Trial Outcomes & Findings for Safety and Efficacy of Therapies for Metastatic Castration-resistant Prostate Cancer (mCRPC) (NCT NCT04631601)

Participants were enrolled at 11 centers in Denmark, Spain, Sweden, the United Kingdom, and the United States between January 2021 and October 2023. This trial was a master protocol with 4 subprotocols. Subprotocols A, B, and C consisted of part 1 (acapatamab dose exploration) and part 2 (acapatamab dose expansion). In Subprotocol C AMG 404 was administered monotherapy (part 3) at the recommended phase 2 dose. Subprotocol D evaluated acapatamab monotherapy.

A total of 55 participants were enrolled and 54 received trial treatment. For subprotocol A, no participants were enrolled in part 2.

Safety and Efficacy of Therapies for Metastatic Castration-resistant Prostate Cancer (mCRPC)

DLTs were defined as any adverse event (AE) (per Common Terminology Criteria for Adverse Events (CTCAE) v5: Grade 5=Death, Grade 4=Life-threatening, Grade 3=Moderate) occurring within 28 days of the first AMG 160 dose, possibly related to the treatment, including: * Grade 5 toxicity * Grade 4 thrombocytopenia * Grade 3 thrombocytopenia with significant hemorrhage * Grade 4 neutropenia \> 5 days * Febrile neutropenia * Grade 3 anemia requiring transfusion * Grade ≥3 non-hematologic toxicity (with exceptions per protocol) * Aspartate transaminase/alanine transaminase \>3x upper limit of normal (ULN) with serum total bilirubin \>2x ULN without cholestasis or another clear cause * Grade ≥3 non-hematological toxicity delaying treatment \> 2 weeks or resulting in \<75% dose administration. The complete list of DLTs are described in the protocol

A TEAE was defined as any untoward medical occurrence in a clinical trial participant irrespective of a causal relationship with the trial treatment that started on or after first dose of investigational product (AMG 160 or AMG 404 for Part 1 and 2; AMG 404 for Part 3). A treatment-related TEAE was defined as a TEAE that had a reasonable possibility of being caused by acapatamab, or AMG 404 (subprotocol C, parts 1 and 2 only). Clinically significant changes from baseline in vital signs and clinical laboratory tests were also recorded as TEAEs.

A TEAE was defined as any untoward medical occurrence in a clinical trial participant irrespective of a causal relationship with the trial treatment that started after the first dose of acapatamab. A treatment-related TEAE was defined as a TEAE that had a reasonable possibility of being caused by acapatamab. Clinically significant changes from baseline in vital signs and clinical laboratory tests were also recorded as TEAEs.

Objective Response is defined as a complete response (CR) or partial response (PR) per RECIST 1.1, confirmed by a repeat assessment at least 4 weeks later. Participants who did not experience a confirmed CR or PR, or did not have any follow-up tumor assessments were regarded as non-responders.

CTC0 response was defined as CTC0 (reduction of CTCs \> 0 to 0 at any post-baseline measurement). The baseline was defined as the last non-missing value on or prior to the pre-dose of AMG 404 assessments on Cycle 1 Day 1.

CTC conversion response was defined as ≥ 5 CTCs/7.5 mL blood at baseline that converted to ≤ 4 CTCs/7.5 mL blood at any post-baseline measurement. The baseline was defined as the last non-missing value on or prior to the pre-dose assessments of AMG 404 on Cycle 1 Day 1.

A PSA response was defined as the below and must have been confirmed by a second consecutive value 3 weeks later: * PSA 30 response: ≥ 30% reduction from the baseline PSA. * PSA 50 response: ≥ 50% reduction from the baseline PSA. * PSA 70 response: ≥ 70% reduction from the baseline PSA. * PSA 90 response: ≥ 90% reduction from the baseline PSA. The baseline was defined as the last non-missing value on or prior to the pre-dose of AMG 404 assessments on Cycle 1 Day 1.

