Talazoparib (Breast Cancer)

Talazoparib (Talzenna), a poly (ADP-ribose) polymerase (PARP) inhibitor, was approved in late 2018 for the treatment of patients with deleterious or suspected deleterious germline BRCA-mutated, HER2-negative locally advanced or metastatic breast cancer.^1,2 Talazoparib is the second agent in the PARP inhibitor class to be approved in this setting; olaparib (in tablet form) was approved for a similar indication earlier in 2018.³

PARP Inhibitors, DNA Repair, and BRCA Mutations

PARP inhibitors have been approved for the treatment of patients with ovarian cancer (see https://jnccn360.org/ovarian/) in a variety of settings since 2014.⁴ However, trials and subsequent approvals of agents in this class for patients with BRCA mutation–positive advanced breast cancer are more recent.^5,6 It has been proposed that growth of DNA repair–deficient tumors, such as those that harbor the germline susceptibility genes BRCA1 and BRCA2, may be impeded by PARP inhibitors in 2 ways: (1) by inhibiting the enzymatic activity of PARP and (2) by trapping PARP at the sites of DNA damage.⁷

PARP inhibitors have an absolute role in the treatment of patients with metastatic breast cancer who have a [germline] BRCA mutation.

Jennifer Keating Litton, MD, Associate Professor in the Department of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston and principal investigator of the EMBRACA trial, explained the rationale for studying talazoparib. “One of the mechanisms described as ‘trapping’ refers to what happens when DNA is damaged and the PARP inhibitor attaches to the damaged DNA, not allowing the cancer cell to divide further. Talazoparib is the strongest ‘trapper’ of all the PARP inhibitors in cell line studies,”⁸ she told JNCCN 360.  

The OlympiAD trial⁵ and the EMBRACA trial⁶ were similarly designed. Each compared the PARP inhibitor (OlympiAD, olaparib; EMBRACA, talazoparib) with the physician’s choice of chemotherapy. Both trials demonstrated that the “PARP inhibitors have an absolute role in the treatment of patients with metastatic breast cancer who have a [germline] BRCA mutation,” Dr. Litton stated. Both trials showed an improvement in progression-free survival. The OlympiAD trial wasn’t large enough or powered to look at overall survival. The EMBRACA trial is larger and “will yield those data eventually, although overall survival data were not yet mature at the time of the first analysis and presentation. The curves look encouraging, but those findings will be event-driven and will be reported when appropriate,” she told JNCCN 360.

BRCA Mutation Testing in Breast Cancer

At this time, not all patients first diagnosed with breast cancer are tested for a deleterious germline BRCA mutation.⁹ NCCN,  ASCO, and recently the American Society of Breast Surgeons have all convened groups to look at questions around BRCA and other genes to be tested, Dr. Litton pointed out, but there is no consensus yet.¹⁰ [Editor’s Note: The NCCN Guidelines for Breast Cancer¹¹ recommend strongly considering “germline BRCA1/2 testing for those with HER2–negative metastatic breast cancer being considered for chemotherapy.”] “Identifying BRCA can be done well,” she said, “but as these gene panels expand, we have discovered many genes with either low or moderate penetrance and even many genes for which we don’t have clinical recommendations. It makes testing and the need for genetic counseling even more important.” At this point, Dr. Litton explained, “we would consider such testing in patients with strong family histories of breast and other cancers, a young age at diagnosis, a triple-negative tumor subtype, and metastatic breast cancer. Now that we have two drugs that appear to be active against tumors driven by deleterious BRCA mutations, there is certainly a compelling reason to consider such testing.”

When the results of such testing are received, “the category that denotes a positive result is called a ‘pathogenic variant,’” Dr. Litton said. Other results that the test may yield are “variant of uncertain significance,” “suspected deleterious,” or “suspected polymorphism.” If testing reveals the presence of a pathogenic variant in BRCA, the patient would be eligible for consideration of a PARP inhibitor such as talazoparib.

“From my perspective,” Dr. Litton noted, “patients with known or suspected deleterious mutations on a Clinical Laboratory Improvement Amendments [CLIA]–certified laboratory test are eligible for treatment with a PARP inhibitor.”[Editor’s Note: The U.S. FDA approval of talazoparib¹ included approval of an assay, BRACAnalysis CDx test, to identify patients with breast cancer with a deleterious or suspected deleterious germline BRCA mutation who would be eligible for treatment.]

