Clinical Trials Unite Doctors, Researchers, and Patients to Advance Treatments
October 1, 2025
By Nicole Davis, PhD
Evaluating new medical therapies in people through a rigorous, systematic process, known as a clinical trial, is the pinnacle of clinical research and the primary mechanism through which novel treatments are proven safe and effective in cancer — or any other disease.
Yet the path from an early first-in-human study to demonstrate safety (known as a phase 1 trial) to a large, randomized, phase 3 study to prove a new treatment is superior to current, standard therapies can often take a decade or more.
"Enrolling in a clinical trial expands treatment options for patients and may provide access to therapies that are more effective than what is otherwise available," says Sara Tolaney, MD, MPH, chief of Breast Oncology at Dana-Farber's Susan F. Smith Center for Women's Cancers. "There is also broader societal impact as future patients benefit from today's participants, whose contributions help advance science and improve outcomes for others. The ripple effect patients create through clinical trial participation is truly profound."
While patients may perceive clinical trials as a last resort, the opposite is often true. "We have clinical trials at every step of the patient journey — from initial diagnosis of primary cancer to the diagnosis of advanced forms to new treatment options for metastatic disease," says Tolaney.
"It's always appropriate for patients to ask their doctor, 'Is there a clinical trial that's right for me,'" adds Erica Mayer, MD, MPH, director of Breast Cancer Clinical Research in Dana-Farber's Breast Oncology Program.
Through a multitude of clinical trials that span a broad range of women's cancers, Dana-Farber investigators are working to expand the slate of treatment options that are available to patients, now, and in the future.
Pursuing New Gynecologic Cancer Treatments
"We are very thoughtful when it comes to matching patients with a clinical trial. Cancer type, histology, number of prior treatments, what types of treatments have been given and which ones the patient has responded to, the genomic features of the tumor — these are just some of the many factors that must be considered," says Ursula Matulonis, MD, chief of Gynecologic Oncology and Brock-Wilson Family Chair at Dana-Farber. "It is important for patients to understand that clinical trials are meant to help them, and the intent of the trial is to help the individual who is participating. Yes, trials help future patients, but also, importantly, current patients as well."
That careful thought is applied not only to advising patients on clinical trials, but also to which clinical trials Matulonis and her colleagues pursue as investigators. For example, difficult-to-treat cancers, such as clear cell ovarian cancer and certain genetically defined cancers, such as those with RAS mutations or CCNE1 amplification, are all important research programs.
"Clear cell ovarian cancer is a relatively rare subtype, representing about 5-10% of all ovarian cancers, and it's difficult to treat," says Panos Konstantinopoulos, MD, PhD, who is director of the Mellen and Eisenson Family Center for BRCA and Related Genes, director of Translational Research in Gynecologic Oncology, and Dana-Farber's Velma Eisenson Chair for Clinical and Translational Research. "These tumors do not respond well to chemotherapy.”
Interestingly, ovarian clear cell tumors are quite similar to clear cell tumors of the kidney at a molecular level. "If you look at the gene expression profile of a clear cell ovarian cancer cell, it more closely resembles a clear cell kidney cancer cell than any other ovarian cancer cell type," says Konstantinopoulos.
This shared biology has led researchers to wonder whether some of the same treatments that are effective in killing renal clear cell tumors would also be effective against their ovarian counterparts. For example, a standard treatment for clear cell renal cancer is an anti-angiogenic drug, such as lenvatinib, combined with pembrolizumab, an immune checkpoint inhibitor.
Based on this rationale, Elizabeth Lee, MD, together with Joyce Liu, MD, MPH, launched a clinical study to test this drug combination in patients with recurrent or persistent clear cell ovarian cancer. The phase 2 trial spans Dana-Farber, the Mayo Clinic, and the University of Chicago, and the initial results were presented in June 2025 at a meeting of the American Society of Clinical Oncology (ASCO). Of the 30 patients enrolled, 17 patients experienced at least a 30% initial shrinkage of their tumors. Lee and Liu are awaiting final results to understand how long this regimen remains effective against the tumors.
"These are encouraging early results," says Liu, who is associate chief and director of clinical research for Gynecologic Oncology. "We're eager for the final report, and hope that this effort will yield a much-needed new treatment option for patients with clear cell ovarian cancer."
