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Study: Promising research using a PARP inhibitor to treat metastatic breast cancer in people with an inherited PALB2 mutation or a tumor mutation in BRCA1 or BRCA2

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Contents

At a glance                  Questions for your doctor
What does this mean for me? In-depth            
Clinical trials Limitations
Guidelines Resources


STUDY AT A GLANCE

This study is about:

This study looked at the usefulness of the  olaparib (Lynparza) for treating breast cancer in participants who did not have an inherited  or  mutation. This study did include people with inherited mutations in other genes, such as and . The study also included people with an acquired tumor mutation in ,  or other  damage response genes found through tumor  testing.

Why is this study important?

Olaparib and other PARP inhibitors have received  approval to treat several types of cancer, including  breast cancer (MBC). For people with  breast cancer, the approval only applies to people with an inherited  mutation. The "Olaparib Expanded" study looked at whether PARP inhibitors may be used to treat MBC in people who do not have an inherited mutation in  or .

Study findings: 

This is an early report on the "Olaparib Expanded" clinical trial, which was presented at the American Society of Clinical Oncology conference in May 2020.

The study enrolled two groups of people with breast cancer: patients with an inherited mutation or patients with an acquired mutation in their tumor in a gene that repairs damage.

People with an inherited mutation in or were excluded from this study.

27 participants had an inherited mutation in the following damage response genes:

  • 8
  • 4
  • 2 and
  • 11  (one patient with an inherited mutation in also had an inherited  mutation but was not counted in the group)
  • 1
  • 1

27 participants had an acquired tumor mutation in the following damage repair genes:

  • 16  or 
  • 4
  • 2
  • 2 CDK12
  • 1
  • 1 BLM
  • 1 FANCA

Among all participants with inherited mutations:

  • None had complete tumor shrinkage.
  • 9 of 27 (33%) had partial tumor shrinkage. All these participants had an inherited mutation.
  • 44 percent of patients had a shrinking or stable tumor after 18 weeks of treatment (the clinical benefit rate for those with an inherited mutations).
    • In addition to patients with inherited mutations, 1 person with a mutation had stable disease.
  • The median duration of response was 9 months.

Among participants with inherited mutations:

  • 9 of 11 patients (82%) had partial tumor shrinkage.
  • Tumors of different sub-types responded to olaparib.
    • 8 had ER-positive, tumors.
    • 1 person had an ER-positive,  tumor.
  • People responded who had received different types of prior therapy.
    • 7 of 9 (88%) responders had prior chemotherapy.
    • 7 of 9 (78%) responders had prior treatment with a CDK4/6 inhibitor.

Among all participant with tumor mutations:

  • 31% of patients had tumors that shrank at least initially:
    • All patients whose tumor shrank had an acquired tumor mutation in or .
    • Of all the patients with a tumor mutation, half had tumors that shrank.
  • Tumors of different sub-types responded to olaparib:
    • 4 had a ER-positive, tumor
    • 4 had a , tumor ().
  • Among the 8 participants who had tumors that shrank:
    • 7/8 had prior chemotherapy.
    • Half had prior treatment with a CDK4/6 inhibitor.
  • 11 of 25 patients (44%) had a shrinking or stable tumor after 18 weeks of treatment (the clinical benefit)
    • In addition to patients with acquired tumor mutation, one patient with an acquired tumor mutation in CDK12 also had stable disease at 18 weeks.
  • The median duration of response was 6.3 months.

and

  • No clinical benefit was seen in participants with or mutations.

Safety and adverse events

  • The most common adverse events (grade 1 or 2) were anemia (20%) and other blood effects, nausea (9%), diarrhea (7%), fatigue, (7%) and hair loss (4%).
  • More severe adverse events (grade 3 or 4) included anemia and other blood effects (16%), nausea (2%) and fatigue (2%).

What does this mean for me?

treatment is currently approved for breast cancer only in people with an inherited mutation in or . These results are promising for people with MBC and an inherited mutation in or an acquired mutation in or

Additional research with larger numbers of patients will be needed to learn if this treatment is useful for people with:

  • inherited mutations in genes other than or .
  • acquired tumor mutations in damage response genes other than and

A larger clinical trial will be opening, which will enroll patients with MBC who have an inherited mutation in or an acquired mutation in or found on tumor testing.

Share your thoughts on this XRAYS article by taking our brief survey

 

Reference

Tung NM, Robson ME, Ventz S, et al. TBCRC 048: A phase II study of olaparib monotherapy in breast cancer patients with germline or in damage response (DDR) pathway genes (Olaparib Expanded). Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020) 1002-1002.

 

Disclosure

FORCE receives funding from industry sponsors, including companies that manufacture cancer drugs, tests and devices. All XRAYS articles are written independently of any sponsor and are reviewed by members of our Scientific Advisory Board prior to publication to assure scientific integrity.