Sarah Donahue, ANP, AOCNP, is a nurse practitioner with the team led by Hope S. Rugo, MD, at the UCSF Helen Diller Family Comprehensive Cancer Center. Several patients with advanced or metastatic breast cancer at the Center were enrolled on the EMBRACA trial, and Dr. Rugo was a coauthor on study results published in The New England Journal of Medicine.⁶

According to Ms. Donahue, “not long ago, BRCA-mutation testing in newly diagnosed breast cancer was limited according to certain strict eligibility criteria, such as a strong family history of disease or triple-negative disease in a young patient. Now, though, all of our patients meet with a genetics counselor and discuss whether they want to proceed with testing for BRCA mutations.”

With many options available for advanced breast cancer, the question of optimal sequencing is key. Patients with advanced or metastatic breast cancer whose tumors harbor a deleterious germline BRCA mutation may also have hormone receptor–positive disease. The presence of more than one therapeutic target raises the question of sequencing.

Hormone Receptor–Positive Breast Cancer

Although patients with BRCA mutations, especially those with BRCA1 mutations, may have triple-negative breast cancer, not all do, Dr. Litton pointed out. In the EMBRACA trial, she said, “more than 50% of patients had estrogen receptor–positive disease.” In the EMBRACA trial design, patients could have had an unlimited number of prior endocrine therapies, which included doublets such as an aromatase inhibitor and a cyclin-dependent kinase (CDK) 4/6 inhibitor, or exemestane and everolimus. Only chemotherapy regimens given in the advanced disease setting were counted as “prior lines of treatment.”

“We have been using talazoparib in a handful of patients so far (fewer than 10),” Ms. Donahue reported, “and most of them have had quite a number of previous therapies. They may have had neoadjuvant or adjuvant chemotherapy as well as endocrine regimens prior to the PARP inhibitor.”

Because the progression-free survival data in studies of the CDK4/6 inhibitors were “outstanding” (≥ 2 years)¹²—regardless of the presence of a BRCA mutation—“I am inclined to start with endocrine therapy, perhaps an aromatase inhibitor plus a CDK4/6 inhibitor, in those with hormone receptor–positive disease,” Dr. Litton suggested. “Then, when we arrive at the point to consider chemotherapy, we could switch to a PARP inhibitor.”

Triple-Negative Breast Cancer

In patients with triple-negative disease, the results of the IMpassion130 trial (ClinicalTrials.gov identifier NCT02425891) may change how “we approach treatment in the first line for those with PD-L1–positive disease,” according to Dr. Litton. “I imagine, for instance,” she elaborated, “that a patient with triple-negative disease and both high levels of PD-L1 and a deleterious BRCA mutation might be started on atezolizumab plus nab-paclitaxel in the first line, followed by a PARP inhibitor on disease progression.” [Editor’s Note: The combination of atezolizumab and nab-paclitaxel was approved in early March 2019 for the treatment of unresectable locally advanced or metastatic PD-L1–positive (≥ 1%) triple-negative breast cancer.¹³ Dr. Litton pointed out that high PD-L1 levels on tumor-infiltrating immune cells (versus tumor cells in general) were associated with response to atezolizumab.]

Role for Platinum-Based Chemotherapy?

“One of the things we don’t yet know,” Dr. Litton indicated, “is how to layer the use of PARP inhibitors with platinum agents. So, we don’t know whether patients with breast cancer who have been treated with a platinum-based regimen will still respond to a PARP inhibitor. Likewise, we don’t know whether patients will respond to platinum-based therapy after having received a PARP inhibitor. We may not see a significant response once there has been disease progression on either a platinum agent or PARP inhibitor,” she added, “but no study has asked those questions.”

Patient Preference, Quality of Life, and Patient-Reported Outcomes

All the patients seemed to be pleased to have the option of an oral treatment rather than infusional chemotherapy.

Patients definitely seem to prefer a once-daily oral therapy, such as talazoparib, to infusional chemotherapy, Dr. Litton confirmed. In addition to patient preference, “adherence to a once-daily regimen may be better than with more frequent dosing,” she said.

Gretchen Santos, MSN, FNP-BC, also on Dr. Rugo’s San Francisco team, concurred. “All the patients seemed to be pleased to have the option of an oral treatment rather than infusional chemotherapy.”

An important part of the EMBRACA trial was the integration of a quality-of-life assessment that used a patient-reported tool for outcomes—European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-30) and its breast cancer module, QLQ-BR23. In addition to improved progression-free survival for talazoparib compared with single-agent chemotherapy, patient-reported outcomes were also superior for the PARP inhibitor.¹⁴

“Patient-reported outcomes were striking in EMBRACA,” Dr. Litton said. It is clear that quality of life, as perceived by patients, was better with the PARP inhibitor than with chemotherapy.”

