Differences in pharmacology, toxicities key to clinical use of PARP inhibitors

The development of targeted treatments has dramatically improved outcomes for patients with several types of cancer.

Until a few years ago, progress in ovarian cancer lagged considerably.

However, the FDA has approved three poly (ADP-ribose) polymerase (PARP) inhibitors for ovarian cancer since 2014. These agents represent the first targeted therapy for this disease.

There are key differences in their indications.

• Olaparib (Lynparza, AstraZeneca) is approved for maintenance treatment of patients who are in complete or partial response to platinum-based chemotherapy, regardless of BRCA mutation status, as well as treatment of patients with germline BRCA-mutated advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy.
• Niraparib (Zejula, Tesaro) has a similar approval to olaparib in the maintenance setting, regardless of BRCA status.
• Rucaparib (Rubraca, Clovis Oncology) is approved only for patients with advanced ovarian cancer who have germline or somatic BRCA mutations and progressed on at least two prior lines of chemotherapy.

In January, the FDA expanded the approval of olaparib, making it the first agent in the United States indicated for treatment of BRCA-mutated breast cancer. The indication covers its use for treatment of patients with germline BRCA-mutated, HER-2-negative metastatic disease who progressed on standard chemotherapy.

Efforts to expand the scope of this novel class of agents must be grounded in a better understanding of who to treat and which PARP inhibitor to select. This will require further dissection of the mechanism by which PARP inhibitors kill cancer cells, nuances in pharmacokinetics and toxicity, and optimization of combination therapy. Identification of markers beyond BRCA also will expand the eligible patient population and improve the effectiveness of these drugs.

Pharmacology

PARP1 binds damaged DNA at single-stranded DNA breaks and other DNA lesions, triggering a series of events that activate its catalytic function promoting DNA repair.

PARP inhibitors interact with the binding site of the PARP enzyme cofactor, b nicotinamide adenine dinucleotide (b-NAD+), in the catalytic domain of PARP1 and PARP2. This interaction halts PARP activity.

The original development of PARP inhibitors was predicated on their ability to sensitize cancer cells to the effects of chemotherapies that result in DNA damage. Researchers then determined PARP inhibition significantly impaired survival of cells with BRCA mutations.

Both BRCA1 and BRCA2 proteins are critical to the repair of double-stranded DNA breaks by a process called homologous recombination repair, which restores the original DNA sequence. BRCA-mutated cancer cells are unable to repair double-stranded DNA breaks by homologous recombination and rely on alternative pathways — such as the PARP pathway — to repair DNA damage.

PARP inhibition in the presence of homologous recombination deficiency results in genetic disarray due to a process called synthetic lethality. Preclinical studies demonstrated that BRCA-mutant tumor cells were as much as 1,000 times more sensitive to PARP inhibitors than those without BRCA mutations, providing the impetus to study these compounds in clinical trials.

Pharmacokinetics and toxicities

PARP inhibitors differ in their ability to trap PARP1.

For example, talazoparib (Pfizer) — not yet FDA approved — traps PARP1 more potently than all three approved inhibitors, and it is approximately 100 times more potent than niraparib.

These differences in PARP1 trapping may be a better predictor of cytotoxicity in BRCA-mutant cells, but they also may produce increased toxicity when combined with conventional doses of cytotoxic chemotherapies.

Key pharmacokinetic differences can affect clinical management of PARP inhibitors.

Niraparib has the longest half-life at 36 hours, which allows for daily dosing. Olaparib, which has a 12-hour half-life, and rucaparib — which has an 18-hour half-life — are dosed twice daily. Olaparib initially was approved in capsule form but more recently changed to tablets, which are more potent and cannot be substituted in a 1:1 conversion.

Olaparib is metabolized primarily by CYP3A4, and extreme caution is advised when prescribing medications that inhibit or induce CYP3A4.

Rucaparib is metabolized primarily via CYP2D6, theoretically resulting in interactions with drugs — such as antidepressants — that inhibit CYP2D6. It is unknown whether pharmacogenetics may further affect drug metabolism and exposure.

Niraparib is metabolized by carboxylesterase enzymes and, thus, has limited drug interactions.

Common toxicities with all PARP inhibitors include anemia, neutropenia, fatigue and gastrointestinal toxicity.

Toxicities appear dose dependent, and most are reversible upon dose reduction or delay. However, it is important to distinguish unique toxicities between PARP inhibitors.

Niraparib has the highest rate of thrombocytopenia (any grade, 61%; grade 3 or grade 4, 34%). This typically is observed 2 weeks to 4 weeks after therapy initiation; thus, weekly complete blood counts are advised for the first month, followed by regular checks every 2 months.

The most common thrombocytopenia-associated clinical event in a phase 3 trial was grade 1 or grade 2 petechiae (5%). No patients experienced grade 3 or grade 4 bleeding events. About 15% of patients discontinued treatment due to toxicity, whereas more than 50% required dose reductions.

Elevations in liver transaminases are highest with rucaparib (grade 1 or grade 2, 74%; grade 3 or grade 4, 12%). However, these elevations are rarely symptomatic and do not always require dose modifications. Further, bilirubin does not increase, and providers are encouraged to follow Hy’s law to estimate risk for hepatic failure.

Rucaparib also can displace serum creatinine by inhibition of the renal transport molecules MATE1, MATE2 and OCT.

