SHARON Trial Shows Promising Results for BRCA-Mutated Pancreatic Cancer Using Stem Cell Transplant
Key Insights
The phase 1 SHARON trial demonstrated that melphalan, BCNU, hydroxocobalamin, and ascorbic acid followed by autologous stem cell transplant was safe and feasible for stage IV pancreatic cancer (search) patients with BRCA1 (search)/2 or PALB2 (search) mutations.
Patients achieved a median progression-free survival of 14.2 months, nearly doubling the 7.5 months seen in the POLO trial with olaparib, despite having more aggressive disease and prior treatment lines.
The treatment showed a 100% disease control rate in non-progressing patients, with 40% achieving durable response free of disease after transplant.
The phase 1 SHARON trial has demonstrated promising efficacy signals for patients with stage IV pancreatic ductal adenocarcinoma (search) (PDAC) harboring BRCA1 (search)/2 or PALB2 (search) mutations, using an innovative approach combining high-dose chemotherapy with autologous stem cell transplant. Results presented at the European Society for Medical Oncology Congress 2025 showed the regimen was both safe and feasible, with encouraging survival outcomes that compare favorably to established BRCA-targeted therapies.
Trial Design and Patient Population
The SHARON trial (NCT04150042) evaluated a combination of melphalan, BCNU, hydroxocobalamin (vitamin B12), and ascorbic acid, followed by autologous stem cell transplant in patients with stage IV PDAC or breast cancer (search) who have germline BRCA1 (search)/2 or PALB2 (search) mutations. The study enrolled patients with more aggressive disease compared to previous trials, with participants having received an average of three prior lines of therapy.
"We were looking at patients with germline mutations and BRCA1 (search)/2, and probably 5% to 10% of the patients with pancreatic cancer (search) harbor a germline mutation in one of these genes," explained Kenneth H. Yu, MD, a gastrointestinal medical oncologist at Memorial Sloan Kettering Cancer Center and lead investigator of the trial.
Superior Efficacy Compared to Standard Care
The trial achieved a median progression-free survival of 14.2 months in patients similar to those in the landmark POLO trial, nearly doubling the 7.5 months observed with olaparib maintenance therapy. Notably, the SHARON trial included a more challenging patient population, enrolling both patients responding to platinum therapy and those with progressive disease.
"In all comers, the patients did well. It's a short duration of follow-up, but on average, patients are living more than 3 years," Yu noted. "In the POLO trial, the median overall survival is only about 20 months. Even in our group of patients who had more aggressive disease, the overall survival number looked to be comparable, if not a little bit better, numerically."
Exceptional Response Rates
Among patients who were not progressing on therapy at enrollment, the trial achieved a 100% disease control rate, with all patients experiencing either partial response or stable disease. Two patients remained free of progression off treatment after transplant, representing a 40% durable response rate free of disease.
At the median follow-up of 14.2 months, 25% of PDAC patients remained disease-free at 11, 23, and 42 months, with the median progression-free survival not yet reached for the overall pancreatic cancer (search) cohort.
Safety Profile and Tolerability
The treatment regimen demonstrated an acceptable safety profile, with expected hematologic toxicities that resolved appropriately. "The transplant seemed to be very safe in patients who have had these BRCA mutations and who undergo the transplants. They all tolerate the transplant well," Yu reported.
The primary adverse effects were infusion-related reactions to vitamin C and vitamin B12, which are investigational additions to the standard transplant protocol designed to enhance DNA damage through reactive oxygen species modulation. The research team has developed supportive care measures to improve tolerance of these vitamin infusions.
Mechanistic Rationale
The trial's scientific foundation rests on the enhanced sensitivity of BRCA-mutated tumors to DNA repair-targeted agents. "The rationale for the SHARON trial was that if we could give other DNA-damaging agents—for example, in stem cell transplants, we give drugs like BCNU or melphalan—they can attack the DNA repair mechanism even more potently, we think, than platinum agents," Yu explained.
Future Development Plans
Based on these encouraging results, investigators plan to enroll 15-20 additional patients in the phase 1 portion before advancing to phase 2. Future development will focus on patients who are not progressing on chemotherapy, as this subgroup demonstrated the most durable responses.
"For patients after surgery, perhaps this can be used to reduce the risk of the cancer coming back, and also in patients with advanced disease who have responded to chemotherapy, as a way of trying to get them a durable period of time away from treatment," Yu outlined for the treatment's potential applications.
The research team is also considering expansion to patients with somatic BRCA1 (search)/2 mutations, though these plans remain in the conceptual stage. The approach represents a potentially transformative treatment option for BRCA-mutated pancreatic cancer (search) patients, offering hope for more durable disease control in this challenging malignancy.