Novel systemic therapies improve survival in prostate cancer patients with visceral metastasis

Novel systemic treatments are similarly effective in reducing the risk of progression or death in patients with metastatic hormone-sensitive (mHSPC) and castration-resistant prostate cancer (mCRPC), irrespective of visceral metastasis status, reports a study.

Furthermore, “[t]he effectiveness of triplet therapy for mHSPC, regardless of the metastatic location, was further supported by treatment ranking analysis,” the investigators said. “However, to date, the lack of detailed data on the visceral metastasis sites (ie, lung vs liver), limits additional analyses.”

To analyse and compare the efficacy of combination systemic therapies, three databases were searched in July 2022 for randomized controlled trials (RCTs) that investigated metastatic prostate cancer patients treated with androgen receptor signaling inhibitor (ARSI) or docetaxel (DOC) plus androgen deprivation therapy (ADT) in addition to standard of care (SOC). [J Urol 2023;210:416-429]

The association between presence of visceral metastases and efficacy of systemic therapies in mHSPC and mCRPC patients were explored, with overall (OS) and progression-free survival (PFS) serving as the primary and secondary outcomes of interest, respectively.

The investigators conducted formal meta-analysis using fixed-effect model and network meta-analysis using random-effect model. They also followed the PRISMA* and AMSTAR** guidelines.

Twelve RCTs were included in the systematic review and eight in the meta-analyses. The addition of ARSI to SOC improved OS in mHSPC patients with visceral metastasis (pooled hazard ratio [HR], 0.77, 95 percent confidence interval [CI], 0.64‒0.94) and in those without (pooled HR, 0.66, 95 percent CI, 0.60‒0.72; no differences in both across and within-trial approach; p=0.13 and p=0.06, respectively).

Using the across-trial approach, however, patients with visceral metastasis derived significantly lower PFS benefit from ARSI plus ADT (p=0.03). Using the within-trial approach, the PFS benefit did not achieve statistical significance (p=0.14).

Analysis of treatment ranking in mHSPC revealed the highest odds of improved OS with darolutamide (DAR) plus DOC plus ADT, irrespective of visceral metastasis. In post-DOC patients with mCRPC, ARSI plus ADT resulted in significant improvements in OS of both patients with (pooled HR, 0.79, 95 percent CI, 0.63‒0.98) and without visceral metastasis (pooled HR, 0.63, 95 percent CI, 0.55‒0.72).

Previous studies reported that visceral metastasis, particularly of the liver, was associated with a higher likelihood of neuroendocrine differentiation, a predictor of biologically and clinically poor survival, which is associated with loss of androgen receptor and resistance to hormonal therapy. [BJU Int 2007;99:807-811; Am J Surg Pathol 2008;32:65-71]

“This could be an explanation for the best OS obtained with treatment intensification (ie, adding chemotherapy to hormonal therapy) in patients with visceral metastasis,” the investigators said. “Our analyses, indeed, confirmed the utility of triplet therapy even for mHSPC patients with visceral metastasis, with the highest clinical benefit being reached for triplet therapy with DAR + DOC + ADT.”

In addition, none of the RCTs analysed reported the differential oncologic outcomes stratified by lung vs liver metastases.

“There is a need for standardizing reporting outcomes in future RCTs to clarify the differential oncologic results stratified by detailed visceral metastatic sites, the number, and timing of emergence of metastatic lesions with possible impact of novel imaging,” the investigators said.

*Preferred Reporting Items for Systematic Reviews and Meta-analyses

**A MeaSurement Tool to Assess systematic Reviews