The PARP promise
2019/11/15中国

Poly-ADP-ribose polymerase (PARP) inhibitors are a new class of drug that are transforming ovarian cancer into a long-term chronic disease. Two of the four treatments already marketed, namely AstraZeneca’s Lynparza (olaparib) and Pfizer’s Talzenna (talazoparib), are currently commercialized in Latin America, having entered the region merely months after their global launch and before markets with higher expected sales such as China and Japan. This is indicative of both drug developers’ interest in these markets, and the desire of healthcare authorities to insure patients have early access to the latest paradigm-changing drug classes, particularly new cancer treatments. GBI SOURCE data shows that, of the 41 novel drugs approved by Brazil’s National Health Surveillance Agency (ANVISA) last year, 10 are anti-cancer products, a trend that extends to other Latin American markets.

The PARP development story
Researchers have dedicated decades of effort to redirecting the very process that originates cancer, namely genetic mutations, against the disease itself. Mutations can arise from DNA damage that occurs routinely in living organisms as a result of errors in replication, production of reactive oxygen species, and exposure to ultraviolet rays or ionizing radiation. In response, evolution has come up with a battery of response mechanisms that constantly monitor and repair these offences.

However, these processes can fail due to environmental factors that overwhelm them, or to genetic predisposition such as deleterious mutations in the proteins involved in these pathways. Such is the case with BRCA1 and BRCA2, necessary for the homologous recombination (HR) pathway that repairs double strand breaks (DSBs) on DNA which, among other causes, can result from the less serious single strand breaks (SSBs) if they go unattended. BRCA1 and BRCA2 mutations thus prevent DNA repair and are associated with increased risk of malignancies, particularly in breast and ovarian cancers. 1

A taste of its own medicine
Because HR-deficient tumor cells have heightened sensitivity to DNA damage, a hypothesis was developed that this weakness could be turned against cancer. One way of achieving this is by hindering the activity of repair enzymes such as the poly-ADP-ribose polymerase (PARP) family of proteins, critical for the base excision repair (BER) pathway that deals with SSBs. By inhibiting PARP, SSBs accumulate in the cell, eventually resulting in DSB accumulation and ultimately overwhelming cells to the point that programmed cell death results.

The discovery process behind PARP has been a particularly long one. Involvement of PARP-1 in the repair of SSBs and the potential for inhibition of the enzyme to enhance the cytotoxic effects of methylating agents was first uncovered in 1980, while the concept of using PARP as a single agent against cancer was first proved in 2005 2. The first generation of inhibitors developed in the 1980s were based on nicotinamide analogues. It became apparent then that a major problem would be to guarantee specificity, since PARP inhibitors must compete at the active site with NAD+, a coenzyme that is widely used by cells for energy production. After a more potent second generation, the current benzamide- or purine-based PARP inhibitors of the third generation show greater potency and specificity for PARP, the improved selectivity allowing for less toxicity and less off-target effect.

The efficacy of PARP inhibition was first confirmed against BRCA-associated ovarian cancers, the first-in-class Lynparza gaining its first approval in December 2014, followed by Clovis Oncology’s Rubraca (rucaparib), Janssen’s Tesaro Therapeutics-licensed Zejula (niraparib), and Pfizer’s Talzenna (talazoparib). PARP inhibition in the maintenance setting for ovarian cancer has produced strong data, Lynparza reducing the risk of disease progression or death by 70% in platinum-sensitive patients, and by 65% in women regardless of BRCA status in the SOLO2 study, while the median investigator-assessed progression free survival (PFS) was 19.1 months, compared with 5.5 months in the placebo arm.

After its initial approval to treat ovarian cancer, AstraZeneca’s Lynparza has also been granted indication extensions for BRCA-positive breast cancer patients, becoming the first PARP inhibitor to be used beyond ovarian cancer and the first targeted treatment option for triple-negative breast cancer patients. Meanwhile, Pfizer’s Talzenna was launched recently as a BRCA-positive breast cancer therapy. Other notable PARP inhibitors under development include AbbVie’s veliparib, which last year stumbled at the final hurdle in two Phase III trials, after failing to reach endpoints in combination with chemotherapy in squamous non-small cell lung cancer (NSCLC) and triple-negative breast cancer.

The genomic instability of some cancer cells benefits PARP inhibition as a strategy and means that PARP inhibitors can be selective for tumor cells over normal cells. Moreover, using a PARP inhibitor as a single agent avoids the toxic effects of chemotherapy and radiation, while as small molecules the drugs have the benefit of being orally available and easily administered to patients.