Objective Response is defined as a CR or PR per RECIST 1.1, confirmed by a repeat assessment at least 4 weeks later. Participants who did not experience a confirmed CR or PR, or did not have any follow-up tumor assessments were regarded as non-responders.

CTC0 response was defined as CTC0 (reduction of CTCs \> 0 to 0 at any post-baseline measurement). The baseline was defined as the last non-missing value on or prior to the pre-dose of acapatamab assessments on Cycle 1 Day 1 \> 0.

CTC conversion response was defined as ≥ 5 CTCs/7.5 mL blood at baseline that converted to ≤ 4 CTCs/7.5 mL blood at any post-baseline measurement. The baseline was defined as the last non-missing value on or prior to the pre-dose of acapatamab assessments on Cycle 1 Day 1.

A PSA response was defined as the below and must have been confirmed by a second consecutive value 3 weeks later: * PSA 30 response: ≥ 30% reduction from the baseline PSA. * PSA 50 response: ≥ 50% reduction from the baseline PSA. * PSA 70 response: ≥ 70% reduction from the baseline PSA. * PSA 90 response: ≥ 90% reduction from the baseline PSA. The baseline was defined as the last non-missing value on or prior to the pre-dose of acapatamab assessments on Cycle 1 Day 1.

Duration of CTC0 response was defined as the time from the date of initial CTC0 response to the earlier of CTC0 progression or death. Participants who had not ended their response at the time of analysis had duration of CTC0 response censored on the date of their last CTC0 or CTC conversion assessment.

Duration of CTC conversion response was defined as the time from the date of an initial CTC conversion response to the earlier of CTC conversion progression or death. Participants who had not ended their response at the time of analysis had duration of CTC response censored on the date of their last CTC0 or CTC conversion assessment.

Duration of PSA response was defined as the time of an initial PSA response (PSA 50) to the earlier of PSA progression or death. Participants who had not ended their response at the time of analysis had duration of PSA response censored on the date of their last PSA measurement.

Duration of response per RECIST 1.1 was defined as the time from the date of an initial objective response (CR/PR) per RECIST 1.1 to the earlier of soft-tissue progression per RECIST 1.1 or death. CR/PR must have been confirmed at least 4 weeks later. Participants who had not ended their response at the time of analysis had duration of response censored at their last evaluable tumor assessment by computed tomography (CT)/magnetic resonance imaging (MRI) scan.

OS was defined as the time from the date of trial Day 1 until death due to any cause. OS time (months) = (date of death - trial Day 1 + 1) x 12/365.25. Any participant not known to have died at the time of analysis was censored based on the last recorded date on which the participant was alive. The median was estimated using the Kaplan-Meier method and the 95% confidence interval was estimated using the method by Kalbfleisch and Prentice.

rPFS was defined as the time from trial Day 1 to radiographic progression. If a participant had no evaluable post-baseline and on-trial disease assessment and was on trial without disease progression (PD) or death recorded, rPFS was censored on the date of the first dose of the investigational product (IP). rPFS was censored at the last evaluable radiographic tumor assessment date for participants who had no PD, death or new anti-cancer therapy reported, started a new anti-cancer therapy prior to PD or death, if death recorded without new anti-cancer therapy and without PD, if death or PD immediately after more than one consecutively missed tumor assessment occurred. The median was estimated using the Kaplan-Meier method and the 95% confidence interval was estimated using the method by Brookmeyer and Crowley.

PSA PFS was defined as the interval from trial Day 1 to the earlier of a PSA progression or death from any cause; otherwise, PSA PFS was censored on the date of the last PSA measurement. If a participant had no baseline or post-baseline PSA measurement and a vital status of alive or known, PSA PFS was censored at trial Day 1. The median was estimated using the Kaplan-Meier method and the 95% confidence interval was estimated using the method by Brookmeyer and Crowley.