This article is relevant for:

People with metastatic breast cancer with an inherited mutation in PALB2 or tumor with a BRCA mutation

This article is also relevant for:

ER/PR +

Her2+ breast cancer

Men with breast cancer

Metastatic cancer

People with a genetic mutation linked to cancer risk

Triple negative breast cancer

Women under 45

Women over 45

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IN-DEPTH REVIEW OF RESEARCH

Study background:

Mutations in  or other  damage response genes (DDR genes, also known as  pathway or  genes) disrupt the cell's ability to repair  damage. Cells with a DDR gene mutation are sensitive to drugs that create more  damage such as PARP inhibitors or chemotherapy.

PARP inhibitors are a class of drugs that affect cells that have a mutated gene. They disable the ADP-ribose polymerase protein, which is part of the repair system within the cell. Tumor cells with a mutation are sensitive to PARP inhibitors and die.

In clinical trials, participants with inherited mutations who were treated with a for their breast cancer had longer progression-free survival (in which the tumor size does not increase) than with chemotherapy. Participants also had a better objective response rate (the amount of reduction in tumor size) and a better quality of life. This response was seen for both estrogen receptor-positive, tumors and those with estrogen/progesterone receptor-negative, tumors (also called or ).

Two PARP inhibitors, olaparib (Lynparza) and  () have been FDA-approved for   breast cancer in people who have inherited  mutations.

PARP inhibitors are also approved for treatment of ovarian, and pancreatic cancers in people with mutations, and are also under investigations for treatment of breast cancer.

Like  and , mutations in some of the other  damage response genes are also associated with an increased risk of breast cancer. Researchers predict that breast cancer among people with inherited mutations in other  repair genes may also be sensitive to PARP inhibitors. In this study, researchers are looking at whether patients with inherited mutations in repair genes other than and or patients with a  tumor mutation in , or other DDR genes respond to the  olaparib.

Researchers of this study wanted to know:

Whether olaparib is useful for treating  breast cancer in patients who have an inherited or tumor mutation in a non-BRCA damage response gene or have a tumor mutation in a gene. 

Populations looked at in this study:

Eligible participants were people with  breast cancer who:

  • Had at least one measurable lesion.
  • Had not progressed (their tumor had not grown) on more than two prior therapies.
  • Had not been treated with a  before this study.
  • Did not have platinum refractory disease, defined as disease which had progressed while receiving platinum chemotherapy, or disease which had developed within 12 months of receiving platinum chemotherapy.
  • Had an inherited or tumor acquired mutation in a  repair gene including , ATR, , BLM, , FANCA/C/D2/F/M, MRE11A, , , or related genes. (People with inherited mutations in  or  were excluded because olaparib is already known to be useful for them).
    • Group 1 were people who had an inherited mutation (not  or )
    • Group 2 were people who had an acquired tumor mutation in or or one of the  damage response genes listed above.

The median age of participants was 59 (ranging from ages 30 to 87); 75 percent had ER-positive, cancer; 5 percent had cancer and 19 percent had , (triple-negative) breast cancer (). Among participants, 19 percent had no prior chemotherapy and 5 percent had previously been treated with platinum chemotherapy. Among those with ER-positive, cancer, 93 percent had been treated with a CDK4/6 inhibitor.

Study design:

This is a single-arm phase 2 study. The overall goal is to determine if tumors of patients with MBC respond to the treatment. Fifty-four patients were enrolled from April 2018 to Jan 2020 and all were treated with the experimental therapy.

Treatment:

  • Olaparib tablets (300 mg) taken twice a day for 3 weeks.

  • Tumors were assessed for growth every 6 weeks for 24 weeks and then every 12 weeks, thereafter.

Patients whose tumors completely or partially shrank or had no tumor growth (stable disease) continued on the study with another cycle of olaparib treatment and assessment.

Patients who had tumors that grew in size (progressed) or who had that required discontinuing treatment were removed from the study.

Evaluation plan:

  • The study’s primary goal was to measure how many participants’ tumors completely or partially shrank in response to the experimental treatment (the objective response rate).
  • Secondary goals of the study were to measure:
    • how many participants had tumors that shrank or did not grow by 18 weeks of treatment (the clinical benefit rate).
    • the average time patients had with no tumor growth (the duration of response).
    • any or adverse events associated with the treatment.

Study findings:  

This is a preliminary report on the Olaparib Expanded Phase 2 clinical trial that was presented at the American Society of Clinical Oncology conference in March 2020.

Of the 54 patients enrolled, 27 were in Group 1 (participants with an inherited mutation in a damage response gene other than or ) and 27 were in Group 2 (participants with an acquired tumor mutation in a damage response gene). 

