CDK4/6 Improved PFS in Older Women with HR+ Metastatic Breast Cancer

Older women with HR–positive breast cancer treated with a CDK4/6 inhibitor may derive a progression-free survival benefit similar to that seen in their younger counterparts

Harpreet Singh, MD

Older women with hormone receptor (HR)—positive breast cancer treated with a CDK4/6 inhibitor may derive a progression-free survival (PFS) benefit similar to that seen in their younger counterparts, according to results from a retrospective study presented today at the 2017 San Antonio Breast Cancer Symposium (SABCS).

In a retrospective analysis of 1992 women, estimated PFS for those younger than 70 years treated with a CDK4/6 inhibitor in combination with an aromatase inhibitor (AI) was 23.8 months (95% CI, 21.9-25.4) versus an estimated 13.8 months (95% CI, 12.9-14.7) for women treated with an AI alone. Estimated PFS was not reached (95% CI, 25.1-not reached) for patients ≥70 treated with a CDK4/6 inhibitor in combination with an AI compared with 16.8 months (95% CI, 13.7-21.9) for those treated only with AI therapy.1

Harpreet Singh, MD, scientific liaison for cancer in older adults and a medical officer in the Office of Hematology and Oncology Products, Center for Drug Evaluation and Research (CDER) at the FDA, presented the results. She and her colleagues analyzed pooled data from prospective, randomized studies examining the 3 approved CDK4/6 inhibitors—palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio)—in combination with an AI for the initial treatment of postmenopausal patients with HR-positive metastatic breast cancer.

Median patient age was 62 years (range, 23-91). Of 1106 patients evaluated for safety and tolerability, 43% were ≥65, and 25% were ≥70.

“We looked for differences in treatment across age subgroups and there appears to be a similar benefit whether a patient is 70 or under,” she said. “Also, we looked at alternative age cutoffs like 65 and 75, and the results are similar.”

The median PFS was 24.8 months for women with estrogen receptor-positive/HER2-negative advanced or metastatic breast cancer assigned to palbociclib and letrozole versus 14.5 months with letrozole alone (HR, 0.58; 95% CI, 0.46-0.72; P <.000001) in the PALOMA-2 trial. The median PFS by blinded independent central review was 30.5 versus 19.3 months in favor of the combination (HR, 0.65; 95% CI, 0.51-0.84; P = .0005).2

In findings from MONALEESA-7 presented earlier at SABCS, median PFS was 23.8 months for women who received ribociclib in combination with tamoxifen or a nonsteroidal AI and goserelin (Zoladex) compared with 13.0 months for those who received the standard endocrine therapy plus placebo (HR, 0.553; 95% CI, 0.441-0.694; P <.0001).3

In results from the MONARCH 3 trial presented at the 2017 ESMO Annual Congress, adding abemaciclib to anastrozole (Arimidex) or letrozole reduced the risk of progression or death by 46% compared with the non-steroidal aromatase inhibitor (NSAI) alone for previously untreated patients with HER2-negative, HR-positive advanced breast cancer.4

The 1106 patients evaluated for safety had received at least 1 dose of a CDK4/6 inhibitor. Adverse events (AEs) that appeared within 30 days of their last treatment dose were included in the analysis.

Rates of grade 1/2 AEs were similar across age cohorts—98% for patients <65 years and ≥65 years, and 99% for those aged 70 or older. However, patients aged 65 and older (80%) and 70 and older (82%) were more likely to experience grade 3/4 AEs compared with younger patients (66%).

The frequency of AEs leading to dose reduction or interruption was similar across age groups—66% for patients <65 years, 75% for those ≥65 years, and 77% for those ≥70 years. Patients older than 70 were more than twice as likely to discontinue treatment due to AEs than those younger than age 65 (17% vs 8%). Sixteen percent of those aged 65 and older discontinued.

Serious AEs were also more common in the 65 and older cohort (31%) and the 70 and older cohort (32%) compared with the youngest cohort (16%).

Singh noted that the findings are limited by the relatively small numbers of older patients enrolled in the clinical trials, particularly those over 75 years. She added that many older adults who enroll in clinical trials tend to be healthier than their peers, with fewer comorbidities and less frailty, so their results may not be representative of the broader population.

Lynn Howie, MD, a medical officer in CDER’s Office of Hematology and Oncology Products and a study co-author, said in a press release that the potential benefit for older patients with breast cancer should be weighed against risk of toxicity. In addition to the higher rates of discontinuation of treatment, older patients often required more modification of dosages to help them manage AEs.

“Health care providers should counsel each patient individually on the potential benefit of these therapies as well as the potential risks, taking into account the patient’s disease characteristics, performance status, comorbidities, social support, and treatment preferences,” Howie said.


  1. Singh H, Howie LJ, Bloomquist E, et al. A U.S. food and drug administration pooled analysis of outcomes of older women with hormone-receptor positive metastatic breast cancer treated with a CDK4/6 inhibitor as initial endocrine based therapy. Presented at: 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, TX. Abstract GS5-06.
  2. Finn RS, Martin M, Rugo HS, et al. PALOMA-2: Primary results from a phase III trial of palbociclib (P) with letrozole (L) compared with letrozole alone in postmenopausal women with ER+/HER2— advanced breast cancer (ABC). J Clin Oncol. 2016;34(suppl; abstr 507).
  3. Tripathy D, Sohn J, Im SA, et al. First-line ribociclib vs placebo with goserelin and tamoxifen or a non-steroidal aromatase inhibitor in premenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer: results from the randomized phase III MONALEESA-7 trial. Presented at: 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, TX. Abstract GS2-05.
  4. Di Leo A, Toi M, Campone M, et al. MONARCH 3: Abemaciclib as initial therapy for patients with HR+/HER2- advanced breast cancer. Presented at: 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract 236O_PR.