Trial Outcomes & Findings for Javelin Parp Medley: Avelumab Plus Talazoparib In Locally Advanced Or Metastatic Solid Tumors (NCT NCT03330405)

The study was conducted in 2 phases: Phase 1b (talazoparib dose level cohorts) and Phase 2 (expansion phase). The Phase 1b study design started at the highest dose of talazoparib (1 mg QD), to be de-escalated to 0.75 and 0.5 mg QD. With DLT rate \<33% among 12 DLT-evaluable patients treated at 1 mg, Phase 2 started. The 2 cohorts at lower dose did not enroll any participants and are not displayed in the results. Only the Phase 1b cohort "Avelumab 800 mg Q2W + Talazoparib 1 mg QD" is displayed.

Phase 1b: 12 participants were enrolled and assigned to study treatment. Phase 2: 211 participants were enrolled and assigned to study treatment.

Javelin Parp Medley: Avelumab Plus Talazoparib In Locally Advanced Or Metastatic Solid Tumors

DLTs=occurrence of any of the following AEs attributable to any study treatment in Cycle 1:Hematologic: grade(G)4 neutropenia lasting \>5 days (absolute neutrophil count \[ANC\]\< 0.5\*10\^9/L); febrile neutropenia; neutropenic infection (ANC\<1.0\*10\^9/L, and G\>3 infection); G\>=3 thrombocytopenia (platelet count \[PC\] \<50.0\*10\^9/L) with bleeding; G4 thrombocytopenia (PC\<25.0\*10\^9/L); G4 anemia (life-threatening; urgent intervention indicated). Non-hematologic: G\>=3 toxicities unless predefined in the protocol; potential Hy's law cases. Non-adherence to treatment schedule: failure to deliver at least 75% of the planned doses of talazoparib during the first cycle of treatment due to treatment-related toxicities; G3 non-hematologic toxicity that delayed administration of either study drug for more than 2 weeks. Dose reductions: any adverse event (AE) that resulted in a dose reduction of talazoparib.

This outcome measure (OM) is reported for participants with solid tumors except mCRPC; for those participants, OR was defined as a complete response (CR) or partial response (PR) per Response Evaluation Criteria In Solid Tumors (RECIST) version(v) 1.1 by investigator. CR: Complete disappearance of all target and non-target lesions with the exception of nodal disease; all target and non-target nodes must decrease to normal size (short axis \<10 mm); all lesions must be assessed. PR: Greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions; all target lesions must be assessed. Non-target PR lesions must be non-progressive disease (PD), where PD is unequivocal progression of pre-existing lesions.

This OM is reported for participants with mCRPC; for those participants, OR was defined as the proportion of participants with a best overall soft tissue response of CR or PR per RECIST v1.1 and with no evidence of confirmed bone disease progression per PCWG3 criteria by investigator. CR: Complete disappearance of all target and non-target lesions with the exception of nodal disease; all target and non-target nodes must decrease to normal size (short axis \<10 mm); all lesions must be assessed. PR: Greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions; all target lesions must be assessed. Non-target PR lesions must be non-PD.

Adverse event (AE) was any untoward medical occurrence in a participant who received any study drug without regard to possibility of causal relationship. TEAEs were those events with onset dates occurring during the on-treatment period. On-treatment period was defined as time from first dose of any study treatment and up to 30 days after last dose or start day of new anti-cancer drug therapy minus 1 day, whichever occurred first. Treatment-related AEs were those related to any study drug (ie, at least one of the study drugs).

AE was any untoward medical occurrence in a participant who received any study drug without regard to possibility of causal relationship. TEAEs were those events with onset dates occurring during the on-treatment period. On-treatment period was defined as time from first dose of any study treatment and up to 30 days after last dose or start day of new anti-cancer drug therapy minus 1 day, whichever occurred first. TEAEs were graded by the investigator using National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) v 4.03 as Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death. In this outcome measure, number of participants with Grade 3 or higher TEAEs were reported.

TEAEs were those events with onset dates occurring during the on-treatment period. On-treatment period was defined as time from first dose of any study treatment and up to 30 days after last dose or start day of new anti-cancer drug therapy minus 1 day, whichever occurred first. Treatment-related AEs were those related to any study drug (ie, at least one of the study drugs). A serious TEAE was any untoward medical occurrence that at any dose resulted in any of following outcomes/considered to be an important medical event: death; life-threatening experience (immediate risk of death); required inpatient hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions); congenital anomaly/birth defect.

