Expert Discusses Palazestrant in Phase 1b/2 Trial, Future Trials

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The discussion delves into the results and implications of the clinical trials, shedding light on the efficacy and safety profile of this combination therapy.

In an interview with Pharmacy Times at the 2023 San Antonio Breast Cancer Symposium, Sean Bohen, MD, PhD, CEO of Olema Oncology, focuses is on the Phase 1b/2 clinical data of palazestrant (OP-1250) when used in combination with the CDK4/6 inhibitor ribociclib. The discussion delves into the results and implications of the clinical trials, shedding light on the efficacy and safety profile of this combination therapy.

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Q: Can you give an overview of palazestrant and its potential role in therapy? (method of action, what it’s being investigated for, etc.)

Sean Bohen: Palazestrant or OP-1250 is a complete estrogen receptor antagonist and a selective estrogen receptor degrader. We are studying this medicine for the treatment of estrogen receptor positive, HER2- breast cancer initially in the second, third line, advanced or metastatic setting with data that we recently presented that supports combining with ribociclib which is a CDK4/6 inhibitor in the first line, advanced or metastatic setting. The basis for this mechanism of action is that the estrogen receptor is a breast cell growth and proliferation signal. That signal is used normally during breast development, for instance, in puberty, but cancer cells co-op that signal and palazestrant binds to the estrogen receptor and completely shuts off that growth and proliferation signal.

Q: How does palazestrant work in combination with ribociclib?

Sean Bohen: Palazestrant, as a complete estrogen receptor antagonist, binds the estrogen receptor and completely suppresses the growth and proliferation signal that the receptor promotes in the cancer. This happens in competition with estrogen with a wild type receptor, but in some cancer cells, the receptor is mutated to be turned on even without estrogen present and OP-1250 or palazestrant is able to bind that receptor and lock it in an inactive conformation. Ribociclib is a CDK4/6 inhibitor, so it acts via a different, but also important mechanism to suppress cancer cell growth. CDKs is our cyclin dependent kinases; they are molecules that are involved in the cell cycle, when the cell proliferates, divides and grows, and so the CDK4/6 inhibitors bind and inhibit that pathway for cell growth estrogen receptor is inhibited by palazestrant through its activity to prevent to also prevent cell growth and proliferation.

Q: What did the trial results show with regard to primary outcomes?

Sean Bohen: The most mature trial results we have were presented at ESMO in October of this year, that was monotherapy data from a large phase 2 trial [with] 86 patients. What we saw in that trial was very good tolerability with oral daily dosing, and also in very heavily pretreated patients, we saw encouraging progression free survival or clinical benefit rate. That data from the basis of our ongoing phase 3 trial called OPREA-01, which is in the second third line setting as a monotherapy versus endocrine therapy monotherapy standard of care. At this meeting SABCS, we presented data to support moving into the first line setting in combination with the CDK4/6 inhibitor. Here we presented drug-drug interaction or pharmacokinetic data from combination with palbociclib, good tolerability with palbociclib, and also very immature but initial efficacy. The CDK4/6 inhibitor preference now is ribociclib because of the survival benefit it has shown in this setting. We presented our initial data with ribociclib here, which again show no drug-drug interactions, and favorable tolerability in combination. We'll be able to update on those combination data for both drugs next year.

Q: Are there any notable safety data at this point?

Sean Bohen: There really wasn't. The combination of the 2 drugs looked very much like the combination of the CDK4/6 inhibitor, they're a little different palbociclib and ribociclib with a standard endocrine therapy. Right now, that's an aromatase inhibitor, or fulvestrant. Really, the only thing we see slightly increased tolerability is some low-grade nausea and vomiting, which is probably related to palazestrant when given in the capsule form and when given in the fasting state, which is what was required for those trials. In the OPERA-01 trial and subsequent trials, we have a tablet formulation, and we will also give the drug either in fed or fasting state.

Q: What is the role of the pharmacist in this treatment paradigm?

Sean Bohen: The pharmacist obviously is vitally important in in any cancer therapy, because patients being well educated, actually taking their medication, they are highly motivated, is vitally important to getting the therapeutic effect. Relative to the heavy pharmacy demand of oncology therapies, however, this one is pretty minimal in in respect with them. This one is more minimal with respect to the fact that it is an oral therapy given daily, the very infrequently with palazestrant is the dose reduced. That role of the pharmacist increases significantly when you combined with a CDK4/6 inhibitor because the CDK4/6 inhibitors are fairly frequently dose reduced, particularly for neutropenia. It's vitally important that the patients are well educated as to what dose they should be taking why, and again, make sure that they are taking the medication. In addition, for palbociclib and ribociclib, the medications are given 3 weeks with a 1 week break in every cycle. Again, there's a there's a large education element to make sure that the patients know to take that CDK4/6 inhibitor with a break and with the with a drug like palazestrant to not take a break, but to take it every single day.

Q: Given these findings, what’s next for research of palazestrant?

Sean Bohen: As I mentioned, the ongoing phase 3 trial OPERA-01 in the second third line setting as a monotherapy is ongoing. It is enrolling presently. At this point we’re going to use the data that we're generating in the combination trial to plan a first line trial in combination with the CDK4/6 inhibitor, likely ribociclib. That trial could start as soon as late next year. Beyond that, there are a lot of combinations that we could study subsequently with other targeted therapies. Endocrine therapy targeting the estrogen receptor is a backbone therapy of the treatment of ER+ HER2- breast cancer. There are many other both established and new agents being tested there, so it gives a very rich lifecycle for future clinical research for palazestrant.

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