Emerging Agents for the Management of HR+ mBC

Aditya Bardia, MD, MPH, leads the discussion on the use of novel CDK4/6 inhibitors, BCL2 inhibitors, and oral SERDS for the treatment of HR+ metastatic breast cancer.

Andrew D. Seidman, MD: I’d like to now shift gears a bit. Aditya, maybe you could introduce us to 2 new trials from ASCO [the American Society of Clinical Oncology annual meeting], VERONICA and DONNA. These trials reflect new strategies, BCL2 inhibition and a new CDK4/6 inhibitor emerging from China, dalpiciclib. Perhaps touch on the oral SERD [selective estrogen receptor degrader] landscape as well. There are some exciting new agents emerging for us.

Aditya Bardia, MD, MPH: Absolutely. I’ll start with DONNA first because we’ve had a good discussion related to CDK4/6 inhibitors. There are 3 CDK4/6 inhibitors approved in the United States: abemaciclib, ribociclib, and palbociclib. At the 2021 ASCO annual meeting, we saw the results of a fourth CDK4/6 inhibitor: dalpiciclib. It was a trial that was similar in design to MONARCH-2 or PALOMA-3 and a hybrid of MONALEESA-3 in the sense that it was on patients who had disease progression on an adjuvant AI [aromatase inhibitor]. It was randomization to fulvestrant vs fulvestrant plus this new CDK4/6 inhibitor. There were no surprises. The combination of fulvestrant plus dalpiciclib showed improvement in progression-free survival.

The question is about usage. We already have 3 inhibitors, so it’s unclear as to where this inhibitor would essentially play a role. Also, we tend to use CDK4/6 inhibitors in the first line in general. For a patient who has progression on an adjuvant AI, fulvestrant plus this new CDK4/6 inhibitor could potentially be an option, but we already have 3 drugs. The usage in the United States with this drug is unclear.

The second trial, VERONICA, was looking at a different class of agent: BCL2 inhibitors. The hypothesis is that estrogen binds to the estrogen receptor [ER] and causes proliferation. That’s through CDK4/6-RB, hence the interest in combining with CDK4/6 inhibitors because the RB pathway is usually intact in ER-positive breast cancer. ER is also associated with survival or the apoptosis pathway. BCL2 is overexpressed in the majority of ER-positive breast cancer. The question was, can you put brakes on that by the use of a BCL2 inhibitor, venetoclax? For practical reasons, the trial was designed as a post-CDK4/6 trial, where patients were randomized to receive fulvestrant or fulvestrant plus venetoclax.

Overall, the trial was negative. There was no improvement in progression-free survival. While the data are not mature, even in terms of overall survival, there was no improvement. Is it because this pathway is not active, or is it because the drug was not used in the right setting? Maybe the use of a BCL2 inhibitor would be better in the endocrine-sensitive setting rather than in the second-line and beyond setting where tumors are generally resistant. Additional biomarker work is ongoing, and we’ll have more clarity in terms of the role of BCL2 inhibitors in ER-positive breast cancer.

Then finally, oral SERDs. We talked about progression on first-line therapy with endocrine therapy plus a CDK4/6 inhibitor, and the patient has disease progression on endocrine plus CDK4/6. It’s usually progression on both of these drugs. In a subset, ESR1 mutations could be driving resistance, particularly to an AI plus CDK4/6 combination. There’s been a lot of interest in oral SERDs. We know fulvestrant is given as a shot. In general, having an oral ER degrader option would be attractive for our patients.

At ASCO, we saw the results of giredestrant. It’s an oral SERD developed by Genentech. We also saw results with amcenestrant, developed by Sanofi. The results of amcenestrant plus CDK4/6 inhibitor were presented at ASCO, and also results related to H3B and the G1 Therapeutics, Inc oral SERD. There are a number of oral SERDs in development. All of them have shown some evidence of efficacy in terms of objective response rates. The difference is in the [adverse] effect [AE] profile. Giredestrant in particular at high doses tends to cause bradycardia, which is not seen with amcenestrant. The H3B compound tends to cause bradycardia as well. There are some differences in terms of the AE profile. The other thing I would highlight is that H3B is a SERCA [selective estrogen receptor covalent antagonist], while the other drugs, giredestrant, amcenestrant, elacestrant, and rintodestrant, are all SERDs, or ER degraders.

Andrew D. Seidman, MD: Aditya, with all of these agents in development, I have so many of my patients who are tired of getting these intramuscular injections in their gluteus maximus every month and are looking forward to getting rid of the needle. How long are we going to need to wait for phase 3 results from any of these agents? Until 2022 or 2023?

Aditya Bardia, MD, MPH: There are 2 randomized phase 2/3 trials that have completed enrollment. The EMERALD trial looked at elacestrant vs endocrine therapy or physician’s choice in the second- and third-line setting. There was a similar trial, AMEERA-3, which looked at amcenestrant vs endocrine therapy or physician’s choice in the second- and third-line setting. Both of these trials have completed enrollment, so we are waiting for the efficacy results. We should have the results from these trials maybe later this year or early next year.

Andrew D. Seidman, MD: Thank you for that overview.

Transcript Edited for Clarity

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