SUMMARY

• AMPLITUDE (NCT04497844) is an ongoing, phase 3, randomized, double-blind, placebo-controlled, multicenter, global study evaluating the efficacy and safety of niraparib and abiraterone acetate (AA) in a dual-action tablet formulation with prednisone plus androgen deprivation therapy (ADT) compared with matching oral placebo/AA with prednisone plus ADT in patients with deleterious germline or somatic homologous recombination repair (HRR) gene–altered mCSPC (N=696).^1-5
  • The primary endpoint of radiographic progression-free survival (rPFS) in the AKEEGA plus prednisone group vs placebo/AA plus prednisone (AAP) group was met:^4,5 
    • BRCA subgroup: not estimable (NE) vs 26.0 months; hazard ratio (HR), 0.52; 95% confidence interval (CI), 0.37-0.72; P<0.0001
    • HRR effector subgroup: NE vs 27.6 months; HR, 0.57; 95% CI, 0.42-0.77; P=0.0003
    • Intention-to-treat (ITT) population: NE vs 29.5 months; HR, 0.63; 95% CI, 0.490.80; P=0.0001
  • Subgroup analyses by alteration type are summarized in Table: Subgroup Analysis by BRCA and non-BRCA Alterations.
  • A summary of adverse events (AEs) is described in Table: Adverse Events. In the AKEEGA plus prednisone group vs the placebo/AAP group, the most common AEs of interest were anemia (51.6% vs 23.9%) and hypertension (43.8% vs 32.5%), respectively.^4,5
• HARMONY (NCT06392841) is an ongoing, phase 2, open-label, multicenter study evaluating the efficacy and safety of AKEEGA with prednisone plus ADT in the treatment-naive/minimally treated Hispanic/Latino (HL) and non-Hispanic Black (NHB) patients with deleterious germline or somatic HRR genealtered metastatic hormone-sensitive prostate cancer (mHSPC). The primary endpoint is prostate-specific antigen (PSA) decline to <0.2 ng/mL at 24 weeks. The study has a planned enrollment of 64 patients (32 HL and 32 NHB).^6,7 The efficacy and safety results have not been published.
• STAMPEDE2 (NCT06320067) is an ongoing, phase 3, randomized, open-label, multicenter platform trial evaluating the efficacy of AKEEGA with prednisolone in patients with deleterious germline or somatic HRR genealtered mHSPC starting ADT. The primary endpoint is overall survival (OS). The study has a planned enrollment of 680 patients.^8,9 The efficacy and safety results have not been published.
• ProBio (Prostate-Biomarker, NCT03903835) is an ongoing, phase 3, outcomeadaptive, multiarm, multiple-assignment, randomized, open-label, international biomarker-driven platform study in patients with de novo mHSPC or first-line (L1) metastatic castration-resistant prostate cancer (mCRPC). Patients entering the mHSPC phase will be randomized to receive either standard of care (SOC) or an experimental treatment with androgen receptor signaling inhibitors (ARSis), docetaxel, or AKEEGA with prednisone based on predefined biomarker signatures. The study has a planned enrollment of 750 patients.^10,11 The efficacy and safety results have not been published.

CLINICAL DATA

AMPLITUDE Study

Attard et al (2025)^4,5 reported the efficacy and safety results of AKEEGA plus ADT vs placebo/AAP plus ADT in patients with deleterious germline or somatic HRR gene–altered mCSPC (N=696).

Study Design/Methods

• A phase 3, randomized, double-blind, placebo-controlled, multicenter, global study.
• The study design is presented in Figure: AMPLITUDE Study Design.
• Key efficacy endpoint testing was conducted using a hierarchical graphical approach, first in the BRCA subgroup (BRCA1 or BRCA2 alterations), then in the HRR effector subgroup (i.e., immediate effectors of HRR at DNA double-strand breaks [BRCA subgroup plus BRIP1, PALB2, RAD51B, RAD54L]), and finally extending to ITT patients (HRR effector subgroup plus CDK12, CHEK2, and FANCA).

Results

Patient Characteristics

• Patient characteristics were well balanced between the two groups (Table: Select Baseline Patient and Disease Characteristics).

