PARP inhibitors: Overview and indications

PARP (poly(ADP-ribose) polymerase) inhibition can be an effective treatment for individuals who have variants in genes that are involved in DNA repair, such as BRCA1/2. There are multiple pathways (controlled by multiple genes) involved in DNA damage repair. The PARP family of proteins controls response to single-strand DNA breaks. Blocking this pathway forces cells to utilize complementary mechanisms to repair DNA damage.

In tumors that already have a DNA repair deficiency, due to pathogenic variants in genes involved in homologous recombination repair (HRR), such as BRCA1/2, disabling the PARP pathway further compromises the cell and leads to increased cell death (Coyne 2017). HRR genes include ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANC, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L. PARP inhibitors are most effective when alternative pathways are non-functional, as occurs when both copies of a gene have variants that prevent the gene from working correctly. This is called bi-allelic loss, and can be due to the presence of one germline and one somatic variant or two somatic variants. Currently, having a single variant in a gene involved in HRR is sufficient to consider treatment with PARP inhibitors (PARPi).

PARPi are currently approved for ovarian, breast, prostate, and pancreatic cancers with certain characteristics. Oncologists may also consider PARPi through clinical trials or off-label for other indications when genomic tumor testing results suggest DNA repair deficiency.

FDA-approved indications

PARPi treatments can be used to treat certain advanced ovarian, primary peritoneum, fallopian tube, breast, pancreatic, and prostate cancers that have BRCA1/2 and other HRR gene pathogenic variants or markers of impaired DNA damage such as loss of heterozygosity (LOH) or homologous repair deficiency (HRD). They can also be used for advanced ovarian, primary peritoneum, and fallopian tube cancers that have previously responded to platinum-based therapy, regardless of the presence of genomic variants.  

PARPi for maintenance therapy

Maintenance therapy is the use of a cancer drug in individuals who have complete or partial remission, with the goal of preventing recurrence or delaying growth of the tumor. There are several approved indications for PARPi for maintenance therapy. These indications include certain advanced ovarian, primary peritoneum, fallopian tube, and pancreatic cancers with variants in genes associated with homologous recombination repair, as well as in certain advanced or recurrent ovarian, primary peritoneum, and fallopian tube regardless of the presence of genomic variants.

FDA-approved PARPi maintenance therapy indications

Cancer site

Drug

Genomic variants

Eligibility

Companion diagnostic

Ovary, primary peritoneum or fallopian tube

Niraparib

n/a

Advanced cancer, complete or partial response to platinum-based chemotherapy

Not required

n/a

Recurrent cancer, complete or partial response to first-line platinum-based chemotherapy

Not required

Olaparib

n/a

Recurrent cancer, complete or partial response to first-line platinum-based chemotherapy

Not required

g/s1 BRCA1/2

Advanced cancer, complete or partial response to first-line platinum-based chemotherapy

For germline variants: Myriad BRACAnalysis CDxTM; Myriad myChoice® CDxTM
Not required for somatic variants

Olaparib + bevacizumab

HRD2 (BRCA1/2 variant OR genomic instability)

Advanced cancer, complete or partial response to first-line platinum-based chemotherapy

Myriad BRACAnalysis CDxTM; Myriad myChoice® CDxTM

Rucaparib

g/s BRCA1/2

Advanced cancer, complete or partial response to first-line platinum-based chemotherapy

FoundationFocus CDxBRCATM

n/a

Recurrent cancer, complete or partial response to first-line platinum-based chemotherapy

Not required

Pancreatic adenocarcinoma

Olaparib

g3 BRCA1/2

Metastatic, no progression more than 16 weeks of a first-line platinum-based chemotherapy regimen

Myriad BRACAnalysis CDxTM; Myriad myChoice® CDxTM

1 g/s: pathogenic or suspected pathogenic germline or somatic variant

2 HRD: homologous repair deficiency

3 g: pathogenic or suspected pathogenic germline variant

PARPi for cancer treatment

FDA-approved PARPi indications for cancer treatment

Cancer site

Drug

Genomic variants

Indication

Companion diagnostic

Breast

Olaparib

g/s1 BRCA1/2

HER2- metastatic cancer, previously treated with chemo

BRACAnalysis CDxTM
FoundationFocus CDxBRCATM
Myriad myChoice® CDx

g/s BRCA1/2

HER2+ cancer, previously treated with endocrine therapy or not appropriate for endocrine therapy

BRACAnalysis CDxTM
FoundationFocus CDxBRCATM
Myriad myChoice® CDx

Talazoparib

g2 BRCA1/2

HER2- locally advanced or metastatic cancer

BRACAnalysis CDxTM

Ovary, primary peritoneum or fallopian tube

Niraparib

HRD3 positive (g/s BRCA1/2 variant OR genomic instability) + 6 months progression

Advanced cancer, treated with 3 or more previous lines of chemotherapy

Myriad myChoice® CDxTM

Olaparib

g BRCA1/2

Advanced cancer, treated with 3 or more previous lines of chemotherapy

BRACAnalysis CDxTM
FoundationFocus CDxBRCATM
Myriad myChoice® CDx

Rucaparib

g/s BRCA1/2

Advanced cancer, treated with 2 or more previous lines of chemotherapy

FoundationFocus CDxBRCATM

Prostate, metastatic castration-resistant

Olaparib

g/s HRR gene variant4

Progressed on hormone therapy (enzalutamide or abiraterone)

BRACAnalysis CDxTM
FoundationFocus CDxBRCATM

Rucaparib

g/s BRCA1/2

Previously treated with androgen receptor-directed therapy and a taxane-based chemotherapy

N/A

1 g/s: germline or somatic variant

2 g: germline variant

3 HRD: homologous repair deficiency

4 Homologous recombination repair (HRR) genes include ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FACL, PALB2, RAD51, and RAD54.

