PARP inhibitors are hotly anticipated to become a key drug class in the treatment of select patients across several tumor types. Developers of PARP inhibitors have high hopes for their commercial success, but will they be able to achieve it through targeting niche populations?

PARP inhibitors have seen their share of ups and downs. The class initially rode a wave of excitement for the high unmet need population of triple-negative breast cancer, but this expectation fell flat with the failure of Sanofi’s iniparib in these patients in 2011. More careful consideration of which patients are most likely to respond to PARP inhibitors has led to the reinvigoration of the drug class, which in 2015 saw its first approval in AstraZeneca’s Lynparza and in 2016 its second approval in Clovis Oncology’s Rubraca.

Development of PARP inhibitors has largely focused on tumors harboring germline BRCA1/2-mutations owing to the synthetic lethality of this combination. Indeed, Lynparza’s FDA accelerated approval is for fourth- and later-line germline BRCA1/2-mutation-positive ovarian cancer. The germline BRCA1/2-mutation-positive population is small however; in breast and ovarian cancer (the indications most frequently associated with this mutation), an estimated 5-10%1 and 15%2 of patients harbor germline BRCA1/2 mutations, respectively. Another threat to the potential of PARP inhibitors is how germline BRCA1/2-mutation-positive patients are currently managed. As germline BRCA1/2 mutations are heritable some carriers are identified before developing cancer; these individuals may have prophylactic surgery to reduce their cancer risk and therefore never become candidates for PARP inhibitors, while others will undergo active surveillance to catch cancers at an early stage when surgery and radiotherapy have the highest curative potential. These steps taken by known BRCA1/2-mutation carriers could shrink the size of the potential treatable population for PARP inhibitors, as most trials of these agents are in advanced/metastatic patients, a setting that many pre-identified BRCA1/2-mutation carriers may never enter due to earlier interventions.

To expand the potential of PARP inhibitors, trials of these agents now reach beyond germline BRCA1/2-mutation-positive breast and ovarian cancers. Late-phase clinical trials are ongoing in other indications including gastric, pancreatic, non-small-cell lung, and prostate cancers. In addition to germline BRCA1/2-mutation carriers, patients with tumors classed more broadly as homologous recombination repair deficient, “BRCA-like”, or as having genomic loss of heterozygosity are being included in trials to see if they benefit from PARP inhibition. PARP inhibitors have also been evaluated in tumors harboring somatic BRCA1/2-mutations as well as mutations and deficiencies in other DNA repair molecules, such as ATM (of note however, the Phase III GOLD trial of Lynparza in ATM-negative advanced gastric cancer failed to meet its primary endpoint). Furthermore, some PARP inhibitor trials see the agents combined with chemotherapy, or strategically positioned to follow on from platinum-based agents, which may potentiate their mechanism of action. These strategies may serve to expand the potential population for PARP inhibitors; indeed, Lynparza has already secured approval as a maintenance therapy for germline and somatic BRCA1/2-mutation-positive ovarian cancer in Europe, and Rubraca’s FDA accelerated approval is for third- and later-line germline and somatic BRCA1/2-mutation-positive ovarian cancer.

Select Trials on PARP Inhibitors

Molecule (Brand) Developer Indication Phase Biomarker population
Niraparib Tesaro Ovarian cancer (recurrent, platinum-sensitive maintenance) III High-grade serous histology or germline BRCA1/2-mutation-positive
Ovarian cancer (first-line maintenance) III Homologous recombination repair deficient
Breast cancer (advanced/metastatic, HER2-negative) III Germline BRCA1/2-mutation-positive
Olaparib (Lynparza) AstraZeneca Ovarian cancer Approved (US, EU) Germline BRCA1/2-mutation-positive, fourth- and later-line (US)

 

Germline or somatic BRCA1/2-mutation-positive, platinum-sensitive maintenance (EU)

Ovarian cancer (first-line maintenance) III Germline BRCA1/2-mutation-positive
Breast cancer (advanced/metastatic, HER2-negative) III Germline BRCA1/2-mutation-positive
Breast cancer (adjuvant, HER2-negative) III Germline BRCA1/2-mutation-positive
Pancreatic cancer (recurrent metastatic, platinum-sensitive) III Germline BRCA1/2-mutation-positive
Gastric and gastroesophageal Junction Cancer (recurrent) III
Prostate cancer (recurrent, metastatic castrate-resistant) III Homologous recombination repair gene mutated
Rucaparib (Rubraca) Clovis Oncology Ovarian cancer (third- and later-line) Approved (US) Germline and somatic BRCA1/2-mutation-positive
    Ovarian cancer (recurrent, platinum-sensitive maintenance) III High-grade serous histologya
    Ovarian cancer (recurrent, platinum-sensitive maintenance) III Germline BRCA1/2-mutation-positive and homologous recombination repair deficient
Talazoparib Pfizer Breast cancer (recurrent advanced/metastatic, HER2-negative) III Germline BRCA1/2-mutation-positive
Veliparib AbbVie Ovarian cancer (first-line maintenance) III High-grade serous histologyb
Breast cancer (advanced/metastatic, HER2-negative) III Germline BRCA1/2-mutation-positive
Breast cancer (neoadjuvant, triple-negative) III b
Non-small-cell lung cancer (advanced/metastatic squamous) III c
Non-small-cell lung cancer (advanced/metastatic non-squamous, previous/current smokers) III c
  1. Results of this trial will be analyzed according to homologous recombination repair deficiency status of patients
  2. This trial is collecting information on germline BRCA1/2 status of participants
  3. While these trials are not biomarker-lead, the eligible populations selected for study (squamous tumors [which are closely associated with a history of smoking] and non-squamous tumors in previous/current smokers) is likely to favor PARP inhibitor mechanism of action, as smoking increases the mutational load in NSCLC tumors.

 

As PARP inhibitors are positioned for specific biomarker-associated populations, developers have partnered with diagnostics manufacturers to develop companion tests for these therapies. For example, Lynparza was approved with Myriad Genetics’s BRACAnalysis CDx, a blood-based diagnostic for germline mutations in BRCA1/2. Furthermore, in order to facilitate PARP inhibitors’ penetration of broader populations, some companies have entered partnerships to develop tests which enable selection of a broader range of patients most likely to respond to PARP inhibition. For example, the approval of Rubraca for somatic and germline BRCA1/2 mutations was accompanied by the first FDA approval of a next-generation-sequencing diagnostic test, Foundation Medicine’s FoundationFocus CDxBRCA.

Thus far, evaluation of PARP inhibitors in populations beyond germline BRCA1/2-mutation-positive patients has largely been restricted to ovarian cancers. Should PARP inhibitors prove efficacious in these trials, it is likely that companies will look to cast their nets wider, evaluating PARP inhibitors in broader populations (such as homologous recombination-repair deficient tumors) in other oncology indications in order to increase their uptake. Expanding the market for PARP inhibitors beyond patients with germline BRCA1/2-mutations will be key to driving meaningful sales growth in this drug class, particularly in high incidence indications such as breast cancer.

References

  1. Campeau PM, Foulkes WD, Tischkowitz MD. Hereditary breast cancer: New genetic developments, new therapeutic avenues. Human Genetics 2008; 124(1):31–42.
  2. Pal T, Permuth-Wey J, Betts JA, et al. BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. Cancer 2005; 104(12):2807–16.

 

Insights in this article are drawn from various Decision Resources Group offerings. More detailed information is available through our Company and Drug analysis, Epidemiology, and Disease Landscape & Forecast content.

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