Trial-Supported Endocrine & Progression Therapy Shift

Joyce O’Shaughnessy, MD:This patient has had 5 years of anastrozole, and unfortunately she has developed metastatic disease in her liver in spite of taking her anastrozole. Certainly we want to move away from the aromatase inhibitor family. We wouldn’t want to continue the aromatase inhibitor, or change to a different one, and then add a CDK4/6 inhibitor, because we now have vast data for exactly this patient population. If a woman’s disease is progressing or recurring on the aromatase inhibitor, or she switches to fulvestrant with a CDK4/6 inhibitor, she will really get substantial benefit.

The FALCON data were very important data, and I really like the trial because it was a head-to-head comparison of fulvestrant versus anastrozole in a completely hormonal-therapy-naive population, a very pure comparison of what is our most effective endocrine therapy; and the answer is fulvestrant. In the overall treated population, the fulvestrant had a superior progression-free survival [PFS] than anastrozole; however, that is a very specific patient population of completely endocrine-therapy-naive population.

Our patient here has been pretreated with anastrozole, and her breast cancer has recurred in spite of the anastrozole, so she doesn’t fit the FALCON study population, which is fulvestrant by itself. Truthfully, now that we have the great data with the CDK4/6 inhibitors, we won’t be using fulvestrant very often in the first-line setting by itself. There may be the occasional patient with small volume, asymptomatic metastatic breast cancer that’s estrogen receptor [ER]­—positive and endocrine therapy sensitive; not a patient who is endocrine therapy sensitive and endocrine therapy naive, who lives a great distance from the cancer center or who has other substantial comorbidities, for which it wouldn’t be in the patient’s best interest to get a CDK4/6 inhibitor. This patient may be an appropriate candidate for fulvestrant alone; however, that’s a very rare patient population, and I think the advantage of the FALCON trial is that it showed us the power of fulvestrant, and that’s why the MONALESSA-3 data are very interesting because it brings the fulvestrant into the first line with ribociclib and shows excellent efficacy, giving physicians the opportunity to utilize fulvestrant in the first line with ribociclib if they so choose.

It’s very likely that this woman is going to go on to treatment with fulvestrant and one of the CDK4/6 inhibitors. Truthfully, it’s very likely that she’s going to benefit from that because the CDK4/6 inhibitors have had a 70% to 80% chance of being beneficial with regard to either a response or clinical benefit in the metastatic population who have never had a CDK4/6 inhibitor before. Unfortunately, it’s very likely that eventually she will have progression of disease on the CDK4/6 inhibitor with fulvestrant.

Today we have little data about what to do for that patient afterward, from the point of view of randomized clinical trials. We just had very important data come out at the European Society of Medical Oncology [ESMO] 2018 Annual Meeting, with regard to the SOLAR-1 trial, that’s going to change practice because it showed that in the 35% to 40% of ER-positive, HER2-negative metastatic breast cancer patients, there will be a PIK3CA [phosphati-dylinositol-3 kinase, catalytic subunit, alpha isoform] somatic mutation in the breast cancer. Those patients will get substantial benefit with regard to PFS having alpelisib, the oral inhibitor of the PI3K kinase added to endocrine therapy. In the SOLAR-1 trial it was fulvestrant.

One option for this patient if she’s found to have aPI3Kmutation is to potentially continue on the fulvestrant and have the alpelisib added. It was only 6% of patients in the SOLAR-1 trial that had had a prior CDK4/6 inhibitor. They benefited equally from the alpelisib compared with patients who had not had a prior CDK4/6 inhibitor. But the number of patients was indeed very small.

I would be looking for aPI3Kmutation in this patient, no question about it. I would also be comfortable if she had a slow progression after the CDK4/6 inhibitor and was asymptomatic. I would be very comfortable with a trial of everolimus for her with exemestane. If she had rapid progression in her liver, combined with other sites of metastases progressing as well, I would then probably favor capecitabine for her.

The important new information here is from the SOLAR-1 with thePI3K-mutant population, which is 35% to 40% of patients like this, ER-positive, HER2-negative, having aPI3Kmutation. It’s going to be important that we look for those mutations and consider alpelisib for that patient.

Transcript edited for clarity.

A 58-Year-Old Woman With Recurrent HR+ Breast Cancer

December 2013

• A 58-year-old postmenopausal woman was referred for further evaluation of a suspicious left-sided lesion found incidentally on routine mammogram
  • MRI revealed a 4.3-cm lesion in her left breast
  • PMH unremarkable
• She underwent lumpectomy with axillary staging
• Biopsy findings:
  • Histology: lobular carcinoma, grade 2
  • Hormone receptor status: ER+/ PR (-)
  • HER2,IHC 1+
  • OncotypeDx RS, 19
• Staging, T2N0M0
• ECOG 0
• She was started on adjuvant anastrozole

September 2018

• On routine follow-up, the patient reports increasing fatigue and intermittent bouts of abdominal pain with nausea
• CT with contrast showed several small lesions in the liver; biopsy confirmed metastatic disease.
  • The patient was started on ribociclib; anastrozole was changed to fulvestrant
  • Imaging at 3 and 6 months showed a partial response