prescribed per approved labeling) with or without 1095 (100 mCi dose, followed by up to 3 additional doses administered at least 8 weeks apart, as determined by dosimetry evaluation and occurrence of dose-limiting events). The primary objective is to determine the efficacy of 1095 plus enza compared to enza alone, based on PSA response (confirmed PSA decline ≥50%) rate according to Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria. Additional objectives include objective response rate based on PCWG3-modified RECIST 1.1, progression-free survival (PFS) defined as the first occurrence of radiographic progression (PCWG3-modified RECIST 1.1), unequivocal clinical progression, or death from any cause, duration of response, overall survival, and the safety and tolerability of 1095 radioligand therapy. Due to the COVID-19 pandemic, enrollment was halted in April 2020 but is reopening in October 2020. Clinical trial information: NCT03939689.

TALAPRO-1: An open-label, response rate phase II study of talazoparib (TALA) in men with DNA damage repair (DDR) defects and metastatic castration-resistant prostate cancer (mCRPC) who previously received taxane-based chemotherapy (CT) and progressed on greater than or equal to one novel hormonal therapy (NHT).

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. TPS342-TPS342 ◽  
Author(s):  
Johann S. De Bono ◽  
Celestia S. Higano ◽  
Fred Saad ◽  
Kurt Miller ◽  
Hsiang-Chun Chen ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Radiographic Progression ◽  
Performance Status ◽  
Objective Response ◽  
Specific Antigen ◽  
Tissue Response ◽  
Parp Inhibition ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Efficacy Analysis

TPS342 Background: There are no approved therapies for mCRPC that has progressed on taxane and NHT. Preclinical studies showed that DDR-positive prostate tumors may be sensitized to PARP inhibition. TALA inhibits PARP, causing cell death in BRCA1/2-mutated cells. Methods: This study (NCT03148795) is enrolling patients (pts) (N ≈ 100) with measurable soft tissue disease per RECIST v1.1, progressive mCRPC, DDR likely to sensitize to PARP inhibition, ECOG performance status ≤ 2, and no brain metastases, who received 1-2 CT regimens (including ≥ 1 taxane-based CT) and progressed on ≥ 1 NHT (enzalutamide/abiraterone acetate). Prior use of PARP inhibitors, cyclophosphamide, mitoxantrone, or platinum-based CT ≤ 6 mos before study or progression on a platinum-based CT at any time are excluded. Pts will receive TALA 1 mg/d orally (pts with moderate renal impairment, 0.75 mg/d) until radiographic progression, unacceptable toxicity, or withdrawal of consent. TALA should not be discontinued based on increased prostate specific antigen (PSA) or circulating tumor cell (CTC) count alone. Primary endpoint is best objective response (OR) rate (complete/partial soft tissue response; exact 2-sided 95% confidence interval). Responses must be confirmed ≥ 4 wks later by computed tomography/magnetic resonance imaging with no evidence of bone progression ≥ 6 wks later per PCWG3 criteria. Secondary endpoints include time to OR, duration of response, PSA decrease ≥ 50%, CTC count conversion (to CTC = 0 and < 5 per 7.5 mL of blood), time to PSA progression, radiographic progression-free survival, overall survival, safety, pt-reported outcomes, and pharmacokinetics of TALA. Efficacy will be assessed every 8 wks for the first 24 wks, then every 12 wks thereafter. An initial safety and efficacy analysis will be performed on 20 pts after ≥ 8 wks of treatment. An interim efficacy analysis is planned when 60 pts have completed ≥ 6 mos of treatment. This study was sponsored by Pfizer Inc. Previously presented at ESMO 2018, FPN 859TiP, De Bono JS et al. Reused with permission. Clinical trial information: NCT03148795.

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.

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