Matching Novel Targets to Treatment Generates Excitement in TNBC

Neelima Vidula, MD

Important targets have emerged in triple-negative breast cancer (TNBC) in recent years, according to Neelima Vidula, MD, and innovative therapeutic interventions, such as PARP inhibitors and antibody-drug conjugates (ADCs), have been developed to match them. As such, germline genetic testing has become an important staple of care.

“It’s very important for patients with advanced TNBC to undergo germline genetic testing. If they're found to have a BRCA1/2 mutation, I would consider using a PARP inhibitor at some point in their course of treatment,” said Vidula. “One of the major benefits of using a PARP inhibitor is that these are oral therapies. They're targeted therapies that tend to be very well tolerated, especially in contrast to chemotherapy, and they can help improve patient quality of life [QoL].”

Beyond PARP inhibitors, the ADC sacituzumab govitecan-hziy (Trodelvy) has also generated excitement. The agent elicited an objective response rate of 33.3% per local assessment, with a median duration of response of 7.7 months, according to data from a phase 1/2 trial. The ORR by independent central review was slightly higher, at 34.3% with a median DOR of 9.1 months. These data led to the April 2020 FDA approval for use in patients with metastatic TNBC who received at least 2 previous therapies for metastatic disease. A recent phase 3 study of sacituzumab versus chemotherapy has confirmed an improvement in both progression-free survival and overall survival with sacituzumab.^1,2

“These were really exciting findings. It's always nice to have phase 3 data that confirms what we are hoping to see from initial studies,” said Vidula. “I believe that based on these findings, sacituzumab govitecan should be considered a standard treatment option for patients with metastatic TNBC.”

In an interview with OncLive^® during the 2020 OncLive Institutional Perspectives in Cancer webinar on Breast Cancer, Vidula, a breast medical oncologist at Massachusetts General Hospital, discussed the current and future utility of PARP inhibitors in triple-negative breast cancer, the promise of sacituzumab govitecan, and the need for germline genetic testing.

OncLive^®: How are PARP inhibitors being used in the clinic? Are they potent enough as single agents?

Vidula: Two PARP inhibitors have received FDA approval for the treatment of [patients with] metastatic HER2-negative germline BRCA-mutant breast cancer. Olaparib [Lynparza] was the first to receive approval, which was based on results from the OlympiAD study. This trial randomized patients with germline BRCA mutations to olaparib versus physician’s choice of chemotherapy, which could be capecitabine, eribulin, or vinorelbine. Results showed that there was an improvement in progression-free survival with the utilization of olaparib compared with chemotherapy in this setting. Based on these data, olaparib was approved by the FDA.

The EMBRACA study led to the approval of the second PARP inhibitor, talazoparib [Talzenna]. This was a randomized study where patients with germline BRCA-mutant, HER2-negative, metastatic breast cancer were randomized to either talazoparib or physician’s choice of chemotherapy, which included eribulin, vinorelbine, gemcitabine, or capecitabine. Again, there was an improvement in PFS. As a result, talazoparib was also FDA approved in this setting. EMBRACA also demonstrated an improvement in patient reported QoL with talazoparib over chemotherapy.

Ongoing studies are also combining PARP inhibitors with a number of other agents, such as immunotherapy and chemotherapy. However, currently, we are generally using PARP inhibitors as single-agent therapies. PARP inhibitors are a really great option because they're oral, targeted, and tend to have less adverse effects. However, germline BRCA mutations [are] only [present in] about 5% to 10% of patients with breast cancer.

Many groups are interested in seeing how we can expand the utility of PARP inhibitors for patients with metastatic disease. One potential avenue for expansion is to see whether these agents are effective in patients with somatic BRCA-mutant metastatic breast cancer, similar to what we have seen in ovarian cancer. This is an area that is ripe for research.

You have participated in research being done in this area. Could you discuss those efforts?

We identified, using cell-free DNA, a liquid biopsy, that some patients with metastatic breast cancer have somatic BRCA mutations that are found in the blood and this is in the absence of having a known germline mutation.³

Based on these findings, we designed an investigator-initiated trial⁴ that is open at Massachusetts General Hospital; it will open soon at other institutions, as well. Here, we are screening patients with metastatic breast cancer using cell-free DNA. If they're found to have a BRCA mutation in cell-free DNA, and they don't have a known germline mutation, they're eligible for that study and can be treated with talazoparib until progression.

