First-line treatment options in metastatic castration-sensitive prostate cancer: A systematic review and network meta-analysis.
Authors: Riaz Irbaz Bin , Naqvi Syed Arsalan Ahmed , Ikram Waleed , Siddiqi Rabbia , Asghar Noureen , Khakwani Kaneez Zahra Rubab , Khalid Atiqa , Hussain Syed A. , Singh Parminder , Bryce Alan Haruo 
Published: February 2022

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Background: Treatment landscape for metastatic castration-sensitive prostate cancer (mCSPC) is rapidly evolving. Recent updates of relevant trials and presentation of PEACE-1 results warranted mixed treatment comparisons to inform the choice of treatment in mCSPC. Methods: MEDLINE and EMBASE, along with conference proceedings were searched using a systematic search strategy to identify relevant abstracts and full-text publications of phase II/III randomized controlled trials (RCTs) assessing first-line treatment options in mCSPC. Outcomes of interest included overall survival (OS), radiographic progression-free survival (rPFS), and grade ≥3 adverse events (AEs). Direct comparisons were made using DerSimonian-Laird random-effects meta-analysis. Fixed-effect frequentist NMA was conducted to compute network estimates using a multivariate meta-regression approach. Relative treatment rankings were assessed in congruency with direct estimates using P-scores. Secondary NMAs were conducted in several substrata (young, and old; Gleason score < 8 and ≥8; performance status 0 and 1-2, low and high volume of disease). Results: This NMA included nine trials (23 references) with nine unique treatments. rPFS was improved with abiraterone acetate and prednisone-docetaxel-androgen deprivation therapy combination (AAP-D-ADT; rank 1) when compared against most treatment options including AAP-ADT (HR: 0.58, 95% CI: 0.44-0.76; rank 5), apalutamide (APA)-ADT (HR: 0.63, 95% CI: 0.46-0.87; rank 4), TAK-ADT (HR: 0.55, 95% CI: 0.36-0.84; rank 6), and enzalutamide(E)-AAP-ADT (HR: 0.70, 95% CI: 0.51-0.97; rank 3), however no significant differences were observed between AAP-D-ADT, and E+ADT (rank 2). Improved OS was observed with AAP-D-ADT (HR: 0.75, 95% CI: 0.59-0.95; rank 2), E-AAP-ADT (HR: 0.68; 95% CI: 0.48-0.97; rank 1), and AAP-ADT (HR: 0.82, 95% CI: 0.70-0.96; rank 3) compared to D+ADT (rank 6). However, most of the mixed treatment comparisons were statistically insignificant in terms of OS. Similarly, in patients with high volume of disease, AAP+D+ADT (rank 1) was observed to significantly improve rPFS compared to AAP-ADT, APA-ADT, E-ADT, and D-ADT; however, no significant differences were observed among treatment comparisons with regards to OS improvement. E+ADT (rank 1) improved rPFS compared to other treatment in low volume disease but was not different for OS. No significant differences were observed among different treatment options when compared across prespecified subgroups. Moreover, AAP+D+ADT was ranked as the least safe with significantly increased risk of grade 3 AEs relative to other treatments. Conclusions: Current NMA suggests that triplet therapy options were ranked as most likely to improve rPFS and OS at the cost of increased toxicity. Doublet combinations may still be preferred for older patients with low volume of disease.