SHARON Trial Offers a Potential Approach for Advanced Pancreatic Cancer

A potential new approach to treating advanced pancreatic cancer has shown benefit for patients, according to Dr. Eileen M. O'Reilly, who sat down for an interview with CURE.

The SHARON trial is a phase 1 study testing a new treatment called GO-4 for patients with advanced pancreatic cancer who have BRCA or PALB2 mutations. GO-4 combines chemotherapy with vitamins and a patient’s own stem cells to help target cancer cells more effectively while protecting healthy cells, according to the trial information.

Early data show that the treatment has been safe, and some patients with pancreatic cancer who were responding to therapy have seen long-lasting benefits. The trial is ongoing and will expand to include patients without BRCA or PALB2 mutations.

During the interview, O’Reilly discussed the trial’s design, early results, patient selection and the multidisciplinary care required to safely deliver this precision-based approach for individuals with pancreas cancer.

O'Reilly is a gastrointestinal medical oncologist at Memorial Sloan Kettering Cancer Center in New York. She serves as the Winthrop Rockefeller Endowed Chair of Medical Oncology, chair of the Human Research Protection Program and Institutional Review Board, co-director of Medical Initiatives at the David M. Rubenstein Center for Pancreatic Cancer Research, and section head of Hepatopancreatobiliary Oncology.

CURE: Can you provide an overview of the SHARON trial and explain its significance in the treatment of advanced pancreatic cancer?

O'Reilly: The SHARON study is a very interesting, unique trial that, to date, has been focused on individuals with pancreas cancer and breast and a couple of other malignancies who have a germline BRCA1, BRCA2 or PALB2 mutation. These are individuals who have a unique genetic context to their cancer, where the cancers tend to respond well to platinum-based therapies and classes of drugs called PARP inhibitors and alkylating agents.

With that backdrop, this study was designed to provide higher doses than we traditionally use of chemotherapy and alkylating agents, combined with several vitamins, which are modulators of various metabolism pathways and may augment the activity of this whole strategy and help surmount resistance, which is a critical issue in treating cancer in general, but very specifically in pancreas cancer.

The idea here is patients are selected based on health and relative well-being. They receive two courses of chemotherapy that are segregated by a period of time, and they initially undergo harvesting of their stem cells, and then their cells are re-infused after the chemotherapy. There's a period of time when blood counts are low and the body is vulnerable, and then the person is carefully monitored, and the blood counts recover. That's done once, and then that's done a second time.

That's the overall structure of the trial. It takes a number of months, and individuals are re-evaluated for the status of their cancer before starting, during the treatment and on completion of the treatments.

Early data from this trial have shown notable responses after just two treatment cycles. What factors do you believe contributed to these durable responses in certain patients?

There is a very intriguing and encouraging signal that's been identified. To put it conservatively, outcomes for a few people have been very striking and very durable, which is very compelling in this disease as a potential strategy that may have a role for this group of individuals in particular, but also perhaps in other subsets of individuals with pancreas cancer.

In terms of the characteristics for those who might be most destined to benefit, I think there are a few that we've observed. Firstly, having disease that's responding to treatments is a good surrogate for having a higher chance of a deeper and a more durable outcome. That's an important point. Having a good level of health and well-being going into this is important.

Another factor may be the extent of the cancer present going into the study, so people who have a lower volume of disease or less visible cancer seem to be more likely to benefit. That context is set by how well a person's prior treatment had worked going into the trial. Those with responding disease, those with less visible cancer, and those with a good level of health and well-being. These are characteristics that suggest a potential for enhanced benefits.

How does the regimen being explored in this trial differ from traditional therapies for pancreatic cancer, and what aspects do you think make it stand out from other approaches?

For most individuals with pancreas cancer, the current mainstays will be chemotherapy-based programs, usually a combination of drugs such as FOLFIRINOX or gemcitabine and nab-paclitaxel. These would be commonly used, guideline-approved, FDA-cleared regimens for this disease, and they have an ability to shrink the cancer, control disease and extend life. Resistance is a common occurrence in the field of cancer in general, and again, specifically in pancreas cancer. We are always looking for ways as to how we can bypass resistance and maybe exploit unique vulnerabilities of certain cancer cells to more effectively target treatment.

