Pembrolizumab with or without enzalutamide in selected populations of men with previously untreated metastatic castration-resistant prostate cancer harbouring programmed cell death ligand-1 staining: a retrospective study

Abstract

Background The purpose of this retrospective study was to evaluate the survival outcomes of pembrolizumab (PEM) plus enzalutamide (ENZ) versus PEM alone in selected populations of men with previously untreated metastatic castration-resistant prostate cancer (mCRPC) harbouring programmed cell death ligand-1 (PD-L1) staining. Methods Consecutive men with previously untreated mCRPC harbouring PD-L1 staining who underwent treatment with PEM plus ENZ (PE) or PEM alone (PA) at our medical centre from January 1, 2017, to January 31, 2021, were retrospectively identified. Follow-up was conducted monthly during the first year and then every 1 month thereafter. The primary outcomes of the study were overall survival (OS) and progression-free survival (PFS). Secondary outcomes were the frequency of key adverse events (AEs). Results In total, 302 men were retrospectively reviewed, 96 of whom were deemed to be ineligible per the exclusion criteria, leaving 206 men (PE: n = 100, median age 64 years [range, 43–85] and PA: n = 106, 65 years [range, 45–82]) who were eligible for the study. The median follow-up for both groups was 34 months (range, 2–42). At the final follow-up, the median OS was 25.1 months (95% confidence interval [CI], 22.3–27.6) in the PE group versus 18.3 months (95% CI, 16.5–20.9) in the PA group (hazard ratio [HR] 0.56; 95% CI, 0.39–0.80; p = 0.001). A marked distinction was also observed in the median PFS (6.1 months [95% CI, 4.7–7.8] for PE vs. 4.9 months for PA (95% CI, 3.2–6.4) for PA; HR 0.55, 95% CI, 0.41–0.75; p = 0.001). There were noteworthy differences in the rate of the key AEs between the two groups (72.0% for PE vs. 45.3% for PA, p < 0.001). Noteworthy differences were also detected for fatigue events (7.0% in the PE group vs. 0.9% in the PA group, p = 0.025) and musculoskeletal events (9.0% for PE vs. 0.9% for PA, p = 0.007), but these events tended to be manageable. Conclusions Among selected populations of men with previously untreated mCRPC harbouring PD-L1 staining, PEM added to ENZ treatment may significantly increase the survival benefits compared with PEM treatment alone regardless of tumor mutation status. The safety profile for PE plus ENZ tends to be manageable.

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 1: Focus on Immunohistochemical Results with Discussion of Pre-Analytical and Interpretation Variables

“…In addition, various PD-L1 antibody clones were rarely simultaneously tested on the same series. Considering the heterogenous or focal expression of PD-L1 by PC cells (Figure 2), the use of TMA reduced the number of evaluable cells, probably causing false-negative results in some cases; conversely, some trials included only PD-L1+ cases, causing a selection bias for the abovementioned positivity rates [154].…”

“…Based on the results of our review, the positivity rate of different PD-L1 antibody clones in tumor cells ranged from 3% (SP142) to 50% (ABM4E54), excluding the single case tested for RM-320. The positivity rate of clone 22C3 (the most used to assess eligibility for administration of pembrolizumab) was 11% after excluding cases with a CPS score of ≥1 (as it was unclear if tumor cells resulted positive), 41% after including those cases, and 78% only considering the cases scored as CPS ≥1 [9,12,13,21,27,32,35,51,77,80,83,90,154].…”

“…9/523 (2%) cases expressed PD-L1 on >50% of tumor cells [66,92], while Wang et al used a cut-off of ≥25% (0/21, 0%) [61]. The remaining studies applied different scoring criteria, also including tumor proportion score (TPS) (9/51 PD-L1+ PCs, 18%) [59] or combined positive score (CPS ≥ 1: 362/464 cases, 78%) [9,154].…”

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 3: PD-L1, Intracellular Signaling Pathways and Tumor Microenvironment

“…Chromosome 9p gains are common DNA copy number aberrations, significantly associated with advanced tumor stage and regional lymph node metastases in sporadic PCs [157,158]. Budczies et al identified a 7.8-Mbp region of 38 genes located in chromosome 9p24, including genes regulating cell cycle and immune-response in PC (such as PD-L1, PD-L2 and JAK2).…”

“…Despite the cytoplasmatic protein tail lacks the canonical motifs for signal transduction, PD-L1 reverse intracellular signaling has been recently demonstrated in immune cells, lymphomas and solid tumors. Some non-canonical signaling transduction motifs have been identified in the intracellular tail, being involved in cancer cell proliferation and survival, inhibition of autophagy, mTOR activation, and IFN-β toxicity [158,184].…”