Either study drug = avelumab only or talazoparib only. TEAEs were those events with onset dates occurring during the on-treatment period. On-treatment period was defined as time from first dose of any study treatment and up to 30 days after last dose or start day of new anti-cancer drug therapy minus 1 day, whichever occurred first. Treatment-related AEs were those related to any study drug (ie, at least one of the study drugs).

All study drugs = all study drugs in the combination. TEAEs were those events with onset dates occurring during the on-treatment period. On-treatment period was defined as time from first dose of any study treatment and up to 30 days after last dose or start day of new anti-cancer drug therapy minus 1 day, whichever occurred first. Treatment-related AEs were those related to any study drug (ie, at least one of the study drugs).

TEAEs were those events with onset dates occurring during the on-treatment period. On-treatment period was defined as time from first dose of any study treatment and up to 30 days after last dose or start day of new anti-cancer drug therapy minus 1 day, whichever occurred first.

The number of participants with newly occurring or worsening hematology abnormalities during the on-treatment period were summarized by worst grade on-treatment. On-treatment period was defined as time from first dose of any study treatment and up to 30 days after last dose or start day of new anti-cancer drug therapy minus 1 day, whichever occurred first. NCI-CTCAE criteria version 4.03 is used. As per NCI CTCAE toxicity grading v4.03, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death.

The number of participants with newly occurring or worsening hematology abnormalities during the on-treatment period were summarized by worst grade on-treatment. On-treatment period was defined as time from first dose of any study treatment and up to 30 days after last dose or start day of new anti-cancer drug therapy minus 1 day, whichever occurred first. NCI-CTCAE criteria version 4.03 is used. As per NCI CTCAE toxicity grading v4.03, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death.

The number of participants with newly occurring or worsening chemistry abnormalities during the on-treatment period were summarized by worst grade on-treatment. On-treatment period was defined as time from first dose of any study treatment and up to 30 days after last dose or start day of new anti-cancer drug therapy minus 1 day, whichever occurred first. NCI-CTCAE criteria version 4.03 is used. As per NCI CTCAE toxicity grading v4.03, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death.

The number of participants with newly occurring or worsening chemistry abnormalities during the on-treatment period were summarized by worst grade on-treatment. On-treatment period was defined as time from first dose of any study treatment and up to 30 days after last dose or start day of new anti-cancer drug therapy minus 1 day, whichever occurred first. NCI-CTCAE criteria version 4.03 is used. As per NCI CTCAE toxicity grading v4.03, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death.

Pharmacokinetics (PK) data analyses included descriptive summary statistics of the pre-dose/Ctrough concentrations for both investigational products and post-dose (for talazoparib) or Cmax concentrations (for avelumab) for each cycle.

Pharmacokinetics (PK) data analyses included descriptive summary statistics of the pre-dose/Ctrough concentrations for both investigational products and post-dose (for talazoparib) or Cmax concentrations (for avelumab) for each cycle. Cmax=maximum concentration. Ctrough=trough concentration. Participants with moderate renal impairment were started at a lower, 0.75 mg QD, dose to compensate for decreased talazoparib clearance.

Immunogenicity blood samples were assayed for ADA using a validated assay. The sample analysis followed a tiered approach of screening, confirmation, and titer determination. Samples tested positive for ADA were further analyzed for neutralizing antibodies (Nab) using a validated assay. Baseline was defined as the last assessment prior to the date/time of the first dose of avelumab. N0, N1, N2, and N3=Number of participants with at least 1 valid ADA result at any time point, baseline (pre-dose on Day 1), baseline and post-baseline, and post-baseline, respectively.

Immunogenicity blood samples were assayed for ADA using a validated assay. The sample analysis followed a tiered approach of screening, confirmation, and titer determination. Samples tested positive for ADA were further analyzed for neutralizing antibodies (Nab) using a validated assay. Baseline was defined as the last assessment prior to the date/time of the first dose of avelumab. N0, N1, N2, and N3=Number of participants with at least 1 valid ADA Result at any time point, baseline (pre-dose on Day 1), baseline and post-baseline, and post-baseline, respectively. n=number of participants in each category.

This OM is reported for participants in Phase 1b; OR was defined as the proportion of participants with a best overall soft tissue response of CR or PR per RECIST v1.1 and with no evidence of confirmed bone disease progression per Prostate Cancer Working Group 3 (PCWG3) criteria by investigator. CR: Complete disappearance of all target and non-target lesions with the exception of nodal disease; all target and non-target nodes must decrease to normal size (short axis \<10 mm); all lesions must be assessed. PR: Greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions; all target lesions must be assessed. Non-target PR lesions must be non-PD.

