Summary

• In MAGNITUDE, the phase 3 study evaluating the efficacy and safety of AKEEGA with prednisone as first-line (L1) therapy in metastatic castration-resistant prostate cancer (mCRPC) for patients with certain homologous recombination repair (HRR) mutations, including BRCA1/2, patients were permitted to receive prior taxane-based chemotherapy in the metastatic castration-sensitive prostate cancer (mCSPC) setting prior to randomization. Patients were subsequently stratified by past taxane-based chemotherapy exposure.^1-6
  • Prior taxane-based chemotherapy was used in 41 (19.3%) of patients in the niraparib/abiraterone acetate with prednisone (AAP) group and 44 (20.9%) of patients in the placebo/AAP group of the HRR+ population and 26 (23.0%) patients and 29 (25.9%) patients, respectively, of the BRCA1/2 subgroup.⁶ 
  • A subgroup forest plot analysis of rPFS, for the BRCA1/2 subgroup, demonstrated similar results between treatment arms for patients with a history of prior taxane-based chemotherapy (hazard ratio [HR], 0.98; 95% confidence interval [CI], 0.48-2.02).⁷
  • Safety analyses were not specifically reported for patients who received prior taxane-based chemotherapy in the MAGNITUDE study.
  • A summary of treatment-emergent adverse events (TEAEs) at final analysis is described in Table: Safety Summary: Final Analysis (HRR+ Population). Grade 3-4 adverse events (AEs) were reported in 157 (74.1%) and 108 (51.2%) patients in the niraparib/AAP and in the placebo/AAP group, respectively. TEAEs leading to discontinuation of any agent occurred in 18.4% of patients in the niraparib/AAP group and 8.1% of patients in the placebo/AAP group. TEAEs of special interest are described in TEAEs of Special Interest: Final Analysis (HRR+ Population).⁶ Safety profiles at the final analysis and second interim analysis were consistent with that of the first interim analysis, with no new safety signals observed.⁵ 
• In AMPLITUDE, the phase 3 study evaluating the efficacy and safety of AKEEGA with prednisone plus androgen deprivation therapy (ADT) in patients with deleterious germline or somatic HRR gene-altered mCSPC, patients were permitted to receive prior docetaxel chemotherapy (≤6 cycles of docetaxel, with last dose ≤3 months prior to randomization) in mCSPC. Patients were subsequently stratified by prior docetaxel use.⁸ 
  • In the HRRm population, 54 (16%) patients in the AKEEGA with prednisone group vs 56 (16%) patients in the placebo/AAP group received prior docetaxel in mCSPC.
  • A subgroup forest plot analysis of rPFS favored the AKEEGA with prednisone group for patients with a history of prior docetaxel use (HR, 0.75; 95% CI, 0.40-1.40).
  • Safety analyses were not specifically reported for patients who received prior docetaxel chemotherapy in the AMPLITUDE study.
  • A summary of TEAEs is described in Table: Adverse Events. In the AKEEGA with prednisone vs placebo/AAP group, treatment-related TEAEs and TEAEs leading to discontinuation were reported in 89% vs 74% and 15% vs 10% of patients, respectively. The most common AEs of interest were anemia (52% vs 24%) and hypertension (45% vs 33%), respectively.
• Results have been reported for a phase 2 study of carboplatin-cabazitaxel-cetrelimab induction followed by niraparib ± cetrelimab maintenance in patients with aggressive variant prostate cancers (NCT04592237).⁹ 

CLINICAL DATA

MAGNITUDE Study

Chi et al (2023, 2025)^2,4-6 and Efstathiou et al (2023)³ reported the efficacy and safety of AKEEGA with prednisone compared with placebo/AAP in mCRPC for patients with (n=423) and without (n=233) certain HRR gene mutations, including BRCA1/2 (n=225). Patients were permitted to receive prior taxane-based chemotherapy in the nonmetastatic castration-resistant prostate cancer (nmCRPC)/mCSPC setting prior to randomization and were subsequently stratified by past taxane-based chemotherapy exposure. Patients who received prior taxane-based chemotherapy for mCRPC were excluded.¹⁰

The study design is presented in Figure: MAGNITUDE Study Design.

