Reply to J. Widder

We read with great interest Dr Widder’s¹ alternative explanations for the findings from NRG-BR002² that was presented at the ASCO 2022 annual meeting. To put the trial into context, we sought to test the hypotheses that ablative metastasis–directed therapy (MTD) using surgery or stereotactic body radiotherapy (RT) to all known macrometastases would not only reduce growth of the treated metastases but also result in fewer new metastases.³ We hypothesized that this dual reduction in metastases from ablative treatment would improve progression-free survival (PFS) and overall survival (OS) in women undergoing first-line therapy for metastatic disease.² The phase IIR/III trial with a sample size of 128 in the phase IIR portion for 92% power and one-sided significance level = 0.15 to determine if adding MDT (arm 2) to standard-of-care systemic therapy (arm 1) shows a signal for improved PFS (hazard ratio, 0.55, corresponding to median PFS from 10.5 to 19 months), to continue to the full phase III trial for OS. Over 60% of the patients had only one metastasis and 80% were estrogen receptor–/progesterone receptor–positive/human epidermal growth factor receptor 2–negative. Thus, the predominant population that enrolled to the trial was previously shown from real-world data to benefit the most from ablative therapies.⁴

With a median follow-up of 30 months, the median PFS in arm 1 was 23 months (70% CI, 18 to 29) and 19.5 months (70% CI, 17 to 36) in arm 2; 24- and 36-month PFSs for arm 1 were 45.7% (70% CI, 38.9 to 52.5) and 32.8% (70% CI, 26.0 to 39.5), respectively, compared with 46.8 (70% CI, 39.2 to 54.3) and 38.1 (70% CI, 29.7 to 46.6) in arm 2; hazard ratio, 0.92 (70% CI, 0.71 to 1.17); and one-sided log-rank P = .36. As PFS did not show signal, we examined the OS. Median OS was not reached in either arm; 36-month OS in arm 1 was 71.8% (95% CI, 58.9 to 84.7) and in arm 2 was 68.9% (95% CI, 55.1 to 82.6; two-sided log-rank P = .54). Analysis of first failure showed new metastases outside index area (arm 1)/RT field (arm 2) developed similarly in both arms at 40%. There were fewer new metastases inside treated/index area for arm 2 (6.7%) versus arm 1 (29.2%), respectively. The treatment was very well tolerated as shown by NRG-BR001.⁵ Thus, the trial demonstrated that although ablative therapies reduced metastases progression in known or targeted areas, it failed to translate into a reduction in new metastases and improved PFS and OS.

NRG-BR002 results support the Fisher⁶ hypothesis that metastatic breast cancer is a systemic disease, and MTD does not affect progression of disease outside the targeted metastasis. The author suggests an alternative trial design: continuing local therapies for as long as they are feasible beyond the first progression after stereotactic body RT in lieu of changing systemic therapies. In this design, the end point would be time to failure of local strategies that is used in some contemporary CNS trial designs. This would address the hypothesis that at the time of imaging and random assignment, there are a finite number of subclinical metastases. If these are still in the realm of an oligometastatic state, subsequent local therapy may still achieve the goal of durable no evidence of disease status and improved OS. Unfortunately, to date, there is no evidence that MTD for oligoprogression changes outcome weakening the value of this approach.⁷ With recent results from Destiny-BREAST04⁸ and other trials, it is also difficult to advocate for a trial design that would withhold beneficial systemic therapies. Given that BR002 demonstrated MTD did not affect first-line therapy outcomes, it is difficult to imagine why the author's suggestion of prolonging local therapy would result in a meaningful outcome.

In conclusion, NRG-BR002 affirmed the null hypothesis—that addition of ablative local therapies to metastatic disease identified at random assignment would not alter future distant progression events or survival. It may well be that other diseases or novel agent combination under investigation in other phase III trials (NRG-LU002, COMET3, and CORE) will yield different outcomes.⁹ For now, BR002 demonstrated that metastasis-specific local therapy for palliation remains the standard of care for breast cancer.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Reply to J. Widder

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.

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