With respect to managing adverse effects, the team recommended regular exercise to combat fatigue. In addition, nausea was well controlled with excellent antiemetic protocols, she noted. “Not only do patients save time with the oral regimen (ie, they do not need to incorporate chemotherapy sessions into their schedules), they also felt significantly better compared with those who received chemotherapy. The data were striking in the EMBRACA trial, but this seems to be a class effect with the PARP inhibitors,” she observed.  

Safety Profile of Talazoparib

The primary adverse effects associated with the PARP inhibitors are hematologic: low white blood cell counts, low red blood cell counts, low platelet counts. “Usually, it is the anemia that causes symptoms,” Dr. Litton said. Anemia can generally be well managed, she advised, with dose delays or dose reductions, and transfusions when indicated. “The vast majority of adverse effects reported in the EMBRACA trial for patients receiving talazoparib were grade 1 and 2 and were well managed,” Dr. Litton stated. 

“We are always concerned about myelodysplastic syndromes and acute leukemias with PARP inhibitors,¹⁵ because they have been observed in the ovarian cancer setting,” Dr. Litton said, noting that the patients in ovarian cancer trials had been heavily pretreated. Those sequelae were not observed in the OlympiAD or EMBRACA trial, Dr. Litton reported. “These concerns are even less likely in an untreated population, such as in the neoadjuvant setting, but we will have to follow these patients to gain a better understanding,” she said.

Illustrating the occasional use of transfusions, Ms. Santos described one patient who experienced symptomatic anemia with shortness of breath and fatigue. She was treated with blood transfusions. She also recalled a patient with significant and persistent thrombocytopenia. “The dose of talazoparib had to be reduced by 50% for that patient,” she explained.

The San Francisco team prescribes antiemetics to have at home whenever a patient is given a new treatment with the potential for nausea and vomiting. “That said, we didn’t see much nausea with talazoparib, although some patients experienced decreased appetite,” Ms. Donahue told JNCCN 360. Because of the low incidence of nausea and vomiting, patients were instructed to fill the antiemetic prescription and to have the medication “on hand,” rather than to use it prophylactically.

Ms. Donahue and Ms. Santos noted that patient information about PARP inhibitors is easy to find online and is generally helpful during the patient education process, particularly when discussing potential adverse effects. “In our experience,” Ms. Donahue added, “talazoparib has not been associated with the same intensity or severity of side effects that occurs with chemotherapy. So, patient education about this agent is not a particularly arduous process for us.”

“So far, in our experience, the occurrence of any side effects with talazoparib has not reduced adherence,” Ms. Santos said.

Next Steps

Extending the duration of response to a PARP inhibitor represents an intriguing and practical clinical question. “All of us have some long-term survivors, both on this EMBRACA trial and on other trials with other agents,” Dr. Litton observed. “What makes those patients different? Can we use the immune system to extend the duration of response to PARP inhibitors? What about combination trials looking at DNA-damaging agents other than PARP inhibitors? Can we expand the pool of patients who are eligible? What about patients with other types of mutations, such as PALB2,¹⁶ or patients with germline or even somatic mutations in the DNA damage–repair pathway? We have to keep in mind that when single-agent PARP inhibitors are given to patients who do not have any of these types of mutations, we don’t usually see responses,” she pointed out.

Talazoparib in the Neoadjuvant Setting

If we could use a once-daily pill for 6 months and achieve pathologic complete response in patients with triple-negative breast cancer, that would be game-changing.

“We presented a trial¹⁷ in which we gave talazoparib alone to eligible patients with newly diagnosed early-stage breast cancer; a higher than 50% pathologic complete response rate was achieved with the PARP inhibitor alone. If we could use a once-daily pill for 6 months and achieve pathologic complete response in patients with triple-negative breast cancer, that would be game-changing,” Dr. Litton told JNCCN 360. “What’s especially encouraging is that none of these younger patients stopped menstruating. So, here is a therapy that potentially does not negatively impact future fertility in these younger women,” she added. The neoTALA trial (ClinicalTrials.gov identifier NCT03499353) is underway to further evaluate these findings. Long-term follow-up is planned.

A Chance to De-escalate Therapy?

“I feel comfortable considering a PARP inhibitor, even in the first line, if the patient has a deleterious germline mutation. I am not concerned about the speed of response,” Dr. Litton stated. “One of the things that we were taught as oncologists is to give a potent chemotherapy combination regimen whenever a patient has metastasis to the liver or other organ and is symptomatic. But we’ve found that we can get a good response with the PARP inhibitors quickly in some patients,” she told JNCCN 360. “Even if the patient is symptomatic, a PARP inhibitor may be effective, providing a better quality of life when compared with several standard chemotherapies.” Although oncologists are accustomed to oral therapies such as endocrine agents taking longer to produce results, she commented, “we saw similar response times [compared with chemotherapy] in the phase III clinical trials.”

