Metastatic HR+ Breast Cancer: Developments and Approvals



Debu Tripathy, MD: The area of treatment for endocrine-sensitive tumors and hormone receptor—positive and HER2-negative cancers has evolved a lot in the past few years. But the evolution really started when aromatase inhibitors first came into the forefront. The more selective aromatase inhibitors were developed in the ’90s. And these initially showed some superiority over tamoxifen but particularly less in the way of side effects, such as thrombotic effects. So, they quickly became the standard for postmenopausal patients and remained so for quite some time. In fact, for premenopausal patients, it was also shown that suppression of the ovaries, even with tamoxifen, was better than tamoxifen alone. So that really became the preferred mode for premenopausal patients also, to undergo either surgical or medical ovarian oblation and treatment with an aromatase inhibitor.

The next class of drugs that came around were the down-regulators, and the prototype of those was fulvestrant. And initially, fulvestrant was dosed incorrectly at 250 mg a month, and ultimately randomized studies showed that the 500-mg dose was the favored dose. In fact, it led to a survival advantage. And that became a standard for second-line therapy. Now more recently, there has been some debate as to whether fulvestrant should be used in the first- or second-line setting. So, head-to-head studies initially showed equivalence. But with the newer dose of fulvestrant in the FALCON trial, which was recently reported, it did show a slight superiority of fulvestrant over aromatase inhibitors as first-line therapy.

Now, this was specifically in patients who had not received endocrine therapy previously, so it was that select group of patients. And in the group of patients who did not have visceral metastases, fulvestrant was actually significantly superior. Now more recently, the biological drugs have come to the forefront as we understand what drives endocrine therapy resistance. Growth factor pathways seemed to be amplified or overactive with resistance to hormonal therapy. So the first drug to be tested large scale was the mTOR inhibitor, a signal transduction pathway inhibitor, and that showed a superiority in second-line therapy. So fulvestrant with everolimus was clearly better than fulvestrant alone, for progression-free survival but not for overall survival. And that became a standard and approved therapy back in 2012.

Sara Hurvitz, MD: Cyclin-dependent kinase 4/6 inhibitors really hit the laboratory around 2004, 2005, when scientists began to look at whether inhibiting the cell’s cycle would have a differential impact on different kinds of breast cancer. Richard Finn and Dennis Slamon in our laboratory at UCLA ran palbociclib, the first one being looked at across a cell line panel of about 50 breast cancer cell lines. And although they went into the experiment thinking that the fastest-growing cell lines—triple-negative, for example—would be most sensitive to inhibition to a cell cycle inhibitor, it was actually the hormone receptor—positive breast cancers and HER2–positive breast cancers that were quite sensitive to this inhibitor. And that actually makes sense when you look at a retinoblastoma protein pathway expression in breast cancers, which really does appear to be mostly in the luminal types of breast cancer. This led to the development of a phase I clinical trial looking at palbociclib in combination with an aromatase inhibitor in women who were postmenopausal with first-line metastatic breast cancer. And the results from that small phase I study were so intriguing and promising that it led to a number of phase II and then phase III clinical trials of this inhibitor as well as 2 others that later hit the market.

Debu Tripathy, MD: More recently, the cyclin-dependent kinase inhibitors have been tested in the first and second lines. And those have actually also showed a clear advantage over either an aromatase inhibitor alone in the first-line setting or fulvestrant alone in second-line therapy. We now have data for all 3 of the available CDK4/6 inhibitors—palbociclib, ribociclib, and abemaciclib—both in the first- and second-line settings. In fact, for ribociclib, the second-line data are being presented at ASCO this year showing a superiority. We don’t really know how to distinguish right now one CDK inhibitor from the other. Abemaciclib has a slightly different toxicity profile. But when one looks at the efficacy in terms of progression-free survival, roughly in doubling of PFS, you see that across all the CDK4/6 inhibitors.

The first-line therapies with CDK inhibitors have generally been with aromatase inhibitors, assuming that that is what patients typically receive as first-line therapy. And these have consistently shown, across all 3 of the drugs, an improvement from around 12 months’ median progression-free survival with an aromatase inhibitor only to around 24 months with a combination, some differences across the different drugs.

In the premenopausal setting so far, there has been 1 completed trial that was just published in Lancet Oncology, the MONALEESA-7, which looked at ribociclib in premenopausal patients. All these patients did have medical ovarian oblation with goserelin and received either an aromatase inhibitor, or they could use tamoxifen. So, that was another new feature to study tamoxifen as the endocrine partner, and then they were randomized to either placebo or ribociclib. And this study also showed similar benefits, roughly a 13-month progression-free survival with endocrine therapy alone and roughly double that with the addition of ribociclib.

Now, one-quarter of those patients were on tamoxifen. The physician and the patient got to choose which of the drugs, as long as the patient hadn’t been on that drug recently in the adjuvant setting. And the benefits with tamoxifen or with an aromatase inhibitor were roughly the same. And then the other 2 CDK4/6 inhibitors, palbociclib and abemaciclib—similarly, in the first-line setting with aromatase inhibitor and second-line setting with fulvestrant—have shown equivalent results.

Transcript Edited for Clarity

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