Increase in serum creatinine was identified in 92% of patients from a phase 3 trial; however, only 1% were grade 3 or grade 4, and they did not appear to be clinically significant as the estimated glomerular filtration rate remained normal. Thus, dose modifications often are not warranted.

Similar transporter inhibition and increase in serum creatinine has been reported with olaparib.

Cost-effectiveness

It is too early to know if one PARP inhibitor is better than another, and head-to-head clinical trials are not on the horizon. Consequently, the market may drive selection.

Although the clinical data for PARP inhibitors are promising, the unfortunate aspect of new oral targeted therapies is their high costs.

Costs associated with PARP inhibitors were 7.1 to 8.3 times higher than those for platinum combinations.

Using a Markov model, Wolford and colleagues demonstrated that platinum-based combinations were the most cost-effective for ovarian cancer treatment ($1,672 per month of PFS), followed by nonplatinum agents ($6,688 per month), bevacizumab (Avastin, Genentech)-containing regimens ($12,482 per month), olaparib ($16,469 per month) and rucaparib ($16,781 per month).

Niraparib was the least cost-effective at $18,157 per month of PFS for patients with BRCA mutations and $18,253 per month of PFS without BRCA mutations. In reality, up to half of all patients who receive PARP inhibitors may receive lower doses due to tolerability, reducing the drug price.

Despite the higher cost, niraparib has been shown to be the most clinically effective of the evaluated agents, leading to a 29.2-month PFS for women with BRCA-mutated ovarian cancer and 17.7 months for those who did not have the mutation.

Future considerations

The success of PARP inhibitors will depend upon strategies to reduce costs, control toxicities, overcome drug resistance, provide benefits to large proportions of patients and optimize combination therapies.

Potential mechanisms of resistance — which require further investigation — include loss of PARP1, BRCA mutation reversion, and emergence of resistant clones through selective pressure when PARP inhibitors target BRCA-defective tumor cells.

Because some of these mechanisms cause resistance to both PARP inhibitors and platinum-based therapies, consideration should be given to therapies provided both before and after PARP inhibitor treatment, as well as novel combination approaches.

The term “BRCAness” has been used to describe tumors that have not arisen from a germline BRCA mutation but nonetheless share the homologous recombination deficient phenotype.

For example, somatic mutations in BRCA and other genes involved with homologous recombination (eg, RAD51, CHEK2, ATM) cause deficiency in the homologous recombination pathway, as does somatic promoter hypermethylation of BRCA1. These tumor cells show sensitivity to platinum-based drugs and PARP inhibitors.

Broadening the eligibility for “BRCAness” to include these tumors may increase the subset of patients likely to benefit, as 15% of women with ovarian cancer have germline BRCA mutations but more than 50% have homologous recombination deficiency by tumor sampling.

Which of these molecular profiling-based biomarkers are most effective for predicting clinical responses to PARP inhibitors, however, is not clear.

Studies are underway to assess combination approaches with immunotherapies and other targeted therapies, including MEK, MYC, PI3K, WEE1, ATR and CHEK1/2 inhibitors.

The combination of PARP inhibitors and immunotherapies is predicated on the hypothesis that tumors with BRCA or “BRCAness” defects have higher mutagenic burden, which may produce a stronger antitumor immune response with agents such as anti-PD1 or anti-PD-L1 therapies.

Conclusion

The FDA has approved three PARP inhibitors for ovarian cancer, albeit with slightly different indications. Olaparib also has a breast cancer indication.

Additional approvals will be granted for these cancers, potentially as first-line therapy or as part of combinations with other therapies.

PARP inhibitors likely will play a major role in the treatment of other solid tumors that have high rates of homologous recombination deficiency, such as bladder cancer, prostate cancer, endometrial cancer and pancreatic cancer.

Recognizing the nuances that differentiate their pharmacokinetics, indications, toxicity profiles and clinical efficacy will be critical to the successful clinical management of these novel targeted therapies.

References:

Evans T and Matulonis U. Ther Adv Med Oncol. 2017;doi:10.1177/1758834016687254.

Fong PC, et al. N Eng J Med. 2009;doi:10.1056;NEJMoa0900212.

Heeke AL, et al. Abstract 1502. Presented at: ASCO Annual Meeting; June 2-6, 2017; Chicago.

Ledermann J, et al. N Engl J Med. 2012;doi:10.1056/NEJMoa1105535.

Ledermann JA, et al. Lancet Oncol. 2016;doi:10.1016/S1470-2045(16)30376-X.

Lord CJ and Ashworth A. Science. 2017;doi:10.1126/science.aam7344.

Mirza MR, et al. N Engl J Med. 2016;doi:10.1056/NEJMoa1611310.

Mukhopadhyay A, et al. Cancer Res. 2012;doi:10.1158/0008-5472.

Scott CL, et al. J Clin Oncol. 2015;doi:10.1200/JCO.2014.58.8848.

Swisher EM, et al. Lancet Oncol. 2017;doi:10.1016/S1470-2045(16)30559-9.

Wolford JE, et al. Abstract 5516. Presented at: ASCO Annual Meeting; June 2-6, 2017; Chicago.

For more information:

Jai N. Patel, PharmD, BCOP, is chief of pharmacology research and associate professor in the division of hematology/oncology at Levine Cancer Institute at Carolinas HealthCare System, as well as adjunct assistant professor at UNC Eshelman School of Pharmacy. He also is a HemOnc Today Editorial Board Member. He can be reached at jai.patel@carolinashealthcare.org.

Disclosure: Patel reports no relevant financial disclosures.