Addition of Eniluracil to Capecitabine May Improve Activity Without Increased Toxicity in Advanced/Metastatic Breast Cancer

Eniluracil (PCS6422) in combination with capecitabine displayed the potential for improved clinical efficacy and maintained a manageable safety profile for the treatment of patients with advanced or metastatic breast cancer, according to topline data from a phase 2 study (NCT06568692).1

Findings from the first 16 of 19 patients enrolled in the study demonstrated that the combination significantly increased exposure to capecitabine cancer-killing drug metabolites without increasing the severity of adverse effects (AEs) compared with capecitabine monotherapy. The full interim analysis from the first 20 patients, including efficacy and safety results, is expected in early 2026.

“These emerging data continue to validate the central premise of our Next Generation Cancer strategy,” David Young, PhD, PharmD, president of research and development and founder of Processa Pharmaceuticals, stated in a news release. “Capecitabine combined with [eniluracil] appears to meaningfully increase exposure to the capecitabine metabolites responsible for killing cancer cells, while reducing exposure to the catabolite metabolites associated with dose-limiting toxicity such as hand-foot-syndrome [HFS], a profile that is difficult to achieve with conventional Mono-Cap dosing.”

Eniluracil is an irreversible inhibitor of the dihydropyrimidine dehydrogenase enzyme that metabolizes 5-FU to noncancer killing catabolites.2 Since the agent eliminates 5-FU metabolism to catabolites until de novo synthesis of dihydropyrimidine dehydrogenase enzyme occurs, 5-FU elimination is temporarily decreased, leading to an increase in both 5-FU systemic exposure and an increase in cancer cell exposure to 5-FU anabolites.

How was the phase 2 study designed?

The open-label, multicenter, global, randomized study enrolled adult patients with unresectable histologically confirmed breast cancer, including those with advanced or metastatic triple-negative breast cancer and those with hormone receptor–positive, estrogen receptor–positive, HER2-negative advanced or metastatic breast cancer. Eligible patients also needed to have measurable disease per RECIST 1.1 criteria per imaging within 28 days of day 1 of cycle 1, not be indicated for other therapies for the treatment of metastatic breast cancer, and have a life expectancy of at least 24 weeks.

The study employed an adaptive design in which the first 18 to 20 patients were randomly assigned 1:1 to receive a single dose of eniluracil at 40 mg plus capecitabine at 150 mg twice daily (arm A) or capecitabine monotherapy at 1000 mg/m2 twice daily (arm C). Once the first 18 to 20 patients are enrolled, the data monitoring committee will determine whether arm B will open and what dose of capecitabine will be used (75 mg BID vs 225 mg BID).

The primary objectives were overall response rate, safety and tolerability, and determining the optimal dosage regimens of the combination. Secondary objectives included disease control rate, duration of response, time to response, progression-free survival, overall survival, and pharmacokinetic measures.

What were the additional topline data from the phase 2 study?

Additional findings from the phase 2 study demonstrated that a greater proportion of patients who received eniluracil plus capecitabine experienced AEs related to capecitabine cancer-killing metabolites. Moreover, the total number of AEs per patient was higher with the combination compared with the capecitabine monotherapy arm. However, the severity of AEs was similar between the 2 arms, indicating that increased activity with the combination did not translate into more severe toxicity.

“As we approach our planned interim analysis, we believe NGC-Cap continues to demonstrate a differentiated pharmacologic profile that could meaningfully improve the therapeutic index of capecitabine-based therapy,” George Ng, the chief executive officer of Processa Pharmaceuticals, added in the news release. “We view this program as a key value driver for the company and an important opportunity for patients with advanced or metastatic breast cancer.”

References

1. Processa Pharmaceuticals provides clinical update on phase 2 study in metastatic breast cancer. News release. Processa Pharmaceuticals. December 17, 2025. Accessed December 17, 2025. https://www.processapharmaceuticals.com/investors/news-events/press-releases/detail/142/processa-pharmaceuticals-provides-clinical-update-on-phase
2. Yound D, Bigora SE, Nyberg M, et al. Adaptive designed eniluracil + capecitabine phase 2 trial in advanced or metastatic breast cancer patients. J Clin Oncol. 2025;43(suppl 16):TPS1133. doi:10.1200/JCO.2025.43.16_suppl.TPS1133