Persephone Trial: Cutting Trastuzumab Duration by Half Safer, Efficacious in HER2-Positive Breast Cancer

More than 4000 women with HER2-positive early-stage breast cancer who were treated with trastuzumab (Herceptin) for 6 months had a similar rate of disease-free survival (DFS) as women who received the drug for double the time. Meanwhile, nearly double the number of women who were treated with trastuzumab for a year dropped out of the trial due to cardiac problems, compared with the short duration.

These results from the Persephone trial will be presented at the upcoming 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, being held June 1-5, in Chicago, Illinois.¹

The 12-month adjuvant treatment with trastuzumab, added to chemotherapy, is adopted from the drug’s registration trials, and is the current standard of care. However, addition of trastuzumab led to significantly high rates of cardiotoxic effects, resulting in several follow-up studies evaluating the high risk of cardiac problems that the drug induces.^2,3

The Persephone trial worked on the hypothesis that a shorter treatment duration could reduce toxicities and cost whilst providing similar efficacy.

Hailed the largest reduced-duration noninferiority international trial, Persephone recruited HER2-positive patients diagnosed with early-stage breast cancer who were then stratified based on their estrogen receptor (ER) status, chemotherapy type, and timing of chemotherapy and trastuzumab. The trial’s primary endpoint was DFS from the time of diagnosis.

The noninferiority query of the 6-month treatment was defined as "no worse than 3%" below the 80% 4-year DFS assumed for the 12-month arm.

Of the 4089 patients randomized to receive the treatment in 152 sites in the United Kingdom between 2007 and 2015:

• 69% were ER-positive
• 41% received anthracycline-based chemotherapy
• 49% received anthracycline and taxane-based chemotherapy
• 10% received taxane-based chemotherapy
• 85% adjuvant chemotherapy
• Sequential trastuzumab was administered in 54% of patients

At a median follow-up period of 5 years, the researchers found near-identical results between the 2 treatment arms: DFS was 89.4% among women in the 6-month arm and 89.8% among women in the 12-month arm (hazard ratio, 1.29).

Significant reduction in cardiac events was observed in the 6-month treated group, compared with the 12-month treated group: only 4% of women treated with trastuzumab for 6 months experienced heart-related issues and stopped treatment. On the other hand, 8% of women in the 12-month group had to stop their cancer care because of cardiotoxicity (P <.0001).

Speaking during a press cast hosted by ASCO prior to the meeting, lead author Helena Earl, MD, professor of Clinical Cancer Medicine, University of Cambridge, United Kingdom, said that the study results from the Persephone trial confirmed the noninferiority of 6-month adjuvant treatment with trastuzumab, compared with the 12-month treatment. “The 6-month treatment also reduced cardiac toxicity and costs the patient and the health system less,” she added.

Ongoing research in this patient population is evaluating quality-of-life and patient-reported outcomes in this study population. The study authors are also conducting health economic assessments of the reduced treatment duration with the drug.

References

1. Earl HM, Hiller L, Vallier AL; PERSEPHONE Trial Investigators. PERSEPHONE: 6 versus 12 months (m) of adjuvant trastuzumab in patients (pts) with HER2 positive (+) early breast cancer (EBC): Randomised phase 3 non-inferiority trial with definitive 4-year (yr) disease-free survival (DFS) results. J Clin Oncol. 2018;36(suppl; 506 abstr).
2. Onitilo AA, Engel JM, Stankowski RV. Cardiovascular toxicity associated with adjuvant trastuzumab therapy. Ther Adv Drug Saf. 2014;5(4):154-166.
3. Patt D. Influence of cardiotoxic risk on treatment choice in adult cancers. Am J Manag Care. 2015;21(SP8):SP271-SP272.