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Clinical Trial
. 2025 Jan 17;30(1):oyae323.
doi: 10.1093/oncolo/oyae323.

Pembrolizumab ± paricalcitol in metastatic pancreatic cancer postmaximal cytoreduction

Vincent Chung  1 , Angela Alistar  2 , Carlos Becerra  3 , Anup Kasi  4 , Erkut Borazanci  5 , Gayle S Jameson  5 , Denise J Roe  6 , Betsy C Wertheim  6 , Derek Cridebring  7 , Morgan Truitt  8 , Michael Downes  8 , Michael T Barrett  9   10 , Ron Korn  11 , Keehoon Lee  10 , Haiyong Han  7 , Ronald Evans  8 , Daniel D Von Hoff  5   7
Affiliations
Clinical Trial

Pembrolizumab ± paricalcitol in metastatic pancreatic cancer postmaximal cytoreduction

Vincent Chung et al. Oncologist. .

Abstract

Lessons learned: Intravenous paricalcitol did not improve the efficacy of pembrolizumab, likely related to the short half-life.

Background: Immunotherapy has limited benefit in the treatment of advanced pancreatic cancer with the tumor microenvironment playing a key role in immune resistance. In preclinical studies, vitamin D receptor (VDR) agonists have been shown to sensitize pancreatic tumors to PD-1 blockade.

Methods: This was a randomized, double-blinded, placebo-controlled, phase II trial to evaluate pembrolizumab with or without paricalcitol as maintenance therapy for patients with metastatic pancreatic ductal adenocarcinoma (PDAC). Participants were ≥18 years; histologically or cytologically confirmed metastatic PDAC showing no disease progression after frontline systemic therapy, and achieving maximal cytoreduction (eg, with no further antitumor effect), Eastern Cooperative Oncology Group (ECOG) status of 0 or 1; adequate organ function. Study treatment included: pembrolizumab 200 mg IV every 3 weeks and either paricalcitol 25 mcg IV 3 times per week or placebo. The primary objective was to evaluate 6-month progression free survival (PFS). Secondary objectives include evaluating the toxicity of the combination and overall survival (OS).

Results: There was no significant difference in 6-month PFS, median PFS, median OS, nor treatment-related AEs between the 2 arms.

Conclusions and relevance: Paricalcitol did not improve the efficacy of pembrolizumab likely related to its short half-life of only 5-7 hours. Microbiome analysis revealed significant difference between long-term (>12 weeks) and short-term (<12 weeks) survival groups across treatment arms. Modulation of the tumor microenvironment will likely require more sustained VDR activity.

Trial registration: Clinicaltrials.gov, ID: NCT03331562.

Keywords: Paricalcitol; adenocarcinoma; maintenance therapy; pancreatic cancer; pembrolizumab.

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Conflict of interest statement