3 patients left the study after the first tumor assessment, without progression of disease:

  • 1 patient withdrew from study
  • 1 patient discontinued treatment due to 
  • 1 patient was lost to follow-up

Table of Olaparib Expanded participants by mutation type

Gene with Mutation Group 1 
Inherited Mutation   
Group 2
Acquired (tumor) Mutation
Excluded 6*
Excluded    9***
4 4
BLM1     0 1
0 1
CDK12 0 2
8* 0
and 2 0
FANCA 0 1
11** 2
1 0
1 0
Total 27 27

Number of participants with a mutation for each group

NOTES ABOUT TABLE:
* 1 patient in the group also had a tumor BRCA1; that patient is not counted with Group 2 in this table, but was included for the BRCA1/BRCA2 analyses. 
** 1 patient with  also had an  mutation but was not included in the group.
***1 patient with a tumor mutation was found to be ineligible due to a germline mutation and was excluded from efficacy analyses. 

Results for Group 1 (participants with inherited mutations)

  • 27 patients had the following inherited mutations:
    • 8 (one patient had a tumor mutation but was not counted with Group 2)
    • 4
    • 2 and
    • 11 (one patient also had an inherited mutation but was not counted with that group)
    • 1
    • 1
  • None of the participants had complete response (copmplete tumor shrinkage)
  • 9 of 27 (33%) had a partial response (decreased tumor size)
    • All (9 of 9) had a mutation
  • The median duration of response was 9 months.
  • At 18 weeks of treatment, the clinical benefit rate (tumor shrank or remained stable) among all participants with an inherited mutation was 44%. 
    • Almost all participants with a clinical benefit at 18 weeks had a mutation. 
    • One participant with an inherited mutation, also had stable disease for 6 months before progressing.

  • Among people with an inherited mutation, 9 of 11 (82%) had partial tumor shrinkage.
    • 8 of the responders had an ER-positive, tumor.
    • 1 responder had an ER-positive, tumor
  • At 18 weeks, the clinical benefit rate (tumor shrank or remained stable) was 100% among participants with tumor mutations.
  • Among the 9 responders: 
    • 7 had received prior chemotherapy
    • 7 had received a prior CDK 4/6 inhibitor

  • The participant with a mutation had a tumor that remained stable in size for 6 months and then progressed.

and

  • None of the 14 participants with  and/or  mutations showed a response to olaparib. Most patients progressed by 6 or 12 weeks of therapy.

Results for Group 2 (participants with tumor mutations)

  • 27 patients had the following tumor mutations:
    • 16 BRCA
      •  and 9 , including one participant from Group 1 who had an inherited  mutation and a  tumor mutation, and one participant with a  and an  tumor mutation who was not counted among participants with .
    • 4 ATM
      • One person had both an  and a FANCF tumor mutation.
    • 2
    • 2 CDK12
    • 1
    • 1 BLM
    • 1 FANCA
  • No participants had a complete response (complete tumor shrinkage)
    • 8 of 26 (31%) had a partial response (decreased tumor size). All 8 patients with tumor shrinkage had tumor mutations.
      • 4 had a tumor mutation
      • 4 had a tumor mutation
  • The median duration of response was 6.3 months.
  • At 18 weeks of treatment, the clinical benefit rate (stable or shrinking tumors) was 44% for all participants with a tumor mutation. The majority of participants with responding or stable tumors at 18 weeks were participants with  tumor mutations.

BRCA1/2

  • Among people with a tumor mutation, 8 of 16 (50%) patients had a partial tumor response. This includes one patient identified from Group 1 who also had an inherited  mutation.
    • 4 of 8 responders (50%) had an ER-positive, tumor.
    • 4 of 8 responders (50%) had an , tumor ().
  • At 18 weeks, 67% of participants with a tumor mutation had stable or shrinking tumors (i.e., 67% clinical benefit rate).
  • Among the 8 participants with a or mutation who responded: 
    • 7 had received prior chemotherapy. 
    • 4 had received a prior CDK 4/6 inhibitor.

BLM

One participant with a BLM tumor mutation had shrinkage at their 6-week evaluation, but this patient withdrew from study before a second confirmation tumor assessment could be performed. This patient was scored as having stable disease.

CDK12

One participant with a CDK12 tumor mutation had tumor shrinkage after six weeks of treatment, but this was not confirmed by subsequent evaluation, so this individual was classified as having stable disease. Disease remained stable for 6 weeks before progressing. The other participant with a CDK12 tumor mutation showed tumor progression at 6 weeks.

Safety and adverse events

Adverse events were similar to those seen previously with olaparib treatment.