Assessment of BRCA1/2 mutations has been a precondition for use of PARP inhibitors in the treatment setting for ovarian cancer. Currently, research is turning towards discovering other forms of cancer with defects in HR, either germline or acquired, that could be susceptible to PARP inhibition. Beyond BRCA1/2 mutation, biomarkers used to predict PARP inhibitor efficacy in patients include DSB quantity, which can be measured from the amount of γ-H2AX protein foci that form due to the DNA lesions. Another biomarker is the lack of HR proteins recruited around Rad51, which under normal conditions assembles these foci in response to DNA damage. New indications are expected to arise by exploiting γ-H2AX and Rad51 foci biomarkers.


A potential combo therapy
Although waiving the benefit of reduced toxicity, PARP inhibitor-based combination therapies are viewed as having potential for use against a wider range of cancers. Since PARP agents can prevent repair that occurs after SSB-inducing chemotherapy, there is the potential for PARP to enhance this cytotoxic effect. As mentioned above, the idea was first proposed in 1980 that modulating PARP-1, the best known member of the PARP family, might augment the effect of alkylator chemotherapy.

Selectivity would also be favored in cases where mismatch repair (MMR), a DNA repair pathway, has been compromised. Since only tumor cells are deficient in MMR, the combination of PARP inhibitors with methylating agents could selectively kill tumor cells.

Furthermore, PARP inhibitors also enhance the cytotoxicity of camptothecins, which promote DNA breakage by inhibiting topoisomerase I, an enzyme that decreases torsional strain on DNA. Use of PARP inhibitors has also been shown to potentiate ionizing radiation via the inhibition of BER, but also possibly through inhibition of inflammatory proteins and altered regulation of cellular metabolism. Scientists recently demonstrated the radiosensitization capability of olaparib in treating cholangiocarcinoma. 3


There are also studies under way assessing PARP inhibitors alongside bevacizumab, with immunotherapy, and even triplet therapy with PARP inhibitors, immunotherapy, and bevacizumab. Combinational PARP inhibitor therapies will need to wait, however, as clinical trials of these treatments have so far failed to determine an acceptable PARP inhibitor dosage below myelosuppressive toxicities.

Finally, activation of PARP is known to contribute to the pathogenesis of a number of human diseases linked to processes of inflammation, mitochondrial dysfunction, oxidative stress, inflammation, and metabolic reprograming, leading researchers to postulate that the drug class may be applicable beyond cancer. Given the risk-benefit considerations of administering a drug that interferes with the regulation of DNA repair, suggested possible diseases where PARP inhibition could be beneficial include acute ischemic stroke, traumatic brain injury, septic shock, acute pancreatitis, severe asthma and acute lung injury, and even chronic diseases such as multiple sclerosis, Parkinson’s disease, severe fibrotic diseases, or Graves’ ophthalmopathy. 4 5

Resistance to PARP inhibitors
Resistance is often found in medical therapies, and PARP inhibitors are not the exception. It can result from restoration of HR by other pathways, or from a secondary mutation in BRCA2 that reverts it to a functional state as a result of a clinical disorder or chemotherapy itself. Overcoming this is a current area of research.

PARP inhibitors in Latin America
AstraZeneca’s Lynparza was the first PARP inhibitor to land in Latin America in 2015 when Mexico approved its use in treating ovarian cancer, with Ecuador, Argentina, Brazil, Peru, and Colombia following suit in the following years, approving indications for ovarian or breast cancers (Table 1). cancers. Determined to not fall behind, Pfizer’s Talzenna entered the Latin America market in August, 2019, when it obtained marketing approval and was almost immediately launched in Argentina, where it is indicated against breast cancer.


Clinical development in Latin America
MNCs are actively carrying out clinical trials on PARP inhibitors in Latin America, with 7% of global studies involving institutions in the region. Latin American locations with the most development are Brazil, Argentina, and Puerto Rico, with 20, 13, and 10 studies respectively (Table 2). The most active developer is AstraZeneca with its candidate olaparib the focus of over half of the projects.

Current development trends show that MNCs are targeting new indications for these drugs, such as prostate and lung cancers.

Outlook
The swift arrival of PARP inhibitors in Latin America evidences the shared interest between regulatory agencies and drug developers in bringing novel cancer treatments to these markets. Currently, Lynparza and Talzenna are not direct competitors as they have different indications in Argentina, the only market where they coexist. However, this drug class is expected to trigger intense competition as more players enter the arena and additional indications are granted in oncology and potentially other therapeutic areas as noted above.

With the aim of maximizing their products’ indications, MNCs are relying on local partners to advance the clinical development of PARP inhibitors, the involvement of Latin American institutions in these studies being on par with the region’s size. This hints that these novel drugs will increase in number in these markets, potentially transforming cancer treatment protocols. However, they will need to demonstrate a clear clinical benefit compared to less expensive drug classes before enjoying widespread adoption by the public health systems.