First-line Systemic Treatment Options for Metastatic Castration-Sensitive Prostate Cancer: A Living Systematic Review and Network Meta-analysis

Abstract

Importance: The effectiveness of triplet therapy compared with androgen pathway inhibitor (API) doublets in a heterogeneous patient population with metastatic castration-sensitive prostate cancer (mCSPC) is unknown.

Objective: To assess the comparative effectiveness of contemporary systemic treatment options for patients with mCSPC across clinically relevant subgroups.

Data sources: For this systematic review and meta-analysis, Ovid MEDLINE and Embase were searched from each database's inception (MEDLINE, 1946; Embase, 1974) through June 16, 2021. Subsequently, a "living" auto search was created with weekly updates to identify new evidence as it became available.

Study selection: Phase 3 randomized clinical trials (RCTs) assessing first-line treatment options for mCSPC.

Data extraction and synthesis: Two independent reviewers extracted data from eligible RCTs. The comparative effectiveness of different treatment options was assessed with a fixed-effect network meta-analysis. Data were analyzed on July 10, 2022.

Main outcomes and measures: Outcomes of interest included overall survival (OS), progression-free survival (PFS), grade 3 or higher adverse events, and health-related quality of life.

Results: This report included 10 RCTs with 11 043 patients and 9 unique treatment groups. Median ages of the included population ranged from 63 to 70 years. Current evidence for the overall population suggests that the darolutamide (DARO) triplet (DARO + docetaxel [D] + androgen deprivation therapy [ADT]; hazard ratio [HR], 0.68; 95% CI, 0.57-0.81), as well as the abiraterone (AAP) triplet (AAP + D + ADT; HR, 0.75; 95% CI, 0.59-0.95), are associated with improved OS compared with D doublet (D + ADT) but not compared with API doublets. Among patients with high-volume disease, AAP + D + ADT may improve OS compared with D + ADT (HR, 0.72; 95% CI, 0.55-0.95) but not compared with AAP + ADT, enzalutamide (E) + ADT, and apalutamide (APA) + ADT. For patients with low-volume disease, AAP + D + ADT may not improve OS compared with APA + ADT, AAP + ADT, E + ADT, and D + ADT.

Conclusions and relevance: The potential benefit observed with triplet therapy must be interpreted with careful accounting for the volume of disease and the choice of doublet comparisons used in the clinical trials. These findings suggest an equipoise to how triplet regimens compare with API doublet combinations and provide direction for future clinical trials.

Figure 1.. Forest Plot Summarizing Evidence for Overall Survival Across Clinically Relevant Subgroups: Volume of Disease and Timing of Metastatic Presentation

The forest plot summarizes relative effect (hazard ratios [HRs]) of different comparisons by volume of disease and timing of metastatic presentation derived from mixed treatment comparisons. An HR greater than 1 indicates potential clinical harm with the treatment; an HR less than 1 indicates potential clinical benefit with the treatment. 95% CIs crossing 1 indicate statistically nonsignificant results. API indicates androgen pathway inhibitors. ^aTriplet therapy is abiraterone or darolutamide plus docetaxel and androgen deprivation therapy (ADT) in overall patient population. Triplet therapy is abiraterone plus docetaxel and ADT in high and low volume of disease. ^bTriplet therapy is abiraterone or darolutamide plus docetaxel and ADT in overall patient population and in synchronous (de novo) metastases. Triplet therapy is darolutamide plus docetaxel and ADT in metachronous (recurrent) metastases.

Figure 2.. Grading of Recommendations Assessment, Development and Evaluation Summary of Findings Table Outlining Certainty of Evidence and Absolute Risks With Triplet Therapy (Columns) Compared With Other Treatments (Rows) in Overall Patient Population

Summary of relative and absolute risks for mixed treatment comparisons derived from frequentist network meta-analysis using 4 levels of certainty: high (further research very unlikely to change confidence in estimate of effect), moderate (further research likely to have important association with confidence in estimate of effect and may change the estimate), low (further research very likely to have important association with confidence in estimate of effect and likely to change the estimate), and very low (very uncertain about the estimate). Values in cells indicate relative and absolute effect estimates for comparisons between triplet therapies (abiraterone and darolutamide triplet therapies) and other treatment options (androgen pathway inhibitor [API] doublet, docetaxel doublet, and androgen deprivation therapy [ADT]). Each comparison consists of absolute reduction in risk of events (upper cell) with triplet therapies compared with other treatments, relative effect hazard ratios (HRs; upper middle cell), sample size contributive to evidence (lower middle cell), and relative rank of treatment in a row (lower cell). AE indicates adverse event; NSAA, nonsteroidal antiandrogen; OS, overall survival; PFS, progression-free survival; RCTs, randomized clinical trials; RR, relative risk; and TAK, orteronel. ^aRated down 2 levels owing to very serious imprecision, considering null effect and wide 95% CIs indicating both potential benefit and harm. ^bRated down 1 level owing to serious imprecision, considering wide 95% CIs. ^cRated down 1 level owing to serious indirectness in definition of PFS used across trials; PFS may be an advantageous end point for APIs owing to fixed dosing schedule of docetaxel compared with most API trials that used an indefinite dosing until disease progression.

Figure 3.. Grading of Recommendations Assessment, Development and Evaluation Summary of Findings Table Outlining Certainty of Evidence and Absolute Risks With Triplet Therapy Compared With Other Treatments by Volume of Disease

Summary of relative and absolute risks for mixed treatment comparisons derived from frequentist network meta-analysis using 4 levels of certainty: high (further research very unlikely to change confidence in the estimate of effect), moderate (further research likely to have important association with confidence in estimate of effect and may change the estimate), low (further research very likely to have important association with confidence in estimate of effect and likely to change the estimate), and very low (very uncertain about the estimate). Values in cells indicate relative and absolute effect estimates for comparisons between triplet therapy (abiraterone triplet) and other treatment options (androgen pathway inhibitor [API] doublet, docetaxel doublet, and androgen deprivation therapy [ADT]) by volume of disease. Each comparison consists of absolute reduction in risk of events (upper cell) with triplet therapy compared with other treatments, relative effect hazard ratios (HRs; upper middle cell), sample size contributive to evidence (lower middle cell), and relative rank of treatment in a row (lower cell). NSAA indicates nonsteroidal antiandrogen; OS, overall survival; PFS, progression-free survival; and RCTs, randomized clinical trials. ^aRated down 2 levels owing to very serious imprecision, considering null effect, wide 95% CIs indicating both potential benefit and harm, and low sample size of less than 1000. ^bRated down 1 level owing to serious indirectness in definition of PFS used across trials; PFS may be an advantageous end point for APIs owing to fixed dosing schedule of docetaxel compared with most API trials that used an indefinite dosing until disease progression. ^cRated down 1 level owing to wide 95% CI.