Summary

• The phase 3 MAGNITUDE study evaluated the efficacy and safety of AKEEGA with prednisone compared with placebo/abiraterone acetate with prednisone (AAP) as first-line (L1) therapy in patients with metastatic castration-resistant prostate cancer (mCRPC) with certain homologous recombination repair (HRR) mutations, including BRCA1/2. Patients who received radiation therapy within 28 days of randomization were excluded.^1-4
  • During the study, concomitant radiotherapy for tumor progression was prohibited, excluding palliative radiotherapy in select cases after discussion with the sponsor.²
  • Study treatment was discontinued for unequivocal clinical progression, which included the need to initiate radiation therapy for tumor progression as defined within the protocol.
• STAMPEDE2 (NCT06320067) is an ongoing, phase 3, randomized, open label, multicenter platform protocol testing treatments in metastatic hormone sensitive prostate cancer (mHSPC).^5,6
  • In the AKEEGA with prednisolone study group, patients with HRR-altered mHSPC starting androgen deprivation therapy (ADT) will be randomized (1:1) to arm A, standard of care (SoC; ADT ± docetaxel ± local radiation therapy) with physician’s choice of androgen receptor signaling inhibitor or arm N, SoC plus AKEEGA with prednisolone, with a recruitment target of ~680 patients. Efficacy and safety results have not been published.⁵ 
  • Randomization is stratified by the planned use of docetaxel and/or prostate radiotherapy and/or stereotactic ablative body radiotherapy/prostate-specific membrane antigen (PSMA)-Lutetium. The primary outcome is overall survival (OS).^5,6
• ASCLEPIuS (NCT04194554) is a phase 1/2, multicenter study evaluating stereotactic body radiotherapy (SBRT) with a 6-month combination of ADT plus AKEEGA with prednisone in patients with high-risk or node positive homologous recombination unselected prostate cancer (N=54).^7,8
  • In phase 1, no dose-limiting toxicities (DLTs) or grade ≥3 rectal or urinary adverse events (AEs) were observed.⁸ 
    • Serious AEs possibly related to study treatment were anemia, non-rectal gastrointestinal, syncope, infection, and musculoskeletal events.
    • The most common grade 3 AEs were hypertension (21%; n=11) and leukopenia (11%; n=6).

CLINICAL DATA

ASCLEPIuS Study

ASCLEPIuS is a phase 1/2 study that evaluated SBRT with a 6-month combination of ADT plus AKEEGA with prednisone in patients with high-risk or node positive homologous recombination unselected prostate cancer (N=54).^7,8 The summary below is focused on the phase 1 portion of the study and results.

Study Design/Methods

• Phase 1/2, multicenter study
• Patients were given 6 months of ADT, AKEEGA, and SBRT to the prostate (37.5-40 Gy) with/without pelvic lymph nodes (25 Gy).
• In phase 1, AKEEGA was administered at 3 dose levels:
  • 100 mg and 200 mg held during SBRT, or 200 mg concurrent with SBRT
• Primary endpoint (phase 1): maximum tolerated dose (MTD) of niraparib using the time-to-event continuous reassessment method
• Select secondary endpoint: change in health-related quality of life (HRQoL)
• DLTs were defined as any persistent grade ≥4 hematologic toxicity or any grade ≥3 rectal/urinary toxicity at least possibly related to treatment as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v5.0.

Results

Patient Demographics

• Of 54 patients enrolled, 8 (15%) patients had cN+ disease and 41 (76%) received nodal radiation therapy.
• Median PSA was 17 ng/mL (range, 1-73 ng/mL).

Safety

• With a median follow-up of 12.1 months (interquartile range [IQR], 9.4-18.9), no DLTs or grade ≥3 rectal or urinary toxicities were observed.
• Serious adverse events (AEs) possibly related to study treatment were anemia, non-rectal gastrointestinal, syncope, infection, and musculoskeletal events.
• The most common grade 3 AEs were hypertension (21%; n=11) and leukopenia (11%; n=6).
• Transient dose reductions or holds of AKEEGA occurred in 10 and 11 patients, respectively.

Patient-reported urinary QoL

• Per EPIC-26 short form results, there were no statistically significant declines in QoL at 6- or 12-months post-treatment compared to baseline (all P>0.15).
• A transient decline in bowel QoL was observed at 6 months (P<0.01), which improved by 12 months (P=0.16).

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 07 April 2025. Summarized in this response are relevant data pertaining to this topic in patients with prostate cancer.