Comparative Survival in Metastatic Hormone-sensitive Prostate Cancer by Volume of Disease and Timing of Metastasis: A Living Network Meta-analysis.

[BACKGROUND AND OBJECTIVE] We aimed to assess the comparative effectiveness of contemporary systemic treatment options across patients with metastatic hormone-sensitive prostate cancer (mHSPC) across clinically relevant prognostic subgroups (synchronous high [SHV] and low [SLV] volume, and metachronous high [MHV] and low [MLV] volume).

[METHODS] This living network meta-analysis was conducted using the living interactive evidence (LIvE) synthesis framework. Phase 3 randomized controlled trials assessing treatment intensification with androgen receptor pathway inhibitors (ARPIs), docetaxel (D), or both were included. Mixed treatment comparisons were conducted for overall population and for each prognostic subgroup (SHV, SLV, MHV, and MLV). Overall survival (OS) and progression-free survival were assessed.

[KEY FINDINGS AND LIMITATIONS] The current report of a living systematic review includes a total of 11 trials (12 668 patients and 12 unique treatments). In the overall population, the results were consistent with those of a previous report. An analysis of OS by prespecified subgroups included nine clinical trials (8990 patients and eight unique treatments). In the SHV subgroup (N = 5171; 57%), ARPI + D + androgen deprivation therapy (ADT) led to a statistically significant improvement in OS compared with D + ADT (hazard ratio: 0.72; 95% confidence interval: 0.62-0.83) and ARPI + ADT (0.71; 0.53-0.97). In the SLV subgroup (N = 2455; 27%), ARPI + ADT led to a statistically significant improvement compared with ADT alone (0.65; 0.52-0.80). There was no statistically significant difference between ARPI + D + ADT and ARPI + ADT (1.08; 0.65-1.79). In the MHV subgroup (N = 589; 6.5%), no statistically significant improvement was observed with ARPI + D + ADT compared with ARPI + ADT (0.89; 0.43-1.85) and D + ADT (0.90; 0.60-1.36). There was no statistically significant difference between ARPI + ADT and D + ADT (1.02; 0.45-2.28). In the MLV subgroup (N = 775; 8.5%), ARPI + ADT led to a statistically significant improvement compared with ADT alone (0.43; 0.29-0.64) and D + ADT (0.41; 0.24-0.70). There was no statistically significant difference between ARPI + D + ADT and ARPI + ADT (1.56; 0.40-6.25). Inherent limitations of this analysis include the inability to account for all relevant variables such as the patient- and cancer-related factors that likely influenced the decision of physicians to offer docetaxel to patients.

[CONCLUSIONS AND CLINICAL IMPLICATIONS] Current evidence suggests that triplet systemic therapy is preferred for patients with SHV mHSPC who are fit for docetaxel. Androgen receptor pathway doublet therapy is preferred for all other patient subgroups compared with ADT alone. There is no role of docetaxel doublet in patients with access to ARPI therapy and if they are able to receive it.