For patients with ovarian cancer, germline and somatic genetic testing for BRCA1/2 and other genes related to homologous recombination repair (HRR) and/or loss of heterozygosity (LOH) is indicated to inform management (NCCN 2020). For women with recurrent or progressive ovarian cancer, germline or somatic testing to specifically to assess appropriateness of PARPi should be offered, if not done previously.

Similarly, germline testing for patients with breast cancer may be offered in a number of situations. If it has not yet been done, germline or somatic testing should be offered to assess for PARPi candidacy in patients with recurrent or stage IV HER2-negative breast cancer.

Companion and complementary diagnostics

Companion diagnostics are available, and in some cases required, to identify candidates who may benefit from PARPi treatment, as specified in the tables above. If a patient is found to have a BRCA1/2 pathogenic variant through a genomic testing assay other than one of the currently approved companion diagnostic tests (BRACAnalysis CDxTM, FoundationFocus CDxBRCATM, and myChoice CDxTM), the individual may still be able to access the desired PARPi drug. Contact the pharmaceutical company and patient’s insurance company to verify access for a specific patient. The FDA maintains a current list of approved companion diagnostic tests.

Emerging indications for PARPi treatment in clinical trials or for off-label consideration

The evidence for the use of PARPi therapy is expanding into different cancer types and in cancers with variants in HRR genes beyond BRCA1/2. Current investigations are also investigating the use of PARPi therapy as part of combination therapy. The discussion below highlights a few of the approaches currently being studied.

Homologous recombination repair genes

Genes other than BRCA1/2 that are involved in DNA damage repair, including ATR, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FACL, NBS1, PTEN, PALB2, RAD51, and RAD54, are being investigated as possible targets for PARPi treatment. Clinical trials are recruiting patients with solid tumors and a germline or somatic HRR gene variant to assess response to PARPi monotherapy or combination therapy.

Other cancer types

Investigators are considering the efficacy of PARPi therapy is for patients with HRR variants regardless of underlying cancer type. The majority of current clinical trials are for solid tumors, but there is preclinical and some Phase I trial data for hematologic cancers as well. Some cancers for which Phase II trial data is supportive are discussed below.

Malignant mesothelioma. Phase II clinical trial (MiST1) shows response to PARPi in patients with relapsed malignant mesothelioma with BAP1 and/or BRCA1 variants (Fennell 2020).

Non-small cell lung cancer. Phase II trial using a combination therapy including PARPi (+temozolomide) shows response in patients SLFN11 positive (Pietanza 2018).

Tumors with biomarkers associated with homologous repair deficiency

In addition to a pathogenic variant in a DNA repair gene, certain tumor biomarkers associated with homologous repair deficiency (HRD) can indicate susceptibility to PARPi. These biomarkers include loss of heterozygosity (LOH), large-scale state transitions, telomeric allelic imbalance, and others. While at least one assay designed specifically to test for HRD exists (Myriad MyChoiceHRD CDx) and LOS (FoundationCDx), most genomic tumor testing panels do not report on these biomarkers with the goal of identifying PARPi treatment candidates. This is an area of ongoing development, and additional HRD biomarkers and assays will likely be available in the future.

Combination therapy

Trials are ongoing to evaluate PARPi in combination with chemotherapy, radiation therapy, hormone therapy, immunotherapy, and other targeted treatments. The combinations below represent only some of those that are being tested in trials.

PARPi + immunotherapy. PARPi therapy leads to DNA damage, increasing the number of mutations present in a tumor (tumor mutational burden) and making it more susceptible to immunotherapy. Current evidence shows efficacy of this approach in breast, ovarian, and prostate cancers, primarily those with BRCA1/2 variants. (Vikas 2020)

PARPi + chemotherapy. PARPi therapy inhibits tumors from repairing certain types of DNA damage. This can prevent cells from being able to repair DNA damage that is the result of chemotherapy, leading to death of cancer cells. Preliminary data supports this approach with some combinations, but there can be issues with myelotoxicity (Boussios 2019).          

PARPi + antiangiogenic agent. PARPi therapy has been shown to decrease angiogenesis. Anti-angiogenesis agents, such as bevacizumab, can cause certain types of DNA repair proteins to be down-regulated, making cells sensitive to PARPi therapy.  There are ongoing clinical trials to assess safety and efficacy of this combination (Boussios 2019).

Other relevant variants

In addition to DNA repair variants, tumor testing may identify variants associated with sensitivity or resistance to PARP inhibition treatment. A tumor with a TMPRSS2-ERG fusion as well as a DNA repair gene variant, for example, may be hypersensitive to PARPi treatment.  Resistance variants include those in SLFN11, 53BP1, REV7, and others. PARPi resistance may be primary or may be acquired over time after ongoing PARPi treatment, both of which can result in treatment failure.

Learn more

Companion diagnostic testing (FORCE, 2018)

Frequently Asked Questions: PARP Inhibition Therapy (JAX, 2020)

References

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