For participants with solid tumors except mCRPC, TTR was defined for participants with confirmed OR (CR or PR) as the time from the first dose of study treatment to the first documentation of objective tumor response. For participants with mCRPC, TTR was defined as the time from the first dose of study treatment to the first objective evidence of soft tissue response with no evidence of confirmed bone disease progression on bone scan per PCWG3. Soft tissue response was defined as a best overall response (BOR) of CR or PR as assessed by Investigator using RECIST v1.1.

For participants with solid tumors except mCRPC, TTR was defined for participants with confirmed OR (CR or PR) as the time from the first dose of study treatment to the first documentation of objective tumor response. For participants with mCRPC, TTR was defined as the time from the first dose of study treatment to the first objective evidence of soft tissue response with no evidence of confirmed bone disease progression on bone scan per PCWG3. Soft tissue response was defined as a best overall response (BOR) of CR or PR as assessed by Investigator using RECIST v1.1.

For participants with solid tumors except mCRPC, DR was defined for participants with confirmed OR (CR or PR) as the time from the first documentation of objective tumor response to the first documentation of objective tumor progression or to death due to any cause, whichever occurred first.

For participants with solid tumors except mCRPC, PFS was defined as the time from the first dose of study treatment to the date of disease progression by RECIST v1.1 or death due to any cause, whichever occurred first. For participants with mCRPC, PFS was defined as the time from the first dose of study treatment to documentation of radiographic progression in soft tissue as assessed by Investigator using RECIST v1.1, in bone as assessed by Investigator using PCWG3, or death, whichever occurred first

This OM is reported for participants with solid tumors except mCRPC; for those participants, PFS was defined as the time from the first dose of study treatment to the date of disease progression by RECIST v1.1 or death due to any cause, whichever occurred first.

This OM was reported for participants with mCRPC; for these participants, PFS was defined as the time from the first dose of study treatment to documentation of radiographic progression in soft tissue as assessed by Investigator using RECIST v1.1, in bone as assessed by Investigator using PCWG3, or death, whichever occurred first.

Time to PSA progression for participants with mCRPC was defined as the time from the first dose to the date that a \>=25% increase in PSA with an absolute increase of \>=2 μg/L (2 ng/mL) above the nadir (or baseline for participants with no PSA decline) was documented, confirmed by a second consecutive PSA value obtained \>=3 weeks (21 days) later.

Overall survival (OS) was defined as the time from the first dose of study treatment to the date of death. Participants without an event (death) were censored at the date of last contact.

OS was defined as the time from the first dose of study treatment to the date of death. Participants without an event (death) were censored at the date of last contact.

PSA response was defined as the proportion of participants with confirmed PSA decline \>=50% compared to baseline. PSA response was calculated as a decline from baseline PSA (ng/mL) to the maximal PSA response with a threshold of 50%. A PSA response must be confirmed by a second consecutive value at least 3 weeks later.

Cancer Antigen 125 (CA-125) response is defined as at least a 50% reduction in CA-125 levels from baseline. The response must be confirmed and maintained for at least 28 days.

CA-125 response is defined as at least a 50% reduction in CA-125 levels from baseline. The response must be confirmed and maintained for at least 28 days.

PD-L1 expression on tumor and infiltrating immune cells were measured by immunohistochemistry (IHC). PD-L1 expression level corresponds to the percentage of positive cells. The PD-L1 Positive category does not apply to cohorts A1 and A2. The PD-L1 High/Low categories only apply to cohorts A1 and A2. Participants were considered positive if their baseline tumor tissue sample demonstrated cell surface PD-L1 expression: 1) for Cohorts E1, E2, and F: \>=1% tumor cells (TC) or \>= 5% immune cells (IC); 2) for Cohort D: TC/IC\>=25%; 3) for Cohorts B1, B2, C1, C2: IC\>=5%; otherwise were considered negative. Categories based on PD-L1 expression level ≥50% and \<50% were defined as High and Low, respectively.

TMB was defined as the total number of mutations in the tumor genome, or number of mutations per megabase of DNA if derived from targeted sequencing. High: TMB score \>=20 muts/mb (number of mutations per megabase of DNA); Medium: TMB score \>=10 muts/mb and \<20 muts/mb; Low: TMB score \<10 muts/mb.

DDR defect positive was determined by presence of one or more pathogenic or likely pathogenic mutations in tissue, DNA and/or blood samples.