Clinical PFS was defined as the time from the first dose to clinical disease progression or death from any cause. If a participant had no evaluable post-baseline or on-trial disease assessment or was on trial without PD or death recorded, clinical PFS was censored on the date of the first dose of the IP. Otherwise, clinical PFS was censored on the date of last assessment. The median was estimated using the Kaplan-Meier method and the 95% confidence interval was estimated using the method by Brookmeyer and Crowley.

Time to radiographic progression was defined as the interval from Day 1 to radiographic progression in the absence of subsequent anticancer therapy. If a participant had no evaluable post-baseline and on-trial disease assessment and was on trial without PD or death recorded, time to radiographic progression was censored on the date of the first dose of the IP. Time to radiographic progression was censored on the date of last evaluable radiographic tumor assessment for participants who: * had no PD but death recorded without new anti-cancer therapy; * had no PD, death, or new anti-cancer therapy; * had PD or death immediately after more than one consecutively missed tumor assessment; * started new anti-cancer therapy prior to PD or death, or prior to any other disease assessment if there is no PD or death. The median was estimated using the Kaplan-Meier method and the 95% CI was estimated using the method by Brookmeyer and Crowley.

Time to PSA progression was defined as the interval from trial Day 1 to PSA progression. If a participant had no evaluable post-baseline or on-trial PSA assessment, time to PSA progression was censored on the date of the first dose of the IP. Otherwise, time to PSA progression was censored on the date of the last PSA assessment. The median was estimated using the Kaplan-Meier method and the 95% confidence interval was estimated using the method by Brookmeyer and Crowley.

Time to subsequent therapy was defined as the interval from trial Day 1 to the time a participant starts/receives the subsequent cancer therapy/subsequent therapy; otherwise, time to subsequent therapy was censored at the last known date of any of the trial assessments prior to initiating the subsequent cancer therapy/subsequent therapy. The median was estimated using the Kaplan-Meier method and the 95% confidence interval was estimated using the method by Brookmeyer and Crowley.

A Gallium PSMA-11 response was defined as a ≥ 50% reduction from baseline in the maximum standardized update value (SUV) using 68Gallium (68Ga)-PSMA-11 positron emission tomography (PET)/CT. PSMA-11 response percentages were based on the number of participants with a baseline PSMA assessment (defined as the last non-missing value on or prior to the pre-dose of acapatamab/AMG 404 assessments) on Cycle 1 Day 1. The 95% confidence interval was calculated based on the Clopper-Pearson method.

Time to symptomatic skeletal events was defined as time from trial Day 1 to the first symptomatic skeletal event, otherwise time to symptomatic skeletal event was censored at the last dose of acapatamab/AMG 404 or end of safety follow-up date, whichever was later. Symptomatic skeletal events included fracture, spinal cord compression and radiation or surgery to bone. The median was estimated using the Kaplan-Meier method and the 95% confidence interval was estimated using the method by Brookmeyer and Crowley.

Alkaline phosphatase levels were collected locally and centrally.

Bone specific alkaline phosphatase levels were collected locally and centrally.

Lactate dehydrogenase levels were collected locally and centrally.

Hemoglobin levels were collected locally.

Data for the neutrophil-to-lymphocyte ratio were collected locally. Neutrophil-to-lymphocyte ratio was calculated by dividing the number of absolute neutrophils by the number of lymphocytes.

Urine N-telopeptide levels were collected centrally.

Serum concentrations of acapatamab were determined using a validated assay.

Serum concentrations of acapatamab were determined using a validated assay.

Serum concentrations of acapatamab were determined using a validated assay.

Serum concentrations of acapatamab were determined using a validated assay.

A TEAE was defined as any untoward medical occurrence in a clinical trial participant irrespective of a causal relationship with the trial treatment that started after the first dose of acapatamab. A treatment-related TEAE was defined as a TEAE that had a reasonable possibility of being caused by acapatamab. Clinically significant changes from baseline in vital signs and clinical laboratory tests were also recorded as TEAEs.