SUMMARY

• In MAGNITUDE, the ongoing, 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, patient-reported outcomes (PROs) were assessed using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire, Brief Pain Inventory-Short Form (BPI-SF), National Cancer Institute (NCI) Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), and the European Quality of Life-5 Dimensions (EQ-5D-5L) questionnaire.^1-6
  • Health-related quality of life (HRQoL) was maintained with niraparib/abiraterone acetate with prednisone (AAP), with no clinically meaningful differences in FACT-P total score (±10) or physical well-being score (±3) change from baseline over time between treatment arms. Results are reported in Table: Changes in FACT-P Categories from Baseline.^3,7
  • In early cycles of niraparib/AAP relative to placebo/AAP, patients reported worsening of side effect bother, lack of energy, and nausea per the FACT-P physical well-being subscale. Most patients reported minimal side effect burden.⁷
  • In the second interim analysis, overall HRQoL (FACT-P total score) was maintained in the BRCA1/2 subgroup during treatment in both the niraparib/AAP and placebo/AAP groups.⁵
    • There was no difference in time to deterioration (TTD) in FACT-P total scores between the niraparib/AAP group (median, 5.5 months; 95% CI, 2.9-7.5) and placebo/AAP group (median, 6.1 months; 95% CI, 3.8-11.1) (HR, 1.07; 95% CI, 0.76-1.50; nominal P=0.7144).⁵ These endpoints were not adjusted for multiple comparisons. Therefore, the P-values displayed are nominal, and statistical significance has not been established.
    • Patients in the BRCA1/2 subgroup treated with niraparib/AAP experienced a delay in time to worst pain intensity (HR, 0.70; 95% CI, 0.44-1.12; nominal P=0.1338). Although median time to pain interference was not reached for either treatment arm, at the 25^th percentile, time to pain interference was 13.5 months vs 12.9 months for the niraparib/AAP and placebo/AAP groups, respectively (HR, 0.67; 95% CI, 0.40-1.12; nominal P=0.1275).⁵ These endpoints were not adjusted for multiple comparisons. Therefore, the P-values displayed are nominal, and statistical significance has not been established.
  • In the final analysis, the overall HRQoL (FACT-P total score) indicated a decline over time for both treatment groups. In the BRCA1/2 subgroup, minor differences favoring the niraparib/AAP group were noted in the later treatment cycles. The differences were less than the established threshold for clinically meaningful change.⁶
    • By the end of treatment, changes in all pain domains from baseline were comparable between the niraparib/AAP and placebo/AAP groups in both the HRR+ population and the BRCA1/2 subgroup.
    • During treatment, the proportion of patients reporting ‘‘not at all’’ or ‘‘a little bit’’ for side-effect bother ranged from 79.8% to 93.6% in the niraparib/AAP group and from 88.2% to 95.9% in the placebo/AAP group.

CLINICAL DATA

MAGNITUDE Study

Chi et al (2023)^3,5 and Efstathiou et al (2023)⁸ reported the efficacy and safety of AKEEGA with prednisone compared to placebo/AAP in mCRPC for patients with certain HRR mutations (n=423), including BRCA1/2 (n=225). Patients were randomized 1:1 to receive niraparib 200 mg by mouth (PO) once daily or matching placebo in combination with abiraterone acetate 1000 mg PO once daily plus prednisone 5 mg twice daily.

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

MAGNITUDE Study Design^1-3

Abbreviations: AA, abiraterone acetate; AML, acute myeloid leukemia; AR, androgen receptor; BPI-SF, Brief Pain Inventory-Short Form; CT, computed tomography; ECOG PS, Eastern Cooperative Oncology Group performance status; GnRHa, gonadotropin-releasing hormone analog; HRR, homologous recombination repair; L1, first-line therapy; mCRPC, metastatic castration-resistant prostate cancer; mCSPC, metastatic castration-sensitive prostate cancer; MDS, myelodysplastic syndrome; MRI, magnetic resonance imaging; NIRA, niraparib; nmCRPC, non-metastatic castration-resistant prostate cancer; ORR, objective response rate; OS, overall survival; PARPi, poly ADP-ribose polymerase inhibitor; PBO, placebo; PFS2, progression-free survival on first subsequent therapy; PO, orally; PSA, prostate-specific antigen; R, randomization; rPFS, radiographic progression-free survival; TCC, time to cytotoxic chemotherapy; TSP, time to symptomatic progression; TTPP, time to PSA progression.
^aNovel second-generation AR-targeted therapy such as enzalutamide, apalutamide, or darolutamide; taxane-based chemotherapy; or >4 months of AAP before randomization.