Efficacy

• A summary of study results is provided in Table: Primary and Secondary Endpoint Results. The median follow-up was 30.8 months (data cutoff: January 7, 2025).
• Subgroup analyses by alteration type are summarized in Table: Subgroup Analysis by BRCA and non-BRCA Alterations.
• The treatment effect of AKEEGA with prednisone vs placebo/AAP on median rPFS in the ITT population was generally consistent across several prespecified subgroups, including patients with high-volume disease at baseline (41.2 months [events/N, 100/269] vs 26.3 months [130/271]; HR, 0.65; 95% CI, 0.50-0.85) and M1 disease at diagnosis (nonestimable [100/301] vs 27.4 months [142/302]; HR, 0.60; 95% CI, 0.47-0.78).
• While not a prespecified analysis, there was an HR of 0.81 (95% CI, 0.56-1.18) for rPFS in patients without BRCA1/2 alterations.
• Of the 196 patients in the placebo/AAP group who discontinued treatment, at data cutoff, 141 (72%) patients were reported to have received a life-prolonging subsequent treatment for prostate cancer chosen based on the treating physician’s judgment and local approvals, which included chemotherapy in 102 patients (72%) and poly(adenosine diphosphate-ribose) polymerase inhibitor (PARPi) therapy in 47 patients (33%). The subsequent therapies used are presented in Table: Subsequent Therapy (ITT Population).
• The objective response rate was 72% (76/106) in the AKEEGA plus prednisone group and 74% (81/110) in the placebo/AAP group.
• Patients who achieved a complete or partial response experienced a longer duration of response in the AKEEGA plus prednisone group than in the abiraterone-alone group (HR, 0.55; 95% CI, 0.35-0.86; nominal P=0.008).
• Patients receiving AKEEGA plus prednisone had improved time for PSA progression compared with those receiving placebo/AAP (HR, 0.50; 95% CI, 0.39-0.65; nominal P<0.0001).
• Health-related quality of life (HRQoL) Functional Assessment of Cancer Therapy-Prostate (FACT-P) scores demonstrated an improvement from baseline at cycle 2 in the placebo/AAP group. The AKEEGA with prednisone group exhibited an initial decline at cycles 2-4 compared with baseline. HRQoL FACT-P scores improved in the AKEEGA with prednisone group by cycle 5, with no difference observed compared with that in the placebo/AAP group from cycles 5-37.

Safety

• A summary of AEs that occurred from the time of the first dose of the trial intervention through 30 days after the last dose in both treatment arms is shown in Table: Adverse Events.
  • Other common AEs of any grade included constipation (35.2% vs 16.4%), nausea (30.8% vs 14.4%), fatigue (26.2% vs 18.4%), arthralgia (21.0% vs 21.3%), back pain (19.6% vs 22.1%), coronavirus disease 2019 (18.7% vs 20.4%), hot flush (18.2% vs 13.8%), leukopenia (16.7% vs 5.2%), vomiting (16.1% vs 8.6%), peripheral edema (15.9% vs 12.1%), weight decreased (15.3% vs 5.2%), and alanine aminotransferase increased (6.3% vs 15.5%) in the AKEEGA with prednisone vs placebo/AAP groups, respectively.

HARMONY Study

Qin et al (2025)⁷ described the study design for an ongoing, phase 2, open-label, multicenter study evaluating the efficacy and safety of AKEEGA with prednisone plus ADT in the treatment-naive/minimally treated HL and NHB patients with deleterious germline or somatic HRR gene–altered mHSPC (planned enrollment, N=64 patients).

