3 · Radiographic Progression-Free Survival: o Unadjusted median rPFS was 19.5 months for niraparib plus AAP versus 10.9 months for placebo plus AAP (HR: 0.55; p = 0.001). o Following IPTW adjustment, median rPFS increased to 22.0 months for niraparib plus AAP and decreased to 8.4 months for placebo (HR: 0.47; p < 0.001). · Time to Symptomatic Progression and Time to Initiation of Cytotoxic Chemotherapy: o Unadjusted TSP was nonestimable for niraparib plus AAP versus 21.7 months for placebo (HR: 0.56; p = 0.0056). After IPTW adjustment, TSP was nonestimable for niraparib plus AAP and 21.3 months for placebo (HR: 0.49; p = 0.0007). o Unadjusted TCC was nonestimable for niraparib plus AAP versus 28.2 months for placebo (HR: 0.60; p = 0.0192). After IPTW adjustment, TCC was nonestimable for niraparib plus AAP and 25.0 months for placebo (HR: 0.49; p = 0.0012). Discussion · The analysis highlights the importance of adjusting for baseline imbalances in clinical trials, particularly in smaller studies where chance imbalances can occur. · IPTW adjustment provided a more accurate estimate of the clinical benet of niraparib plus AAP, reinforcing the ndings from the pre-specied multivariable analysis (MVA). · The results suggest that niraparib plus AAP offers signicant clinical advantages for patients with mCRPC and BRCA1/2 mutations, which are associated with poor prognosis. Strengths and Limitations · A key strength of the IPTW method is its ability to create balanced pseudopopulations while retaining data from most participants, enhancing the robustness of the ndings. · Limitations include the potential impact of unadjusted baseline characteristics and the lack of a pre-specied method for handling missing data, although the majority of patients had complete data. · The analysis did not explore the impact of baseline imbalances on adverse events, which is crucial for assessing overall treatment benet versus risk. Conclusions · The IPTW analysis conrmed the clinical benet of niraparib plus AAP in patients with mCRPC and BRCA1/2 alterations, showing a greater reduction in the risk of death and progression compared to unadjusted analyses. · These ndings support the use of niraparib plus AAP as a rst-line treatment option and emphasize the need for robust methodologies in future clinical trials to account for baseline imbalances. · The study's results are relevant for regulatory and cost-effectiveness assessments, providing a framework for future analyses in targeted populations.
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