Personalized treatments are transforming the landscape of care for people living with ER-positive (ER+)/HER2-negative (HER2-) metastatic breast cancer (MBC), by making therapy more effective and more tolerable. For those living with ER+/HER2- MBC, the standard first-line therapy usually includes hormone (endocrine) therapy paired with a CDK4/6 inhibitor.
While these treatments work very well at first, cancer cells can figure out ways to outsmart them and become resistant to them. Today, researchers are focused on developing personalized therapies that can target specific areas that promote treatment resistance and drive cancer growth.
“The pace of new drugs coming out is dramatically changing outcomes for patients,” says medical oncologist Sara Tolaney, M.D., “but it also means that we are needing to adapt our treatment strategies and decision-making quickly and to figure out how to best select the optimal therapy for patients and what drugs to use at the right time.”
This is why clinical trials are now focusing on more personalized treatment strategies for people living with advanced and metastatic breast cancers, including ER+/HER2- MBC.
The OPERA-02 Clinical Trial
Dr. Tolaney is a principal investigator in the phase 3 OPERA-02 clinical trial. The OPERA-02 study is running concurrently with the ongoing phase 3 OPERA-01 clinical trial, where researchers are investigating whether a new hormone therapy called palazestrant (OP-1250) could be a better treatment option than existing hormone therapies for people with ER+/HER2- MBC.
Palazestrant is a complete estrogen receptor antagonist (CERAN) and a selective estrogen receptor degrader (SERD) developed by Olema Oncology. It has been granted U.S. Food and Drug Administration (FDA) Fast Track designation for the treatment of ER+/HER2- MBC that has progressed after a hormone therapy with a CDK4/6 inhibitor.
For OPERA-02, Dr. Tolaney and her team are investigating whether a combined treatment of palazestrant and a CDK4/6 inhibitor called ribociclib will work better for people with ER+/HER2- MBC in a first line setting (initial treatment) versus an aromatase inhibitor combined with ribociclib.
“The OPERA-02 study is asking, can we change the endocrine backbone from an aromatase inhibitor to an oral CERAN (palazestrant), which might be a more effective anti-estrogen drug, and could potentially allow someone to have their disease controlled for much longer,” explains Dr. Tolaney.
A New Strategy to Prevent Treatment Resistance
The OPERA-02 study is designed for patients whose tumors have progressed after previous hormone therapy. In earlier studies, palazestrant has shown that it can block and break down the estrogen receptor more effectively than fulvestrant, which only partially blocks the estrogen receptor’s ability to promote cancer growth.
Drugs like fulvestrant are designed to block the “lock” – the estrogen receptor – to prevent the “key” – estrogen – from opening the “door” to cancer growth. However, this lock can be picked open by changes in the cell that allow tumors to grow without estrogen.
As a CERAN, palazestrant completely blocks the estrogen receptor’s “lock” mechanism, and prevents cancer cell growth, even in cancers with ESR1 mutations.
Results from a phase 1b/2 trial were presented at ESMO showing how a combined treatment of palazestrant and ribociclib can stop the proliferation (cell growth and division) of cancer cells effectively. As Dr. Tolaney explains, these two drugs work even better together, as palazestrant blocks the cancer cell’s main growth signal, ribociclib prevents cancer cells from dividing and spreading.
“With a CDK inhibitor, you’re making that cancer cell go to sleep and eventually die,” explains Dr. Tolaney. “And that does work synergistically with the hormone therapy. So, we find that they work much better together than they would individually.”
Improving Quality of Life
Aside from exploring whether this new treatment can extend progression-free survival and promote a longer life span for patients, another goal of the study is to ensure it is safe, tolerable and has minimal side effects.
For some patients, aromatase inhibitors can sometimes cause arthralgia or joint aches and pains. Researchers of OPERA-02 are seeing improved outcomes for patients who are taking palazestrant in place of an aromatase inhibitor.
“We do find that when we use drugs like palazestrant, we’re not seeing those kinds of side effects, and so that’s a big advantage for these drugs,” says Dr. Tolaney. “They are so well-tolerated, I think that’s what’s really exciting.”
In rare cases, some patients have developed a low white blood cell count, or neutropenia, from taking ribociclib. However, the addition of palazestrant has not worsened overall rates of neutropenia when given in combination with ribociclib, which researchers see as another win.
More Personalized Treatments Mean Better Outcomes for Patients
The more researchers learn about the diverse genetic changes behind each person’s breast cancer, the better they can target the root causes and create more effective treatments. By targeting cancer cells before they have a chance to mutate, drugs like palazestrant could help prevent these mutations before they even happen.
“We do need to figure out ways to keep cancer controlled longer, and there are lots of different strategies that are being explored,” Dr. Tolaney observes.
By participating in clinical trials, patients can access many new experimental treatments designed to be more targeted and possibly more effective, offering the potential for better outcomes and quality of life.
“We’re selecting treatments more appropriately for our patients, so we have a better likelihood of picking the right drug that’s going to be most effective for them,” says Dr. Tolaney. “This is just an incredible improvement over the last few years and really exciting for patients to know that treatments just keep getting better and better.”
Learn more about the OPERA-02 trial.
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Did you know? Komen has invested in more than 700 new discoveries and over 400 potential treatments in the research pipeline for MBC.
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Olema Oncology is a sponsor for the Spotlight on Clinical Trials series and the sponsor of OPERA-02.
