PENELOPE-B: Palbociclib Disappoints in HR+, HER2– Breast Cancer

Sara Freeman

December 10, 2020

The CDK4/6 inhibitor palbociclib provides no significant benefit in patients with hormone receptor–positive (HR+), HER2-negative primary breast cancer, according to first results from the PENELOPE-B trial.

In this phase 3 trial, adding palbociclib to standard endocrine therapy did not improve invasive disease-free survival (iDFS) in patients who were at high risk of relapse following neoadjuvant chemotherapy (NACT).

There was no significant difference in iDFS rates with palbociclib or placebo at 2 years (88.3% vs. 84%), 3 years (81.2% vs. 77.7%), or even 4 years (73% vs. 72.4%), with a stratified hazard ratio of 0.93 (P = .525).

"This, unfortunately, was a negative trial," said Ruth M. O'Regan, MD, of the University of Wisconsin–Madison, who independently commented after the trial's virtual presentation at the 2020 San Antonio Breast Cancer Symposium.

Discussing the iDFS curves for palbociclib and placebo over time, O'Regan observed that there was a slight benefit for palbociclib in the range of 4.3%, compared with placebo at 2 years and 3.5% at 3 years. The benefit was small but "still meaningful," she added. However, "at 4 years, you can see the curves have completely come together."

"This begs the question of whether this trial was just treating patients with occult metastatic disease because I think these curves kind of mirror what we might see in the first-line metastatic setting," O'Regan suggested.

Study Details

The PENELOPE-B trial was designed to see if palbociclib could improve iDFS in women with HR+, HER2-negative primary breast cancer who were at high risk of relapse following NACT.

The clinical-pathologic stage plus estrogen receptor and grade (CPS-EG) staging system was used to identify patients at high risk for relapse. A CPS-EG score of 3 or higher or 2 or higher with nodal involvement was used as an entry criterion. This has been associated with a 3-year disease-free survival rate of 77%, noted Sibylle Loibl, MD, PhD, head of the German Breast Group in Neu-Isenburg, who presented PENELOPE-B data at the meeting.

The trial enrolled 1,250 women who did not have a pathological complete response after NACT. After surgery, with or without radiotherapy, patients were randomized to receive 13 cycles of either palbociclib or placebo (125 mg once daily; 21 days on and 7 days off treatment). All patients received concomitant endocrine therapy according to local standards.

"Although the compliance was lower in the palbociclib arm than the placebo arm, it was still satisfactory, and the relative dose intensity was over 80%," Loibl noted.

The primary endpoint was iDFS rate. As noted previously, there were no significant between-arm differences in 2-, 3-, or 4-year iDFS rates.

Likewise, there were no significant differences between palbociclib and placebo in terms of the secondary endpoints, which included the type of iDFS event (distant recurrences, invasive locoregional recurrences, contralateral breast cancer, second primary invasive nonbreast cancer, and death without previous event).

Subgroup iDFS analyses showed no differences between the study arms. "No group could be identified with a higher benefit from palbociclib," Loibl reported.

An interim overall survival (OS) analysis showed no significant differences between palbociclib and placebo. The 2-year OS rate was 96.3% with palbociclib and 94.5% with placebo. The 3-year OS rates were 93.6% and 90.5%, respectively. The 4-year OS rates were 90.4% and 87.3%, respectively.

"Today, the results of the PENELOPE-B study do not support the addition of 1 year of palbociclib to endocrine therapy. Long-term follow up from all neoadjuvant CDK4/6 inhibitor studies should continue and must be awaited," Loibl concluded.

Findings in Context

PENELOPE-B is the second phase 3 trial to show no benefit for palbociclib in the treatment of early high-risk breast cancer. The first was the PALLAS trial, which was reported only a few months ago at the European Society for Medical Oncology Virtual Congress 2020.

In PALLAS, palbociclib plus endocrine therapy was compared with endocrine therapy alone in the treatment of women with HR+, HER2-negative early breast cancer, but there was no additional benefit seen.

The results of both PENELOPE-B and PALLAS contrast those recently seen with another CDK4/6 inhibitor, abemaciclib, in HR+/HER2-negative early breast cancer.

Results of the phase 3 monarchE trial showed that, when abemaciclib was added to endocrine treatment, there was a significant (P = .0096) 25% relative risk reduction (HR, 0.75; 95% confidence interval, 0.60-0.93) in iDFS, compared with endocrine therapy alone. These results were also presented at the ESMO Virtual Congress 2020 and published in the Journal of Clinical Oncology.

While it's not clear why one CDK4/6 inhibitor may be of benefit in HR+/HER2-negative early breast cancer while the other is not, "PENELOPE-B is clearly quite a different trial to the other two adjuvant CDK inhibitor trials," O'Regan observed.

For one thing, PENELOPE-B participants were only eligible for the trial if they did not have a pathological complete response after NACT. In addition, PENELOPE-B is a smaller trial, enrolling well under a third of the number of patients who participated in the PALLAS and monarchE trials. Furthermore, the CPS-EG score, rather than anatomic staging, was used to determine eligibility.

"Abemaciclib could be a more effective CDK inhibitor; that's most certainly a possibility," O'Regan suggested. "However, it's not supported by the metastatic first-line trials, which have remarkably similar hazard ratios and favor CDK inhibitors."

Perhaps the shorter duration of palbociclib treatment in the PENELOPE-B trial (12 months vs. 24 months) had an effect.

"Clearly, we need to await the results of NATALEE that uses 3 years of ribociclib," O'Regan said. It also remains to be seen if the results of the monarchE trial hold up with longer follow-up.

The PENELOPE-B trial was sponsored by the German Breast Group in collaboration with Pfizer, the AGO Study Group, NSABP Foundation, and the Breast International Group. Loibl disclosed grant and other support from Pfizer during the conduct of the study and relationships with other companies outside the submitted work. She also disclosed intellectual property rights and being a pending patent holder (EP14153692.0) for a method to predict response to anti-HER2–containing therapy and/or chemotherapy in patients with breast cancer, and she disclosed a relationship with Medscape, which is owned by the same company as MDedge. O'Regan disclosed relationships with Novartis, Eli Lilly, Genentech, PUMA, Macrogenics, Immunomedics, Biotheranostics, and Eisai.

SOURCE: Loibl S et al. SABCS 2020, Abstract GS1-02.

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