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Precision Oncology

Patient selection for PARP inhibitor treatment in BRCA-& HRR-associated cancers.

by Dr William Tan and Ms Ashley Yau

Poly (ADP-ribose) polymerase inhibitors (PARPi), namely olaparib, rucaparib, niraparib, and talazoparib, are precision medicines recently added to the armamentarium of personalized cancer therapy. Since its first approval by the U.S. Food and Drug Administration (FDA) in 2014, a paradigm shift has been seen in the management of BRCA– and homologous recombination repair (HRR)-associated cancers, such as ovarian, breast, prostate, and pancreatic cancer. Much research efforts have been focusing on the identification of cancer patients who would benefit from effective PARPi treatment. These efforts have led to the rapidly evolving PARPi landscape due to the continued expansion of their indications and the necessary genetic biomarker testing required for patient selection. Hence, it is inevitable that clinicians are faced with challenges in their daily practice to keep up with this fast development.

In this article, we review the current body of evidence and address these pertinent questions: How to select patients who would likely benefit from PARPi treatment? Which genetic biomarkers should be tested? What specimens should be used?

 

How Do PARP Inhibitors Work?

PARPi are pharmacological agents that block the activity of a family of DNA damage repair proteins known as PARPs. The most abundant and best characterized member of the family is PARP1, which is responsible for repairing single-strand breaks through base-excision repair (BER). If the existing single-strand breaks remain unrepaired and persist through the DNA replication process, double-strand breaks are formed as a result. In normal cells, double-strand breaks can be properly repaired through an error-free homologous recombination repair (HRR) mechanism. This process is orchestrated by a myriad of proteins including BRCA1/2 and other HRR proteins to preserve the integrity of DNA, which is imperative for cell survival.

By contrast, tumour cells that harbour a deleterious mutation in BRCA or other HRR genes in a condition collectively known as HRR deficiency (HRD). Repair of these double-strand breaks relies on a compensatory, error-prone non-homologous end-joining mechanism.1 In this setting, PARPi causes the formation of double-strand breaks in tumour cells with HRD by trapping the enzyme PARP1 at the sites of single-strand DNA breaks, thereby causing replication fork blockade that further exacerbates DNA breakage and genomic instability.2 This prevents cell division to progress further and ultimately leads to cell death in a phenomenon called synthetic lethality, whereby a combination of two individually non-lethal defects (i.e., PARP inhibition and HRD) leads to a unique vulnerability (Figure 1).2

BRCA1/2 Mutation and PARP Inhibitor Sensitivity

BRCA1 and BRCA2 are tumour suppressor genes which are integral to the proper function of the HRR pathway. Early clinical development of PARPi has been focused on targeting cancers associated with BRCA1/2 mutations such as breast and ovarian cancer, which resulted in the U.S. Food and Drug Administration (FDA) approval of PARPi in these biomarker-selected cancers (Table 1).

Olaparib is the first drug approved as a PARPi. The first approved indication was for fourth-line or later therapy of germline BRCA-mutated (gBRCAm) advanced ovarian cancer which had been treated with more than or equal to three prior lines of chemotherapy (Figure 2). In subsequent years, the approved indications of olaparib in ovarian cancer quickly expanded beyond gBRCAm, and now include both germline and somatic BRCA mutation (sBRCAm) for first-line maintenance therapy.

Similar trend in genetic biomarkers testing using tumour tissue was observed based on the approval of other PARPi, such as niraparib and rucaparib. This supports the notion that testing for gBRCAm alone using whole peripheral blood is not adequate to select patients for PARPi treatment in ovarian cancer. Notably, about five to eight percent of ovarian cancer (Figure 3) is attributable to sBRCAm and germline testing alone would potentially exclude these patients who may benefit from PARPi treatment.3-9 Recent approval of olaparib and rucaparib for use in metastatic castrate-resistant prostate cancer (mCRPC) patients harbouring g/sBRCAm further substantiates this point. However, for breast cancer and pancreatic ductal adenocarcinoma (PDAC), a much greater proportion of patients carries gBRCAm than sBRCAm (breast cancer: ~20% vs. 2%, respectively; PDAC: ~4% vs. 0.5%, respectively).3-9 It may partly explain why the registration trials of PARPi in these two cancers only recruited patients with gBRCAm. Whether patients with sBRCAm may also benefit from PARPi treatment in these cancers remain to be determined.

 

Beyond BRCA and “BRCAness”

The term “BRCAness” was used to describe a shared phenotype of high sensitivity to both platinum-based chemotherapy and PARPi, and a higher overall survival rate observed between BRCA-mutated and non-BRCA-mutated ovarian cancers.10 Aberration of certain genes involved in the HRR pathway other than BRCA1/2, such as ATM, BARD1, BRIP1, CHEK1, CHEK2, FAM175A, MRE11A, NBN, PALB2, RAD51C and RAD51D, may be the underlying molecular mechanism that gives rise to the characteristics of “BRCAness” in ovarian cancer.11 This existing phenotype is not surprising because other HHR proteins, such as PALB2 and RAD51, directly mediate and execute the repair of double-strand DNA damage. While ATM/ATR and CHEK2 act as sensors of DNA breakage, facilitating subsequent recruitment and activation of BRCA1/2 and other effector proteins. Given the divergent roles of these proteins in HRR, genetic aberrations in specific HRR genes may confer certain PARPi sensitivities and should be dissected at the individual-gene level.

