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

IN-DEPTH REVIEW OF RESEARCH

Study background:

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

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

In clinical trials, participants with inherited BRCA mutations who were treated with a PARP inhibitor for their metastatic 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, HER2-negative tumors and those with estrogen/progesterone receptor-negative, HER2-negative tumors (also called triple-negative breast cancer or TNBC).

Two PARP inhibitors, olaparib (Lynparza) and talazoparib (Talzenna) have been FDA-approved for HER2-negative metastatic breast cancer in people who have inherited BRCA mutations.

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

Like BRCA1 and BRCA2, mutations in some of the other DNA 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 DNA repair genes may also be sensitive to PARP inhibitors. In this study, researchers are looking at whether patients with inherited mutations in DNA repair genes other than BRCA1 and BRCA2 or patients with a  tumor mutation in BRCA1, BRCA2 or other DDR genes respond to the PARP inhibitor olaparib.

Researchers of this study wanted to know:

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

Populations looked at in this study:

Eligible participants were people with metastatic breast cancer who:

• Had at least one measurable metastatic lesion.
• Had not progressed (their tumor had not grown) on more than two prior therapies.
• Had not been treated with a PARP inhibitor before this study.
• Did not have platinum refractory disease, defined as disease which had progressed while receiving platinum chemotherapy, or metastatic disease which had developed within 12 months of receiving platinum chemotherapy.
• Had an inherited or tumor acquired mutation in a DNA repair gene including ATM, ATR, BARD1, BRIP1, BLM, CHEK2, FANCA/C/D2/F/M, MRE11A, NBN, PALB2, RAD50, RAD51C, RAD51D or related genes. (People with inherited mutations in BRCA1 or BRCA2 were excluded because olaparib is already known to be useful for them).
  • Group 1 were people who had an inherited mutation (not BRCA1 or BRCA2)
  • Group 2 were people who had an acquired tumor mutation in BRCA1 or BRCA2 or one of the DNA damage response genes listed above.

The median age of participants was 59 (ranging from ages 30 to 87); 75 percent had ER-positive, HER2-negative cancer; 5 percent had Her2-positive cancer and 19 percent had ER/PR-negative, HER2-negative (triple-negative) breast cancer (TNBC). Among participants, 19 percent had no prior chemotherapy and 5 percent had previously been treated with platinum chemotherapy. Among those with ER-positive, HER2-negative 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 toxicity 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 toxicity 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 DNA damage response gene other than BRCA1 or BRCA2) and 27 were in Group 2 (participants with an acquired tumor mutation in a DNA 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 toxicity
• 1 patient was lost to follow-up

Table of Olaparib Expanded participants by mutation type

Number of participants with a mutation for each group

NOTES ABOUT TABLE:
* 1 patient in the CHEK2 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 PALB2 also had an ATM mutation but was not included in the ATM group.
***1 patient with a tumor BRCA2 mutation was found to be ineligible due to a germline BRCA2 mutation and was excluded from efficacy analyses. 

Results for Group 1 (participants with inherited mutations)

• 27 patients had the following inherited mutations:
  • 8 CHEK2 (one patient had a BRCA tumor mutation but was not counted with Group 2)
  • 4 ATM
  • 2 CHEK2 and ATM
  • 11 PALB2 (one patient also had an inherited ATM mutation but was not counted with that group)
  • 1 BARD1
  • 1 RAD50
• 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 PALB2 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 PALB2 mutation. 
  • One participant with an inherited RAD50 mutation, also had stable disease for 6 months before progressing.

PALB2

• Among people with an inherited PALB2 mutation, 9 of 11 (82%) had partial tumor shrinkage.
  • 8 of the responders had an ER-positive, HER2-negative tumor.
  • 1 responder had an ER-positive, HER2-positive tumor
• At 18 weeks, the clinical benefit rate (tumor shrank or remained stable) was 100% among participants with PALB2 tumor mutations.
• Among the 9 PALB2 responders: 
  • 7 had received prior chemotherapy
  • 7 had received a prior CDK 4/6 inhibitor

RAD50

• The participant with a RAD50 mutation had a tumor that remained stable in size for 6 months and then progressed.

CHEK2 and ATM

• None of the 14 participants with CHEK2 and/or ATM 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
    • 7 BRCA1 and 9 BRCA2, including one participant from Group 1 who had an inherited CHEK2 mutation and a BRCA1 tumor mutation, and one participant with a BRCA1 and an ATM tumor mutation who was not counted among participants with ATM.
  • 4 ATM
    • One person had both an ATM and a FANCF tumor mutation.
  • 2 PALB2
  • 2 CDK12
  • 1 BRIP1
  • 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 BRCA tumor mutations.
    • 4 had a BRCA1 tumor mutation
    • 4 had a BRCA2 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 BRCA tumor mutations.

BRCA1/2

• Among people with a BRCA 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 CHEK2 mutation.
  • 4 of 8 responders (50%) had an ER-positive, HER2-negative tumor.
  • 4 of 8 responders (50%) had an ER/PR-negative, HER2-negative tumor (triple-negative breast cancer).
• At 18 weeks, 67% of participants with a BRCA tumor mutation had stable or shrinking tumors (i.e., 67% clinical benefit rate).
• Among the 8 participants with a BRCA1 or BRCA2 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 toxicity (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 BRIP1, FANCA, BLM, RAD50 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 ATM and CHEK2 mutations and promising response among those with inherited PALB2 and BRCA 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 PALB2 mutation or a BRCA1 or BRCA2 tumor mutation showed responses to olaparib treatment across tumor subtypes, indicating that this PARP inhibitor may be useful for treatment of metastatic breast cancer in these patients. No clinical benefit was seen in participants with ATM or CHEK2 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.

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Posted 6/18/20