Konstantinopoulos is also pursuing a phase 2 clinical trial evaluating a new potential treatment called belzutifan for patients with advanced clear cell ovarian cancer as well as other forms of gynecologic clear cell cancer. This effort, which is now enrolling patients, draws inspiration from kidney cancer, too: belzutifan has been approved to treat patients with advanced clear cell kidney cancer. The drug blocks the activity of a key oxygen-sensing protein (called HIF2α) and came to fruition through the pioneering work of Dana-Farber's William G. Kaelin Jr., MD.
"This trial was funded through a very competitive, international process," says Konstantinopoulos. "We expanded the study to include patients with all forms of gynecologic clear cell cancer because these are very rare tumors, and we didn't want to exclude patients who might benefit from belzutifan."
In addition to studying the activity of belzutifan in these patients, Konstantinopoulos and his colleagues will also examine the molecular features of patients' tumors to determine if there are specific markers that correlate with drug response.
"Clinical trials can be very important for patients with rare cancer subtypes," says Elizabeth Stover, MD, PhD, an oncologist who leads a new center in Gynecologic Oncology dedicated to rare cancers. "Often there are fewer standard of care options for patients with rare cancers — in part, because there are fewer patients who have these rare tumor types, which makes it more challenging for them to be studied in clinical trials dedicated to that cancer subtype. As a result, the oncology community often has less information about how best to treat these tumors."
While clinical trials can help address unmet needs in treating rare tumor subtypes, they can also help fill important gaps in oncologists' understanding about how to treat more common subtypes, too. Konstantinopoulos is leading one such study, called ALPINE, which is geared toward patients with a specific subtype of endometrial cancer, called NSMP (for non-specific molecular profile). These tumors lack many of the molecular markers that are used to characterize endometrial tumors and represent more than half of all endometrial cancers.
In previous work published in the Journal of Clinical Oncology, Konstantinopoulos and his colleagues discovered that patients with relapsed NSMP tumors respond particularly well to a combination therapy that includes letrozole (a hormone-blocking therapy) and abemaciclib (a CKD4/6 inhibitor). Now, the ALPINE trial, a single-arm, phase 2 study, will evaluate the effectiveness of moving this therapeutic combination earlier in treatment — not in patients who have relapsed, but in those who have completed first-line therapy and are at high risk of recurrence.
"There is a high unmet need in these patients, and we hope to create a new treatment paradigm where letrozole/abemaciclib will be given as maintenance therapy after first line treatment," says Konstantinopoulos.
New Frontiers in Breast Cancer Treatment
Tolaney and her colleagues are also working to advance novel therapeutic combinations for breast cancer patients; one effort is the phase 3 ASCENT-04 trial. The researchers are investigating the effectiveness of sacituzumab govitecan combined with pembrolizumab, an immune checkpoint inhibitor, in patients with triple-negative metastatic breast cancer.
Sacituzimab govitecan is part of a growing class of new drugs known as antibody drug conjugates, or ADCs. These drugs chemically link an antibody that binds to a specific protein on the surface of tumor cells — in this case, Trop2, which is highly expressed on triple-negative breast cancer cells — with a potent chemotherapy drug. The molecular duo acts as a targeted, tumor-seeking missile, designed to deliver cancer-killing material directly to tumor sites within the body.
Previous studies have demonstrated that sacituzumab govitecan, even when administered on its own, works better than standard chemotherapy in patients with previously treated, triple-negative metastatic breast cancer.
"There is also a lot of data to suggest that antibody drug conjugates can work synergistically with checkpoint inhibitors through a mechanism known as immunogenic cell death, which leads to enhanced killing of tumor cells," explained Tolaney.
The phase 3 ASCENT-04 trial was designed with these pieces of evidence in mind. Notably, it is the first time a clinical trial in breast cancer combines an ADC with checkpoint inhibition could lead to the combination becoming standard of care. A total of 443 patients with newly diagnosed, PD-L1-positive, triple-negative metastatic breast cancer were randomized into two treatment groups: sacituzumab govitecan plus pembrolizumab or standard chemotherapy plus pembrolizumab.
Patients in the first group showed significantly better outcomes, with a progression-free survival of 11.2 months (compared to 7.8 months for patients receiving chemotherapy plus pembrolizumab). At this point, not enough time has passed to report results on overall survival. Tolaney is hopeful that the findings will support regulatory approval to make the combination a standard treatment option.
Tolaney and her colleagues are also investigating another ADC, called trastuzumab deruxtecan (or T-DXd). In the DESTINY-Breast09 phase 3 trial, the researchers are evaluating the use of T-DXd in combination with pertuzumab in patients with previously untreated, advanced, or metastatic HER2-positive breast cancer. The thinking is that these two agents together can deliver a one-two punch to HER2-positive breast cancer cells.