In a sub-analysis of Study 19, ovarian cancer patients with tumours harbouring loss-of-function mutations in HRR genes other than BRCA derived greater progression-free survival benefit from olaparib (HR = 0.21; 95% CI, 0.04-0.86) than patients with no detectable BRCA or HRR mutation (HR = 0.71; 95% CI, 0.37-1.35).12 Albeit interesting, this finding warrants further investigation in a prospective study. In accordance with these findings, the European Society for Medical Oncology (ESMO) and the European Society of Gynaecologial Oncology (ESGO) jointly recommend in 2019 that testing for mutations in other HRR genes, in particular RAD51C, RAD51D, BRIP1, and PALB2, should be considered in patient with ovarian cancer.13 More recently, the U.S. FDA also approved olaparib for mCRPC with germline or somatic pathogenic mutations in any one of 14 HRR genes (ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L) based on the findings from PROfound trial.14 These findings particularly exemplify the importance of identifying the candidate genes that contribute to the “BRCAness” phenotype in different BRCA– or HRR-associated cancers. In this way, more patients may be appropriately selected for effective PARPi treatment given that mutation in other non-BRCA HRR genes constitutes a substantial proportion of patients with these cancers (Figure 3).

Genomic Scars as a Predictor of PARP Inhibitor Sensitivity

Genomic scarring refers to the gain or loss of large chromosomal regions which are the end-products resulting from a defective HRR pathway. It serves as an indicator of genomic instability. Genomic scar analysis using an HRD score was evaluated in NOVA trial15 and more recently in QUANDRA16 and PAOLA-117 trials based on the total number of occurrences of three biomarkers, namely loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LSTs). Tumours were scored on a scale of 0-100 with a cut-off score of 42. Any tumour that scored more than or equal to 42 or had a deleterious or suspected deleterious BRCA1/2 mutation was considered to have defective HR repair.

In contrast, tumours scoring less than 42 was considered to have functional HR repair.18 These biomarkers reflect the degree of tumour genomic instability and are highly associated with defective HRR function in ovarian cancers. For instance, LOH is highly correlated with defects in BRCA1/2, PTEN, FANCM and RAD51C, while a high TAI or LST score indicates DNA repair defects in BRCA1/2 wild-type and BRCA1/2-mutated ovarian cancers, respectively.19,20 However, the NOVA trial shed important insight that the HRD scoring method may not possess adequate precision to deselect patients who would not benefit from niraparib. This notion was based on the observation that a statistically significant progression-free survival rate increase was also seen in the HRD-negative group.21

Measurement of tumour genomic LOH represents another method of measuring genomic scarring. The phase II ARIEL2 trial evaluated the validity of measuring tumour genomic LOH for predicting rucaparib response in the treatment setting.22 Tumours scoring above the LOH cut-off of 14 percent (LOH-high) were considered HRD-positive. In this trial, 80 percent of BRCA-mutant tumours, 29 percent of BRCA wild-type, LOH-high tumours, and 10 percent of BRCA wild-type, LOH-low tumours responded to rucaparib.22 In the phase III ARIEL3 trial, the LOH cut-off was raised to 16 percent for the prediction of rucaparib response in the maintenance setting following platinum-based chemotherapy.23

Findings from these studies further demonstrated that the use of HRD scoring method may help identify patients with BRCA wild-type, platinum-sensitive ovarian cancers. However, it may not be sufficiently precise to exclude a clinical benefit from PARPi treatment, especially among BRCA wild-type ovarian cancers in either the treatment or maintenance setting. More clinical trials are warranted to further investigate the role of these HRD biomarkers in predicting benefits from PARPi.

 

Future Perspectives

Today, clinical trials using genomic biomarker analysis as part of their outcome indicators will be able to use these future research results to help identify which biomarkers are suitable for inclusion in subsequent experiments. BRCA alone is clearly not sufficient for use as the best candidate biomarker for evaluating PARPi response, and a list of related markers needs to be further validated in the future. In addition, there is currently no clear evidence explaining why the PARPi response exists in tumours that do not have typical HRR gene mutations. PARP protein has a mechanism of action beyond DNA repair, so the benefits of PARPi may not be limited to BRCA or even BRCAness-related tumours. Therefore, a better understanding on the molecular mechanism of PARPi’s actions and the underlying mechanism behind PARPi resistance (e.g., BRCA reversion mutations) will be critical for the advancement of PARPi as a precision medicine. [APBN]

All photos, diagrams, and tables in this article are credited to the authors.

References

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About the Authors

Dr. William Tan is the Regional Medical Science Liaison of ACT Genomics

 

 

 

Ms Ashley Yau is the Associate Manager (Marketing and Visual) of ACT Genomics