This is an interesting clinical trial that will help us determine whether there's a role for PARP inhibition in patients who have somatic BRCA mutations. Based on our prior work, it's possible that a significant proportion of patients with metastatic disease carry these mutations in the blood, so this study may help expand the population of patients with metastatic breast cancer who may benefit from a PARP inhibitor.

It is known that these patients should undergo germline testing, but would you recommend that patients also undergo somatic testing with the understanding that there are ongoing clinical trials like the one you’re involved in?

Absolutely. It's very helpful for patients to have some form of tumor genotype testing, whether it's in the blood through a cell-free DNA assay, or in a tumor tissue lesion itself that was biopsied; this may help identify novel targets and could potentially direct patients to an appropriate clinical trial.⁵

Unfortunately, advanced TNBC remains incurable. As such, having more treatment options for patients is a wonderful thing. At Massachusetts General Hospital, we use a lot of cell-free DNA, as well as tumor tissue genotyping, to help identify targets. We try to recommend eligible patients to targeted therapy clinical trials. This concept of treatment matching is very exciting.

Speaking of new agents, the ADC sacituzumab govitecan has generated excitement in this space. What data have been reported with this agent and what is its role in the paradigm?

Sacituzumab govitecan, a TROP2-directed ADC (antibody-drug conjugate), is an exciting agent; it actually combines an anti-TROP2 antibody with a cleavable linker, and SN38, which is an irinotecan derivative. The initial study that was done with this agent in advanced TNBC was a phase 1/2 study. Results demonstrated a PFS of 5.5 months and an overall survival [OS] of 13 months in patients with TNBC who have been heavily pretreated, which prompted the FDA to give this agent a breakthrough drug designation.

At the 2020 ESMO Virtual Congress, we saw results from the ASCENT trial, which is a phase 3 confirmatory study of sacituzumab govitecan in metastatic TNBC. This was a randomized study that enrolled patients with metastatic TNBC and treated them with either sacituzumab govitecan or physician’s choice of chemotherapy. This trial was halted early due to the compelling efficacy results.

Data demonstrated an improvement in PFS with sacituzumab govitecan compared with physician’s choice of chemotherapy. The median PFS in the sacituzumab govitecan arm was 5.6 months compared with 1.7 months in the chemotherapy arm, which was statistically significant. Furthermore, we also saw an improvement in OS with sacituzumab govitecan. The median OS in the arm receiving sacituzumab govitecan was 12 months compared with 6.7 months in the arm receiving physician’s choice of treatment. Again, this was a significant improvement.

References

1. FDA grants accelerated approval for Immunomedics’ Trodelvy in previously-treated metastatic triple-negative breast cancer. News release. Immunomedics, Inc. April 22, 2020. Accessed December 4, 2020. https://yhoo.it/3eCev8R.
2. Immunomedics announces ASCENT study to be stopped for compelling efficacy. News release. Immunomedics, Inc. April 6, 2020. Accessed December 4, 2020. https://bit.ly/3lQ7i7C.
3. Vidula N, Dubash T, Lawrence MS, et al. Identification of somatically acquired BRCA1/2 mutations by cfDNA analysis in patients with metastatic breast cancer. Clin Cancer Res. 2020;26(18):4852-4862. doi:10.1158/1078-0432.CCR-20-0638
4. Evaluation of talazoparib, a PARP inhibitor, in patients with somatic BRCA mutant metastatic breast cancer: genotyping based clinical trial. ClinicalTrials.gov. Updated September 11, 2020. Accessed December 4, 2020.
5. Vidula N, Juric D, Niemierko A, et al. Comparison of tissue genotyping (TG) vs circulating tumor DNA (ctDNA) for selection of matched therapy and impact on clinical outcomes among patients with metastatic breast cancer. J Clin Oncol. 2018;35(suppl 15):1020. doi:10.1200/JCO.2018.36.15_suppl.1020