In an interim analysis, the researchers found that those who received T-DXd plus pertuzumab had a median progression-free survival of 40.7 months compared to 26.9 months for the control group (who received the current standard therapy consisting of taxane plus trastuzumab and pertuzumab).
"Even at this very early timepoint, we see an almost doubling of progression-free survival," says Tolaney. "We don't see that kind of result very often in oncology and so we believe that this could become a new standard first-line treatment."
Patients participating in the DESTINY-Breast09 trial will continue to be followed as more data is collected. Meanwhile, Tolaney and her colleagues plan to apply for regulatory approval.
"Both of these trials, while testing different therapeutic combinations in different breast cancer subtypes, share a common goal," says Tolaney. "And that is to provide the evidence needed to move the most effective drugs we have available in the first-line setting — making it possible for patients to get access to those drugs as early as possible in their treatment."
The results of ASCENT-04 and DESTINY-Breast09 underscore another important point. Many patients receive multiple treatments throughout their disease, so even a regimen that halts their cancers briefly can be meaningful, prolonging survival and opening the door perhaps for them to access more novel therapies.
Partnering With Patients
In addition to participating in large, global efforts that test the newest cancer medicines and help bring them to regulatory approval, Dana-Farber researchers also design and lead clinical trials that seek to answer important questions about how to optimize existing, FDA-approved treatments. These investigator-initiated trials represent an important pillar of clinical cancer research.
We have the ability to take the challenges we observe in clinic, partner with patients through the design and running of a trial addressing the challenging question, and then bring the data back to the clinic to help make patients' experiences better.
"We have the ability to take the challenges we observe in clinic, partner with patients through the design and running of a trial addressing the challenging question, and then bring the data back to the clinic to help make patients' experiences better," says Mayer.
For example, Mayer is leading an investigator-initiated, single arm, phase 2 study, called TRADE, which is designed to test whether a dose escalation strategy for abemaciclib — a CDK4/6 inhibitor, reduces early side effects and enables more patients to stay on the drug and receive its therapeutic benefit. Abemaciclib can be prescribed for patients with early-stage, hormone receptor-positive, HER2-negative breast cancer as part of a treatment regimen after surgery.
Mayer and her colleagues presented initial results from TRADE at the 2025 ASCO meeting, demonstrating that a 4-week dose escalation approach significantly reduced the number of patients who had to stop abemaciclib or use a lower dose, with almost 95% of patients continuing treatment at 12 weeks.
"We believe this is a very actionable result that doctors can take back to their patients to help make their experience of taking abemaciclib more tolerable and enable them to achieve its full therapeutic potential," says Mayer.
Mayer is also on the leadership teams for two global phase 3 trials that are evaluating novel therapies for patients with metastatic, hormone receptor-positive, HER2-negative breast cancer. These new drugs — known as next-generation selective estrogen receptor degraders (SERDs) — bind to the estrogen receptor and promote its degradation within the cell, thereby blocking the hormone's effects on cancer growth.
The interest surrounding these drugs stems from two key features. First, their mechanism of action is distinct among other hormone-blocking drugs so SERDS may offer unique benefits to patients who develop resistance to standard therapies. In addition, the next-generation SERDs are given orally, which is preferable to a monthly injection for first-generation drugs.
The evERA trial is investigating the efficacy of giredestrant, a next-generation SERD, in combination with another targeted medication, everolimus, in patients with advanced forms of hormone receptor-positive, HER2-negative breast cancer. And the SERENA-6 trial is testing the effectiveness of another next-generation SERD, camizestrant, in patients with advanced hormone receptor-positive breast cancer.
In addition, this trial is also evaluating the use of early molecular testing (via circulating tumor DNA) to detect resistance mutations in the estrogen receptor gene prior to any changes in patients' tumors — something known as molecular progression in the absence of clinical progression. Patients in whom these mutations are detected move on to receive the experimental drug, camizestrant, in combination with a CDK4/6 inhibitor, versus staying on their existing therapy.
Initial results from the SERENA-6 trial point not only to the efficacy of the new SERD — with a progression-free survival of 16 months compared to 9.2 months for the control arm — but also underscore the power of molecular testing early in a patient’s treatment journey.
"There are more data to come from SERENA-6, but what has been reported so far is very exciting and supports further development of camizestrant," says Mayer.