Results

Patient Characteristics

• Baseline characteristics were broadly comparable between treatment arms; however, rates of visceral metastases, bone metastases, and Eastern Cooperative Oncology Group performance status (ECOG PS) of 1 were imbalanced to the disadvantage of the niraparib/AAP group.²
• Prior taxane-based chemotherapy use at baseline is shown in Table: Prior Taxane-Based Chemotherapy in the MAGNITUDE Study.

Efficacy

• In a subgroup forest plot analysis, OS in patients with past taxane-based chemotherapy was reported as follows in the niraparib/AAP vs placebo/AAP groups:⁶ 
  • HRR+ population: 22.82 months vs 31.31 months (HR, 1.251; 95% CI, 0.720-2.174)
  • BRCA1/2 subgroup: 25.40 months vs 31.31 months (HR, 1.192; 95% CI, 0.590-2.410)
• In a subgroup forest plot analysis, rPFS in patients with past taxane-based chemotherapy was reported as follows in the niraparib/AAP vs placebo/AAP groups:⁷
  • BRCA1/2 subgroup: 13.4 months vs 13.7 months (HR, 0.98; 95% CI, 0.48-2.02)

Safety

• Safety analyses were not specifically reported for patients who received prior taxane-based chemotherapy in the MAGNITUDE study.
• At the second interim analysis, a total of 211 patients in the niraparib/AAP group and 203 patients in the placebo/AAP group reported AEs, described in Table: Summary of Most Common (≥10% in Either Group) TEAEs at IA2 (HRR+ Population).⁴
• At the final analysis,⁶ the safety profile in the BRCA+ subgroup was consistent with that of the HRR+ population and remained consistent with prior analyses. Safety data from the final analysis are summarized in Tables: Safety Summary: Final Analysis (HRR+ Population) and TEAEs of Special Interest: Final Analysis (HRR+ Population).
• Safety profiles across the first interim analysis, second interim analysis, and the final analysis were consistent, with no new safety signals.⁵

AMPLITUDE STUDY

Attard et al 2025)⁸ reported the efficacy and safety of AKEEGA with prednisone plus ADT compared with placebo/AAP plus ADT in patients with deleterious germline or somatic HRR gene-altered mCSPC (N=696). Patients were permitted to receive prior docetaxel chemotherapy (≤6 cycles of docetaxel, with last dose ≤3 months prior to randomization) in the mCSPC setting and were subsequently stratified by prior docetaxel use.

The study design is presented in Figure: AMPLITUDE Study Design.

Results

Patient Characteristics

• Patient characteristics were well balanced between the 2 groups.
• Prior docetaxel chemotherapy use at baseline is shown in Table: Prior Docetaxel Chemotherapy Use in the AMPLITUDE Study (HRRm Population).

Efficacy

• A subgroup forest plot analysis of rPFS favored the AKEEGA with prednisone group for patients with a history of prior docetaxel use (HR, 0.75; 95% CI, 0.40-1.40). The median rPFS in the AKEEGA with prednisone group vs placebo/AAP group was 41.2 months (events: n=18) vs not estimable (events: n=23).

Safety

• Safety analyses were not specifically reported for patients who received prior docetaxel chemotherapy in the AMPLITUDE study.
• A summary of AEs reported in both treatment arms is shown in Table: Adverse Events. Other common AEs of any grade included constipation (35% vs 16%), nausea (31% vs 14%), fatigue (26% vs 18%), and arthralgia (21% each), in the AKEEGA with prednisone vs PBO/AAP groups, respectively.

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 28 May 2025. Summarized in this response are relevant data limited to the phase 3 MAGNITUDE and AMPLITUDE studies in patients with mCRPC and mCSPC, respectively.