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SAN ANTONIO -- Two chemotherapy-free combinations failed to outperform chemotherapy for slowing hormone receptor (HR)-positive metastatic breast cancer (MBC) that progressed on an aromatase inhibitor (AI), results of a randomized trial showed.

Palbociclib (Ibrance) plus either fulvestrant or exemestane led to a median progression-free survival (PFS) of 7.5 to 8.0 months, whereas women treated with capecitabine had a median PFS of 10 to 11 months. A secondary analysis of all patients treated with palbociclib also failed to move the PFS needle versus chemotherapy.

The performance of the palbociclib-fulvestrant combination also provided no support for evidence suggesting that patients with the acquired ESR1 mutation associated with AI resistance would respond to fulvestrant, as reported at the .

"The did not meet its two co-primary endpoints," said Miguel Martin, MD, of the Instituto de Investigacion Sanitaria Gregorio Maranon in Madrid. "Similar results were observed in all patients and in the subgroup with luminal breast cancer. However, treatment with palbociclib plus endocrine therapy was generally better tolerated than capecitabine."

The CDK4/6 inhibitor palbociclib, in combination with endocrine therapy, has emerged as standard therapy for patients with HR-positive/HER2-negative MBC. Capecitabine has demonstrated good tolerance and activity in HR-positive breast cancer and is frequently used in the treatment of MBC. The relative efficacy of palbociclib/endocrine therapy versus capecitabine in postmenopausal patients with MBC and prior aromatase inhibitor therapy had not been established, Martin noted in his introduction to the results.

Trial Details

The randomized PEARL trial addressed the unresolved issue of the relative efficacy and safety of palbociclib/endocrine therapy versus capecitabine in patients with HR-positive/HER2-negative MBC and progression on or resistance to prior aromatase inhibitor therapy. The trial evaluated two palbociclib-based strategies in separate cohorts.

The first cohort received palbociclib plus the AI exemestane or single-agent capecitabine. The second cohort received palbociclib plus fulvestrant or single-agent capecitabine. The second cohort was enrolled in follow-up to evidence linking the ESR1 resistance mutation in HR-positive MBC to prior exposure to an aromatase inhibitor. Additional retrospective data suggested that patients with the mutation derived little or no benefit from AI therapy but might benefit from fulvestrant.

Each cohort consisted of 300 patients with HR-positive/HER2-negative MBC and disease recurrence or progression on prior AI therapy. One prior line of chemotherapy for MBC was allowed but not prior capecitabine. Randomized therapy continued until disease progression, symptomatic deterioration, or development of unacceptable toxicity.

The trial had co-primary objectives: the PFS of palbociclib plus fulvestrant versus capecitabine irrespective of ESR1 mutational status (cohort 2) and the PFS of palbociclib plus either endocrine therapy in patients with ESR1 wild-type tumors (cohorts 1 and 2).

In both cohorts combined, the patients had a median age of about 60. Two thirds of patients had visceral metastases, 65-70% had bone metastases, 35-40% had nodal involvement, and more than 40% had liver metastases. About a fourth of patients randomized to palbociclib had ESR1-mutated disease, and 70-80% of the patients had sensitivity to prior hormonal therapy.

In cohort 1, about 80% of patients had received three or more prior regimens and another 40% had received two regimens. In cohort 2, half the patients had received two prior regimens and 20-25% had received three or more.

Key Results

After a median follow-up of 13.5 months, analysis of the first co-primary objective (cohort 2) showed a median PFS of 7.5 months with palbociclib and fulvestrant versus 10.0 months with capecitabine. For the second co-primary objective (all ESR1 wild-type patients from both cohorts, N=393), median follow-up was 18.89 months. At that point, median PFS was 8.0 with endocrine therapy and 10.6 months with capecitabine.

In general, subgroup analysis for both objectives tended to favor chemotherapy for most groups.

A key secondary objective was PFS for all patients combined, irrespective of ESR1 mutation status. With a median follow-up of 17.64 months for both cohorts combined, the median PFS was 7.4 months for patients who received palbociclib and endocrine therapy vs 9.4 months for patients randomized to capecitabine.

An analysis of PFS by intrinsic breast cancer subtypes in cohort 2 showed no superiority for palbociclib-fulvestrant in patients with luminal A or B subtype, both luminal subtypes combined, or nonluminal subtypes. The same was true of an analysis of PFS by intrinsic subtype, limited to patients with ESR1 wild type. Objective response rate and clinical benefit rate also did not differ between randomized groups in cohort 2 or in the ESR1 wild-type subgroup.

Adverse events affected a similar proportion of patients in the palbociclib- and capecitabine-treated patients but discontinuation associated with AEs occurred more often with capecitabine (12.8% vs 2-5%). With respect to grade 3 or greater AEs, decreased neutrophil count was more common with the palbociclib regimens (56-57% vs 5.5%), whereas palmar-plantar erythrodysesthesia, diarrhea, fatigue, and anemia occurred substantially more often with capecitabine.

Serious AEs occurred in 21.8% of the capecitabine-treated patients vs 13-16% of the palbociclib groups. Treatment-related deaths occurred in 1.3% of patients who received exemestane, 3.4% of those treated with fulvestrant, and 1.7% of capecitabine-treated patients.

An unidentified oncologist in the audience asked Martin about the practical implications of the findings: "We have two treatments, and it's quite likely I'll have both of them available to me, and I've got to choose. Does it matter, for long-term survival, which one I give first? Are you going to be able to give us any information about that later?"

Martin pointed out that CDK4/6 inhibitors are being used earlier in breast cancer and said the choice the speaker mentioned likely will not be an issue in the future.

The audience member continued: "We're still going to be using capecitabine when nothing else has worked. It would be useful for us to know whether it would have made a difference if we used it before the CDK4/6 inhibitor and aromatase inhibitor or fulvestrant."

Martin said he had no answer to that question.

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