Obesity's Role in Breast Cancer
Researchers have long recognized that obesity is associated with poor outcomes in breast cancer patients. People who have obesity when diagnosed have a higher risk of recurrence as well as lower survival compared to leaner patients. Jennifer Ligibel, MD, director of the Leonard P. Zakim Center for Integrative Therapies and Healthy Living and a Dana-Farber breast oncologist, is leading a phase 3 clinical trial to test the effectiveness of a weight loss program, in combination with standard treatment, in reducing breast cancer recurrence in patients with early-stage disease and obesity. The study, known as the Breast Cancer Weight Loss, or BWEL trial, enrolled nearly 3,200 patients from over 600 sites across the U.S. and Canada. The weight loss program was delivered via telephone and a web portal, and included one-on-one coaching on healthy diet and exercise habits.
"This effort is the largest study to test the effect of weight loss on breast cancer recurrence," says Ligibel. "We're awaiting results on the impact of the weight loss program on the risk of recurrence, but we have already shown a number of benefits of the weight loss program."
Those include evidence that the two-year weight loss program works: Patients in the program lost about 6% of their body weight compared to patients in the comparison group. In addition, Ligibel and her colleagues presented data at the San Antonio Breast Cancer Symposium in December 2024 showing that patients in the program had significant reductions in blood-based metabolic and inflammatory markers, including insulin, leptin, insulin resistance, and C-reactive protein levels.
Ligibel hopes to have data regarding breast cancer recurrence in the next one to two years. In addition, she hopes the BWEL data will also shed light on the biological underpinnings of obesity and breast cancer risk.
I think sometimes patients can be apprehensive about clinical trials, worried that they may not receive good care, or that they could be randomized to a placebo and not get treatment. But in oncology, there is almost never a situation where someone has an active cancer and is not receiving treatment if they are a part of a clinical trial.
"Randomized clinical trials are essential for the development of new drugs, but they are also critical for lifestyle questions," says Ligibel. "Although we tell people, 'Yes, you should live a healthy lifestyle,' we don't help them do it. Part of the importance of BWEL is to show that this intervention works and to show how we can help people lose weight, exercise more and eat a healthy diet — evidence we need so that patients can get a prescription for a program like this as part of their cancer care.
"I think sometimes patients can be apprehensive about clinical trials, worried that they may not receive good care, or that they could be randomized to a placebo and not get treatment," Ligibel adds. "But in oncology, there is almost never a situation where someone has an active cancer and is not receiving treatment if they are a part of a clinical trial. These studies really provide important opportunities for patients to access new medications, new therapies, and new ideas."
Teamwork Drives Innovation
Collaborations between bench scientists, who study the biology of cancer cells in the laboratory, and clinicians, who treat cancer patients in the clinic, are a cornerstone of clinical research at Dana-Farber. These vital partnerships are central to two early-stage clinical trials, both targeting a key protein called BCL-xL. This protein helps cancer cells evade death, particularly in response to chemotherapy and other cancer-killing treatments.
For nearly a decade, researchers at Dana-Farber and elsewhere, including Stover, Liu, Kristopher Sarosiek, PhD, at the Harvard T.H. Chan School of Public Health, and Joan Brugge, PhD, at Harvard Medical School, have been studying the role of the intrinsic cell death pathway known as apoptosis in cancer. A deep interest has been in understanding how cancer cells rely on certain anti-apoptotic proteins, like BCL-xL, and whether these dependencies can be exploited with drugs and other treatments to more effectively kill tumor cells.
Now, Stover and her colleagues are launching a clinical trial to study a novel BCL-xL-directed drug, which instead of interfering with BCL-xL activity, targets the protein for degradation. The phase 1 study combines the novel BCL-xL degrader with weekly paclitaxel, a standard chemotherapy drug for ovarian cancer, and is enrolling patients with recurrent and platinum-resistant ovarian cancer.
"This is an early proof-of-concept that in ovarian cancer you can push cells further with an anti-apoptotic drug — essentially hitting them where they are weak — and then really knock them out with chemotherapy," says Stover.
A similar approach is at play in another clinical trial in ovarian cancer led by Liu and her colleagues, which combines a BCL-xL inhibitor with a MEK inhibitor. Laboratory experiments revealed that this drug combination could work synergistically in ovarian cancers that are treatment resistant. These findings helped lay the foundation for the phase 1 trial, which is open to patients with recurrent ovarian and endometrial cancers.
"These collaborations truly are a linchpin of our work, enabling us to advance novel drugs and therapeutic combinations for our patients," says Liu.