Study Design/Methods

• PROs were collected to evaluate pain, prostate cancer symptoms, treatment-related tolerability, and overall HRQoL.^2,4
  • Disease-related symptoms were assessed with the BPI-SF and FACT-P questionnaire.
  • Treatment-related tolerability and experiences were assessed with select items from the PRO-CTCAE and a single item from the FACT-P regarding “side effect bother.”
  • Overall HRQoL was to be measured with FACT-P and the EQ-5D-5L. The FACT-P threshold for deterioration was defined as ≥10 decrease in total score.
• During the treatment phase, all PROs were collected on day 1 (±3 days) of every cycle for cycles 1-7, select cycles 8-12 (cycles 8, 10, and 12 OR 9 and 11), every other cycle for cycles 13-24, every 3 cycles for cycles 25 and after, and at the end of therapy.²
• In the follow-up phase, BPI-SF, FACT-P, and EQ-5D-5L were to be assessed every 3 months for up to 2 years after end of therapy.²
• Visit-specific assessments were conducted and completed before any tests, procedures, or other consultations to prevent influencing patient perceptions.²
• PRO changes from baseline were compared between treatment arms using repeated measures analysis.²
• Proportional hazards regression models were used to compare TTD in worst pain intensity between arms.²

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.^3,7
• Compliance for FACT-P and BPI-SF assessments was >80% through cycle 23.⁷
• Baseline mean pain and HRQoL were consistent across arms, as reported in Table: PRO Baseline Scores in the BRCA1/2 Subgroup and HRR+ Population.⁶

HRQoL

Primary Analysis

• HRQoL was maintained with niraparib/AAP therapy (n=190) in HRR+ patients, with no clinically meaningful differences in FACT-P total score (±10) or physical well-being score (±3) change from baseline over time or when compared with placebo/AAP (n=184).^3,7 Results are reported in Table: Changes in FACT-P Categories From Baseline.
  • In early cycles of niraparib/AAP relative to placebo/AAP, patients reported worsening of side effect bother, lack of energy, and nausea per the FACT-P physical well-being subscale. Most patients reported minimal side effect burden.⁷

Second Interim Analysis

• Overall HRQoL (FACT-P total score) was maintained in the BRCA1/2 subgroup during treatment in both the niraparib/AAP and placebo/AAP groups.⁵
• There was no difference in TTD in FACT-P total scores between the niraparib /AAP group (median, 5.5 months; 95% CI, 2.9-7.5) and placebo/AAP group (median, 6.1 months; 95% CI, 3.8-11.1) (HR, 1.07; 95% CI, 0.76-1.50; nominal P=0.7144).⁵ These endpoints were not adjusted for multiple comparisons. Therefore, the P-values displayed are nominal, and statistical significance has not been established.
• Patients in the BRCA1/2 subgroup treated with niraparib/AAP experienced a delay in time to worst pain intensity (HR, 0.70; 95% CI, 0.44-1.12; nominal P=0.1338). Although median time to pain interference was not reached for either treatment arm, at the 25^th percentile, time to pain interference was 13.5 months vs 12.9 months for the niraparib/AAP and placebo/AAP groups, respectively (HR, 0.67; 95% CI, 0.40-1.12; nominal P=0.1275).⁵ These endpoints were not adjusted for multiple comparisons. Therefore, the P-values displayed are nominal, and statistical significance has not been established.

Final Analysis

• Baseline FACT-P scores were comparable between the treatment groups for all assessed subscales, and a positive overall HRQoL was reported in both the HRR+ population and the BRCA1/2 subgroup.⁶
  • Analysis of the FACT-P total score indicated a decline over time for both treatment groups. In the BRCA1/2 subgroup, minor differences favoring the niraparib/AAP group were noted in the later treatment cycles. The differences were less than the established threshold for clinically meaningful change.
• Baseline BPI-SF scores were low in both treatment groups in the BRCA1/2 subgroup and the HRR+ population, remaining <3 for most treatment cycles. By the end of treatment, changes in all pain domains from baseline were comparable between the niraparib/AAP and placebo/AAP groups in both the HRR+ population and the BRCA1/2 subgroup.⁶
  • In the BRCA1/2 subgroup, median TTD in BPI-SF worst pain was not reached in the niraparib/AAP group and was 32.2 months in the placebo/AAP group (HR, 0.81; 95% CI, 0.52-1.25).
  • In the HRR+ population, median TTD in BPI-SF worst pain was 30.6 months in the niraparib/AAP group and 32.3 months in the placebo/AAP group (HR, 0.93; 95% CI, 0.69-1.28).
• TTD for FACT-P subscales and BPI-SF scales for the BRCA1/2 subgroup is summarized in Table: TTD for FACT-P Subscales and BPI-SF Scales for the BRCA1/2 Subgroup.

• During treatment, the proportion of patients reporting ‘‘not at all’’ or ‘‘a little bit’’ for side-effect bother ranged from 79.8% to 93.6% in the niraparib/AAP group and from 88.2% to 95.9% in the placebo/AAP group.⁶
  • In comparison to the baseline, most patients reported stable bother or an improvement in relation to treatment side-effects during treatment: niraparib/AAP group, 60.0-75.0%; placebo/AAP group, 62.2-85.2%.
  • The rate of worsening of side-effect bother by ≥1 points was initially higher in the niraparib/AAP group than in the placebo/AAP group during the early treatment cycles, but this trend reversed in later cycles. Worsening was reported by only 1 point in most cases.

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 25 September 2024. Summarized in this response are relevant data limited to the phase 3 MAGNITUDE study in patients with mCRPC.