Vincent Chung reports having received research funding from Merck for Investigator Sponsored Trials (IST). Angela Alistar reports being a speaker for Merck and reviewing ad boards for Merck. Carlos Becerra reports consulting for Ipsen, Bristol Myers Squibb, and DaZen. Anup Kasi reports consulting or advisory role for Ipsen and Cardinal Health; and reports research funding (institutional) from TESARO, Astellas Pharma, Rafael Pharmaceuticals, Geistlich Pharma, Cardiff Oncology, FibroGen, Bavarian Nordic, Novocure, Cend Therapeutics, and Ability Pharma. Erkut Borazanci reports consulting for BPG, Qurient, Taiho, Clearnote, Conjupro, Elevation Oncology, Nanology, and VCN. Gayle Jameson reports having received research funding from Bristol Myers Squibb. Michael Barrett reports grants from National Cancer Institute on pancreas: UH3 CA238926-02-2: HRD-IA signatures in pancreatic ductal adenocarcinoma and R01 CA265050.-1: New Therapeutics for Pancreatic Cancer; and reports being the CEO of a National Cancer Institute funded start-up Binary Genomics. Ron Korn reports being employed by Imaging Endpoints Core Lab; and reports being an adjunct faculty at TGen/City of Hope; and reports being a consultant for HonorHealth Research Institute; and reports being a shareholder for Globavir, Renibus, and Verve; and reports patents for PCT/US2017/047026, US10854338B2, US10332634B2. Haiyong Han is an SAB member of Stromatis Pharma and a consultant for ImproveBio, Inc. Daniel Von Hoff reported Stock and Other Ownership Interests: Medtronic, CerRx, SynDevRx, UnitedHealthcare, Anthem Inc, Stromatis Pharma, Systems Oncology, Stingray Therapeutics, Orpheus Bioscience, AADi, Origin Commercial Advisors, Halia Therapeutics, Lycia Therapeutics, (3+2) Pharma. Consulting or Advisory Role: Imaging Endpoints, Senhwa Biosciences, Alpha Cancer Technologies, CanBas, Lixte Biotechnology, RenovoRx, TD2, Phosplatin Therapeutics, SOTIO, Immunophotonics, Genzada Pharmaceuticals, L.E.A.F. Pharmaceuticals, Oncology Venture, Verily, Atheneex, Novita Pharmaceuticals, Vicus Therapeutics, Agenus, Samumed, BioXCel Therapeutics, Sirnaomics, AiMed, Erimos Pharmaceuticals, Pfizer, ImmuneOncia, Viracta Therapeutics, AlaMab Therapeutics, NeoTx, Xerient, Noxxon Pharma, Lycia Therapeutics, EXACT Therapeutics, ImaginAb, SignaBlok, Compass Therapeutics, OnQuality Pharmaceuticals, Sellas Life Sciences, Catamaran Bio, Thirona Biosciences, Bristol Myers Squibb, Remix Therapeutics, SMP Oncology fka SDP/Tolero, Bessor Pharma, Coordination Pharmaceuticals, Orphagen Pharmaceuticals, Red Arrow Therapeutics, Soley Therapeutics, Invios GmbH, Mekanistic Therapeutics, POINT Biopharma, Peptomyc, Remunity, SIWA Therapeutics, Xenthera, Indaptus fka Decoy, Panavance Therapeutics fka Geistlich, CyMon Bio, Bryologyx, Moleculin Biotech, EnGeneIC, Race Oncology. Research Funding: Lilly, Genentech, Celgene, Incyte, Merrimack, Plexxikon, Minneamrita Therapeutics, Abbvie, Aduro Biotech, Cleave Biosciences, CytRx Corporation, Daiichi Sankyo, Deciphera, Endocyte, Exelixis, Five Prime Therapeutics, Gilead Sciences, Merck, Pfizer, Pharmacyclics, Phoenix Biotech, Samumed, Strategia, Halozyme. Patents, Royalties, Other Intellectual Property: Intramedullary Catheter, Methods of Human Prostate Cancer, Use of 5,6-Dihydro-5-Azacytidine in the Treatment of Prostate Cancer, Targeting Site-2 Protease (S2P) for the Treatment of Pancreatic Cancer (pending), Targeting Ecto-5-Nucleotidase (Cd73) for the Treatment of Pancreatic Cancer, Targeting a Protein Tyrosine Phosphotase-PRL-1 for the Treatment of Pancreatic Cancer (pending), Targeting a Protein PRC1 for the Treatment of Pancreatic Cancer (pending), Targeting Ecto-5-Nucleotidase (CD73) for the Treatment of Pancreatic Cancer (pending), Protein Kinase Inhibitors (pending), Methods, Compounds and Compositions with Genotype Selective Anticancer Activity (pending), Methods and Kits to Predict Therapeutic Outcome of BTK Inhibitors (pending), Muscle Fatigue Substance Cytokines and Methods of Inhibiting Tumor Growth Therewith (pending), 2-aryl-pyridylazoles for the Treatment of Solid Tumors such as Pancreatic Cancer (pending). The other authors declare no conflicts of interest.

Figures

Figure 1.
Figure 1.
CONSORT diagram
Figure 2.
Figure 2.
(A) Progression-free survival by investigator assessment. Median PFS by investigator assessment was 2.2 months in the pembro + placebo arm and 2.0 months in the pembro + paricalcitol arm (P = .87). PFS rate at 6 months was 2 patients (16.7%) in the pembro + placebo arm and 0 patients (0.00%) in the pembro + paricalcitol (P = 0.20). (B) Progression-free survival by independent assessment. Median PFS by independent assessment was 4.0 months in the pembro + placebo arm and 3.1 months in the pembro + paricalcitol arm (P = .91). PFS rate at 6 months was 1 patient (12.5%) in the pembro + placebo arm and 0 patients (0.00%) in the pembro + paricalcitol (P = .37). (C) Overall survival. Median OS demonstrated no significant difference between the pembro + placebo (10.2 months) and pembro + paricalcitol (10.4 months) arms.
Figure 3.
Figure 3.
Analysis of Composition of Microbiomes with Bias Correction(ANCOM-BC) results present the genus and species-level microbial features that exhibit a significant fold enrichment or depletion of at least 100-fold with P-values less than 0.05 in (A) Pembro + placebo, and (B) Pembro + paricalcitol treatments. Blue bars represent microbial features enriched in the >12 weeks survival group, and orange bars represent microbial features depleted in the >12 weeks survival group compared to the <12 weeks survival group. An asterisk denotes genus observed in both treatment groups.
See this image and copyright information in PMC

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