Effect of abiraterone-prednisone in metastatic castrationsensitive prostate cancer (mCSPC) with neuroendocrine and very high-risk features in the PEACE-1 trial

The PEACE-1 trial demonstrated improved overall survival (OS) in de novo mCSPC patients treated with a combination of androgen deprivation therapy, docetaxel, and abiraterone (AA) plus prednisone. Prostate cancers with neuroendocrine differentiation (NEPC) are rare. Most trials exclude de novo NEPC, thus their standard of care remains uncertain. As NEPC was allowed in PEACE-1, we aimed to assess the effect of AA in NEPC and those with very high-risk factors (Gleason >8, liver metastases). We reviewed local pathological reports (biopsy site, WHO pathological classification, chromogranin A (CgA), and synaptophysin immunohistochemical [NE IHC] staining) from patients randomized in PEACE-1. Baseline characteristics were compared between patients with and without NEPC. Prognostic value of NEPC and high-risk factors on radiographic progression-free survival (rPFS) and OS was studied by Cox models. Predictive value of these factors was assessed by adding an interaction between AA and each factor. Pathological reports were available for 1087 out of 1172 patients (97%). NE IHC was only locally performed in 18% of patients and NEPC diagnosed in 2.4%. Among reports with NE IHC, 13.2% (n =26) of patients had an adenocarcinoma with NE differentiation and 0.5% had pure NEPC. PSA at baseline was significantly lower in NEPC than in adenocarcinoma without NEPC (p=0.003). Baseline disease burden, visceral metastasis, and Gleason scores were similar in both group. NE features predicted for both rPFS (median 1.6 vs 2.9 years; HR 2.2, 95%CI [1.4-3.5], p=0.0004) and OS (median 2.4 vs 5.1 years; HR 2.7, 95%CI [1.7-4.4], p<0.0001). The effect of AA could not be reliably assessed due to an insufficient number of NEPC. The Gleason score (6-7 vs 8 vs 9-10) had no impact on the effect of AA on OS (p=0.73). Among patients with liver metastases (n=36), AA improved rPFS (HR 0.3, 99.9%CI [0.08-1.00], p=0.06) and tended to improve OS (HR 0.5, 95.1%CI [0.23-1.10], p=0.22). Only a very small minority of men with mCSPC are diagnosed with NEPC by their local pathologist, questioning the need for more systemic IHC in these men. AA significantly improves rPFS in patients with liver metastases.