Study Design/Methods

• Patients will receive AKEEGA with prednisone plus ADT for 24 weeks, after which they will proceed to an adaptive approach:
  • Cohort A: patients with PSA >4 ng/mL have an option to continue AKEEGA with prednisone plus ADT for a maximum of 2 years or stop niraparib and add docetaxel (6 cycles) to AAP plus ADT, followed by SOC treatment.
  • Cohort B: patients achieving PSA ≤4 ng/mL will continue AKEEGA with prednisone plus ADT. At 12 months of treatment, patients with PSA ≥0.2 ng/mL will continue AKEEGA with prednisone plus ADT for a maximum of 2 years and patients with PSA <0.2 ng/mL have the option to continue AKEEGA with prednisone plus ADT for a maximum of 2 years or discontinue all treatment and monitor, with an option to start SOC treatment at disease progression.
• Key inclusion criteria: self-identified HL or NHB; mHSPC (minimal treatment i.e., bicalutamide ≤45 days, ADT ± AAP ≤45 days allowed); HRR gene alterations, including BRCA1/2, BRIP1, CHEK2, FANCA, PALB2, RAD51B, and/or RAD54L
• Key exclusion criteria: predominant neuroendocrine or small cell carcinoma; other treatment in mHSPC setting; symptomatic brain metastases⁶ 
• Primary endpoint: PSA decline to <0.2 ng/mL at 24 weeks
• Secondary endpoints: OS, objective response rate, PSA progression-free survival (PFS), rPFS, time to subsequent anti-cancer therapy, and safety⁶ 
• Other secondary endpoints: quality of life, genomic correlates⁶ 

The efficacy and safety results of the HARMONY study have not been published.

STAMPEDE2 Study

Howlett et al (2024)⁹ described the study design for an ongoing, phase 3, randomized, open-label, multicenter platform trial evaluating the efficacy of AKEEGA with prednisolone in patients with deleterious germline or somatic HRR genealtered mHSPC starting ADT.

Study Design/Methods

• Patients identified as biomarker-positive (HRR gene alterations) will be randomized 1:1 to receive either SOC with physician’s choice of ARSi or AKEEGA with prednisolone.
• Prior randomization into the STAMPEDE2 stereotactic ablative body radiotherapy (SABR) or prostate-specific membrane antigen (PSMA)-Lutetium trials is permitted.
• Randomization is stratified by the planned use of docetaxel and/or prostate radiotherapy and/or SABR/PSMA-Lutetium therapy.
• Key exclusion criteria: >6 months ADT, evidence of PSA progression on ADT +/- ARSi
• Primary endpoint: OS
• Secondary endpoints: rPFS, failure-free survival, prostate cancer-specific survival, toxicity, quality of life, and cost-effectiveness

The efficacy and safety results of the STAMPEDE2 study have not been published.

ProBio Study

De Laere et al (2022)¹⁰ described the study design for an ongoing, phase 3, outcomeadaptive, multiarm, multiple-assignment, randomized, open-label, international biomarker-driven platform study in patients with de novo mHSPC or L1 mCRPC. The information summarized below is limited to the de novo mHSPC treatment phase.

Study Design/Methods

• Patients with de novo mHSPC will be randomized to receive either SOC or an experimental treatment with ARSis, docetaxel, or AKEEGA with prednisone. Local therapy to the prostate will be allowed across all treatment arms.
• Patients were stratified by prespecified biomarker signatures (inferred from diagnostic tissue and/or liquid biopsy profiling), previous treatment, and fraction of circulating tumor DNA (ctDNA).
• Key inclusion criteria: ≥18 years old; histologically confirmed prostate adenocarcinoma starting systemic therapy for metastatic disease, including de novo mHSPC; distant metastatic disease documented by positive bone scan or metastatic lesions on computed tomography/magnetic resonance imaging; adequate health and hematologic, hepatic, and renal functions, as assessed by investigator; albumin ≥28 g/L; Eastern Cooperative Oncology Group/World Health Organization performance score of 0-2
• Key exclusion criteria: failure to detect ctDNA or somatic alterations in primary tumor biopsies; prior systemic therapy (including ADT); other malignancies within 5 years except nonmelanoma skin cancer; myocardial infarction, unstable angina, angioplasty, bypass surgery, stroke, transient ischemic attack, or New York Heart Association class III or IV congestive heart failure ≤6 months prior to randomization; uncontrolled hypertension
• Primary endpoint: to determine whether a biomarker signature and treatment combination is superior to SOC with respect to PFS
• Secondary endpoints: to determine whether biomarker-driven treatment selection can improve PFS for the experimental arms combined vs the control arm and whether a treatment class is superior for a certain biomarker signature by comparing the experimental arms against each other
• Other secondary endpoints: PSA PFS, rPFS, response rates, time to second progression, OS, quality of life, health economics, drug safety, and identification of new biomarkers and superior treatment sequencing regimens

The efficacy and safety results of the ProBio study have not been published.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 03 June 2025.