Choosing Aromatase Inhibitors and Next-Generation SERDs for Breast Cancer

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• Aromatase Inhibitor Types and Selection
• Clinical Efficacy Comparison
• Fulvestrant Challenges and Limitations
• Oral SERDs Development and Promise
• Clinical Trial Landscape and Future Directions
• Adjuvant Therapy Challenges
• Full Transcript

Aromatase Inhibitor Types and Selection

Dr. Marc Lippman, MD, explains that aromatase inhibitors come in two main types for breast cancer treatment. Type one includes steroidal, irreversible inhibitors like exemestane. Type two comprises non-steroidal, reversible inhibitors including anastrozole and letrozole. These medications work by blocking estrogen production in postmenopausal women with hormone receptor-positive breast cancer.

Clinical Efficacy Comparison

According to Dr. Marc Lippman, MD, randomized clinical trials show no significant difference between aromatase inhibitor types. He emphasizes that these drugs are essentially cross-resistant and equally efficacious in breast cancer treatment. Dr. Marc Lippman, MD, notes that while some patients might report different side effects with different inhibitors, the clinical outcomes remain comparable. The choice between medications often comes down to individual patient tolerance rather than efficacy differences.

Fulvestrant Challenges and Limitations

Dr. Marc Lippman, MD, discusses the current Selective Estrogen Receptor Degrader (SERD) available for metastatic breast cancer. Fulvestrant requires monthly intramuscular injections, which can be uncomfortable for patients. The pharmacology presents significant challenges in achieving effective drug concentrations. Dr. Marc Lippman, MD, explains that fulvestrant operates at the very edge of effective concentrations, making optimal dosing difficult.

Oral SERDs Development and Promise

The development of oral Selective Estrogen Receptor Degraders represents a major advancement in breast cancer treatment. Dr. Marc Lippman, MD, expresses excitement about these new agents, noting they appear more potent than fulvestrant. Early data suggests oral SERDs may work in patients who have progressed on fulvestrant therapy. These new medications are currently in advanced clinical trials and may receive FDA approval soon.

Clinical Trial Landscape and Future Directions

Dr. Marc Lippman, MD, describes ongoing clinical trials combining oral SERDs with CDK4/6 inhibitors for breast cancer treatment. This combination approach could represent a significant step forward in metastatic breast cancer management. The natural progression of cancer therapies typically moves from metastatic to adjuvant settings. Researchers are also considering SERDs for potential breast cancer prevention trials, though these present substantial challenges.

Adjuvant Therapy Challenges

Dr. Marc Lippman, MD, highlights the difficulties in conducting adjuvant therapy studies for early-stage breast cancer. Patients with T1N0 breast cancer discovered by mammography have excellent outcomes with standard endocrine therapy. Only about 10% of these patients experience recurrence within five years. Improving these results requires treating tens of thousands of women with long follow-up periods, making such studies extremely expensive and time-consuming. Dr. Anton Titov, MD, facilitates this discussion about the practical challenges in breast cancer research advancement.

Full Transcript

Dr. Marc Lippman, MD: Aromatase inhibitors can be of two types. Exemestane is type one, or steroidal, irreversible aromatase inhibitor. Anastrozole and letrozole are examples of type two, non-steroidal, reversible aromatase inhibitors.

Dr. Anton Titov, MD: How to choose correct aromatase inhibitors for specific breast cancer patient?

Dr. Marc Lippman, MD: It makes no difference whatsoever. For the aromatase inhibitors, it makes no difference. This is a case of drug companies marketing, trying to lobby one against the other just because they have two drugs. Randomized trials of one aromatase inhibitor versus another suggest no difference.

In my view, aromatase inhibitors are almost completely cross-resistant. Rarely a patient says, "Gee, this drug makes me feel terrible. I'll try a different one." Sometimes, either it's lucky or psychological, or there's some minor difference in the pharmacology. Then switching from one aromatase inhibitor to another one works. Still, they are almost equally efficacious.

So there's only one SERD around now: Selective Estrogen Receptor Degrader. That's fulvestrant. It is challenging to use because you have to take it by injection in your behind once a month, and it's a little bit uncomfortable.

But the main problem with fulvestrant is that its pharmacology is such that you really are at the very edge of effective concentrations. It's very hard to get enough drug into people.

There are newest trials of oral Selective Estrogen Receptor Degraders. Oral SERDs are more potent. It turns out that many SERDs seem to work in patients who have progressed on fulvestrant or had fulvestrant failures. Everybody's excited about SERDs. I'm very excited about Selective Estrogen Receptor Degraders.

It remains to be seen how they will replace fulvestrant. Maybe they'll become first-line drugs. The trials being discussed are underway with CDK4/6 inhibitors. So this may be a very important step forward in more effective treatment for women with breast cancer.

I'd rather not use brand names of oral SERDs because they are still in development. But the most recent oral SERDs have already been in randomized clinical trials. I suspect they are about to be in front of the FDA. I think approvals this spring or summer are likely for at least one of oral Selective Estrogen Receptor Degraders.

Selective Estrogen Receptor Degraders are often used in metastatic breast cancer. As I've said several times in our discussion today, the natural history of cancer therapies is to immediately try to advance them to the adjuvant chemotherapy setting. And I suppose even consider SERDs in breast cancer prevention trials.

But no one wants to do prevention clinical trials. It's too expensive. They are too costly. There is too much of a downside. Drug companies are desperately afraid of prevention clinical trials. And that's unfortunate, but it's the truth.

The problem with adjuvant chemotherapy in breast cancer studies is good news. The good news is this: if you take patients with early-stage breast cancer, even though I've told you that they can continue to relapse for decades, the fact is this. You take women who are discovered by mammography to have T1N0 breast cancer. You put them on standard endocrine therapy. You're not going to see 10% of them recur in five years.

So if you're going to try to improve on that result, think of the tens of thousands of women you have to treat. Think how long you have to follow these women with breast cancer. So the data here will be very slow coming and very expensive to obtain.