  • The most common adverse events (grade 1 or 2) were anemia (20%) and other blood effects, gastrointestinal effects, including nausea 9%, diarrhea 7%, fatigue (7%) and hair loss (4%).
  • More severe adverse events (grade 3 or 4) included anemia and other blood effects (16%), nausea (2%) and fatigue (2%).
  • Two participants discontinued treatment due to  (one for anemia and one for elevated liver function tests).
  • 8 participants (15%) received reduced doses of olaparib due to adverse events (4 anemia, 3 nausea and 1 limb weakness/pain).

Limitations:

  • When this information was presented at the ASCO meeting in May 2020, 15 participants were still undergoing treatment as part of this study.
  • Particularly small study size. Too few participants with , FANCA, BLM, or CDK12 mutations were included to understand whether or not olaparib is effective specifically for people with these mutations. While other results are more consistent with prior studies (lack of response among those with and mutations and promising response among those with inherited and tumor mutations), additional studies are needed to confirm these results.
  • This is a single-arm phase 2 study. No comparison of this treatment was made with standard of care or other PARP inhibitors.
  • A single olaparib dose was tested. It remains possible that some mutation carriers may need a higher dose or different treatment frequency to see a benefit.
  • Numbers of tumor subtypes were small. While this treatment appears promising for all subtypes, more study is needed to verify this observation.

Conclusions

Participants with an inherited  mutation or a or tumor mutation showed responses to olaparib treatment across tumor subtypes, indicating that this may be useful for treatment of breast cancer in these patients. No clinical benefit was seen in participants with or mutations, although the numbers of people tested were small. This data is preliminary, and additional studies with larger numbers of participants is needed to see if these findings can be confirmed.

Share your thoughts on this XRAYS article by taking our brief survey.

Posted 6/18/20

Expert Guidelines
Expert Guidelines

The National Comprehensive Cancer Network (NCCN) indicates that tumor testing can help determine if a person with breast cancer would benefit from .

  • For tumors that are hormone receptor-positive, , testing for PIK3CA mutations is recommended to help identify patients who would benefit from a known as a PI3K inhibitor.
  • For tumors that are hormone receptor-negative, , testing for PDL-1 is recommended to help identify patients who might benefit from .
  • For  breast tumor types, testing for MSI-H/dMMR may help identify patients who would benefit from

Updated: 12/09/2021

Expert Guidelines
Expert Guidelines

The National Comprehensive Cancer Network has guidelines on who should undergo genetic counseling and testing. If you have been diagnosed with breast cancer, you should speak with a genetics expert about genetic testing if any of the following apply to you:     

  • You have a blood relative who has tested positive for an inherited mutation 
  • You have any of the following:  
    • Breast cancer at age 50 or younger  
    • Male breast cancer at any age
    • Ovarian cancer at any age  
    • at any age 
    • Two separate breast cancer diagnoses
    • Eastern European Jewish ancestry and breast cancer at any age 
    • breast cancer 
    • Testing of your tumor shows a mutation in a gene that is associated with
    • breast cancer and high risk for recurrence
    • Lobular breast cancer and a family history of diffuse gastric cancer

OR 

  • You have one or more close family members who have had:  
    • Young-onset or rare cancers 
    • Breast cancer at age 50 or younger
    • Male breast cancer, ovarian cancer, pancreatic cancer, or   cancer at any age
    • Two separate cancer diagnoses 
    • cancer at age 55 or younger or prostate cancer 

The American Society of Breast Cancer Surgeons (ASBrS) released guidelines in 2019 that recommend all women diagnosed with breast cancer have access to genetic testing for inherited mutations in breast cancer genes. 

If you are uncertain whether you meet the guidelines above and you are interested in or considering genetic testing, you should speak with a cancer genetics expert

 

Updated: 11/22/2021

Questions To Ask Your Doctor
Questions To Ask Your Doctor

  • I have breast cancer and a mutation; should I consider treatment with a ?
  • What are the risks and benefits of treatment with a ?
  • I have a personal or family history of cancer, but I have not had genetic testing; should I consider having genetic testing?
  • I have breast cancer and an inherited mutation in a gene that is not or BRCA2; are there any therapies or clinical trials that I should consider?
  • Should I have tumor testing to see which treatment would be most useful for treating my breast cancer?
  • As a person with an inherited mutation in a damage response gene, what other cancer risks should I be aware of?

Open Clinical Trials
Open Clinical Trials

The following are studies looking at PARP inhibitors as treatment for advanced breast cancer: 

A number of other clinical trials for treating patients with breast cancer can be found here.

Updated: 06/26/2022

Open Clinical Trials
Open Clinical Trials

The following are studies looking at treatment for people with advanced

Updated: 08/23/2022

Peer Support
Peer Support

The following organizations offer peer support services for people with, or at high risk for breast cancer:

Updated: 09/02/2022

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