One of the recurrent themes in breast cancer in the modern era is the potential to de-escalate therapy. “We’ve seen it in patients with HER2-positive disease, and perhaps now,” Dr. Litton suggested, “those with deleterious BRCA mutations can be ‘de-escalated’ to a PARP inhibitor.”

Disclosures

Jennifer Keating Litton, MD, has received research funding from Pfizer, AstraZeneca, Genentech, EMD Serono, and Novartis; has served on an advisory board or as a consultant for Pfizer and AstraZeneca; has served on the Editorial Board of NIH PDQ; has served as a guideline panel member for NCCN and ASCO; has received royalties from UpToDate; and has served as a speaker for MedLearning Group, Physician’s Education Resource, and Everday Health.

Sarah Donahue, ANP, AOCNP, reported no conflicts of interest. 

Gretchen Santos, MSN, FNP-BC, has served on the advisory board for Novartis.

 References

1. U.S. Department of Health and Human Services. U.S. Food & Drug Administration. FDA approves talazoparib for gBRCAm HER2-negative locally advanced or metastatic breast cancer. Available at: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm623540.htm. Accessed April 18, 2019.

2. Talzenna™ (talazoparib). FDA prescribing information. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211651s000lbl.pdf. Accessed April 18, 2019.

3. U.S. Department of Health and Human Services. U.S. Food & Drug Administration. FDA approves olaparib for germline BRCA-mutated metastatic breast cancer. Available at: https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm592357.htm. Accessed April 18, 2019.

4. Kim G, Ison G, McKee AE, et al. FDA approval summary: Olaparib monotherapy in patients with deleterious germline BRCA-mutated advanced ovarian cancer treated with three or more lines of chemotherapy. Clin Cancer Res 2015;21:4257–4261.

5. Robson M, Im SA, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med 2017;377:523–533.

6. Litton JK, Rugo HS, Ettl J, et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med 2018;379:753–763.

7. Lord CJ, Ashworth A. PARP inhibitors: Synthetic lethality in the clinic. Science 2017;355:1152–1158.

8. de Bono J, Ramanathan RK, Mina L, et al. Phase I, dose-escalation, two-part trial of the PARP inhibitor talazoparib in patients with advanced germline BRCA1/2 mutations and selected sporadic cancers. Cancer Discov 2017;7:620–629.

9. Grindedal EM, Heramb C, Karsrud I, et al. Current guidelines for BRCA testing of breast cancer patients are insufficient to detect all mutation carriers. BMC Cancer 2017;17:438.

10. Breast cancer genetic testing guidelines exclude almost half of high-risk patients. The ASCO Post, May 8, 2018. Available at: http://www.ascopost.com/News/58820. Accessed April 18, 2019.

11. Gradishar WJ, Anderson BO, Abraham J, et al. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. Version 1.2019. Accessed April 26, 2019. To view the most recent version of these guidelines, visit NCCN.org.

12. Pernas S, Tolaney SM, Winer EP, et al. CDK4/6 inhibition in breast cancer: current practice and future directions. Ther Adv Med Oncol 2018;10:1–15.

13. U.S. Department of Health and Human Services. U.S. Food & Drug Administration. FDA approves atezolizumab for PD-L1 positive unresectable locally advanced or metastatic triple-negative breast cancer. Available at: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm633065.htm. Accessed April 18, 2019.

14. Ettl J, Quek RGW, Lee KH, et al. Quality of life with talazoparib versus physician’s choice of chemotherapy in patients with advanced breast cancer and germline BRCA1/2 mutation: patient-reported outcomes from the EMBRACA phase III trial. Ann Oncol 2018;29:1939–1947.

15. Fulcher N, Shenolikar RA, Durden E, et al. Incidence of secondary myelodysplastic syndrome and acute myeloid leukemia in patients with ovarian and breast cancer in real world setting in the U.S. [abstract]. J Clin Oncol 2017;35(suppl):5574.

16. Antoniou AC, Casadei S, Heikkinen T, et al. Breast-cancer risk in families with mutations in PALB2. N Engl J Med 2014;371:497–506.

17. Litton JK, Scoggins M, Ramirez DL, et al. A feasibility study of neoadjuvant talazoparib for operable breast cancer patients with a germline BRCA mutation demonstrates marked activity. Available at: https://www.nature.com/articles/s41523-017-0052-4. Accessed April 26, 2019.