Arguably, this approach is one of precision medicine because it's based on impacting DNA repair, which is altered when a person has a BRCA or a PALB2 mutation. Their cancer cells are less able to repair damage, for want of a better word, that happens as a result of a treatment, and that process is much more pronounced in the cancer cells relative to normal cells in the body. This treatment approach from the SHARON study extends that to a greater degree, suggesting that giving higher doses of treatment may be able to further overcome those more resistant cells and dampen them down even more with this approach. With the combinations that are used as part of the treatment, it's preventing some of the bypass pathways, and it's protecting some normal cells from some of the side effects of treatment.

There is very interesting, very compelling science behind the treatment design, and I think we're collectively encouraged to see that it's been largely well-tolerated, certainly been safe, and that we're able to deliver this treatment, which is complex and multidisciplinary, and see these outcomes.

Supportive care and close monitoring are critical for patients participating in novel clinical trials. How did you and your team guide patients through the trial, both medically and emotionally?

In the context of the trial, we need to consider how we can maximize the benefits and minimize the side effects and discomfort. When there are complexities to the treatments, they can require a lot of resources, a lot of support, and a lot of expertise from multiple disciplines, therefore a team-based approach is key.

Here, that involves collaborating with gastrointestinal oncology (oncologists who specialize in these malignancies) and collaborating with our transplant team, who have expertise in conducting and overseeing patients who undergo various types of transplants. It requires expertise from infectious disease to treat infection, from pharmacy for safe drug preparation and delivery, from nursing staff, and from all our data management, and all the large group of people that it takes to look after individuals.

It involves a lot of monitoring, a lot of oversight and a lot of careful review. We encourage, of course, individuals who are participating in this or any study to be very forthright with what they're experiencing, and early intervention is key, especially when blood counts are low, and a person's body is vulnerable in terms of infection.

There is the other layer that isn't clear to participants: all the important regulatory requirements that go into the conduct of a trial. There is an independent safety review committee reviewing the data, and there is an Institutional Review Board (IRB) and privacy board that is protecting the rights and welfare of participants in studies. These require regular reporting and accountability for the safe conduct of this and other clinical trials. It is a large group of people and a large-scale effort that's involved in this and other studies.

Other disciplines that are really helpful are social support systems, sometimes from the Counseling Center, from our dietitian colleagues, and from physical therapists. They all facilitate and have an important role to play in terms of multidisciplinary input and care for people with cancer.

Can you describe how the study is evolving beyond BRCA1, BRCA2 and PALB2, and what considerations are being made to ensure safety, feasibility and identification of the optimal target population?

Currently, it's focused on BRCA1, BRCA2, and PALB2. The discussion is extending to other genetic contexts and even non-genetic contexts to understand if this continues to be safe and feasible, and whether there might be a signal in other populations of individuals with this disease.

We are taking the early experience and scaling it, but scaling it in a conservative, safe way to expand the potential value of this type of approach. As this continues, we want to refine as much of the protocol as we can to maybe streamline some parts of it, and to learn if slightly different doses might even be better. To some degree, broadening the patient population can make it a little easier and quicker to identify those particular endpoints, but ultimately, and key, will be understanding who the target group of individuals for the study are, and if that extends beyond core homologous repair deficiency genes.

What are the key takeaways for patients and families considering this novel pancreatic cancer study?

I think it's "stay tuned." This is a highly novel strategy in the treatment of pancreas cancer, which is taking some older observations in science and medicine and applying them in a very focused, precision-enriched group of individuals who we think are most likely to benefit from this approach.

Overall, a lower burden of cancer in general, in terms of the visible amount of disease, and having a good level of health and well-being is probably the best entry point to this type of study, along with. This approach is not going to be for everybody. I think when a person or their family hears about this, it's going to be an important discussion with their team. It's a big commitment; it takes a fair amount of time, it requires some time away from family, and there can be some potentially serious side effects. Fortunately, that hasn't been observed, and everything has been safely managed.

These are all things that one would weigh up in the context of the early signal and establishing the precedent that this may have a role in how we treat a subgroup of individuals with pancreas cancer.

Transcript has been edited for clarity and conciseness.

Reference

1. “General Oncology Announces Promising Preliminary Phase 1 Results from SHARON Trial Presented at ESMO 2025,” by General Oncology. News release; Oct. 18, 2025.

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