Poly (ADP ribose) polymerase (PARP) inhibitors are among the most exciting new classes of oncology drugs, and their development has coincided with the increasing recognition of the therapeutic vulnerability in targeting DNA damage response and DNA repair. The initial clinical testing of PARP inhibitors began nearly a decade ago, following the discovery that these agents in vitro had heightened anticancer activity in cancer cells that harbored BRCA mutations compared to BRCA wild-type cancer cells with intact DNA repair. This observation was followed by clinical trials testing olaparib (Lynparza), which was the first PARP inhibitor to enter clinical trials and the first to receive both U.S. and European regulatory approval in 2014. At the 2008 ASCO Annual Meeting, after I listened to the initial phase I results of olaparib and witnessed the anticancer efficacy in heavily pretreated BRCA-mutated ovarian cancer, I knew PARP inhibitors were going to be important anticancer drugs.
At the 2008 ASCO Annual Meeting, after I listened to the initial phase I results of olaparib and witnessed the anticancer efficacy in heavily pretreated BRCA-mutated ovarian cancer, I knew PARP inhibitors were going to be important anticancer drugs.— Ursula A. Matulonis, MD
PARP inhibitors exert their anticancer effects by inhibiting the functions of PARP enzymes, which are instrumental in binding to single-strand DNA damage and initiating repair; these drugs also trap PARP on DNA at sites of damage, leading to the disabling of DNA repair. PARP inhibitors work by exploiting the concept of synthetic lethality, meaning that if two separate gene aberrations or mutations coexist, cell death occurs, but if only one of them exists, the cell is viable. As a result, PARP inhibitors show their greatest activity in cancer cells with mutations in genes that are instrumental in performing homologous recombination, which is critical in the repair of double-stranded DNA breaks. Thus, the combination of two genetic events—the presence of a BRCA mutation and the use of a PARP inhibitor that blocks single-strand DNA break repair—leads to synthetic lethality and cell death.
PARP inhibitors have other mechanisms of anticancer efficacy, ie, the PARP enzymes, PARP1 and PARP2, have roles, for example, in immune function, which also may influence and enhance the anticancer properties of PARP inhibitors. Several PARP inhibitor resistance mechanisms have been identified, including restoration of DNA repair through the development of BRCA reversion mutations. This process restores the open reading frame of the BRCA gene, thereby generating PARP inhibitor resistance. Other mechanisms of resistance include loss of 53BP1 and REV7, both involved in DNA repair, as well as increased drug efflux mechanisms such as seen with ABCB1 upregulation.1,2 Understanding and overcoming PARP inhibitor resistance are critical areas of study, given that patients receiving them will eventually develop cancer progression.
The clinical development of PARP inhibitors in oncology has taken several different directions, including single-agent and combination testing. Single-agent strategies have led to the current success of PARP inhibitors in ovarian cancer along with multiple regulatory approvals. Single-agent PARP inhibitors have been used for either primary treatment of recurrent ovarian cancer (olaparib, rucaparib [Rubraca]) or as maintenance treatment following anticancer response using platinum-based chemotherapy (niraparib [Zejula], olaparib).
Because of the myelosuppression observed with PARP inhibitors, combining these agents with chemotherapy has required dose reductions of the PARP inhibitor and/or the chemotherapy agents and often an abbreviated treatment schedule. The rationale behind testing PARP inhibitor combinations has been to enhance the effectiveness of either or both agents; mechanisms of synergy or additive effects are multifactorial, based on the exact combination and the cancer being studied, and could include increasing homologous recombination deficiency in the cancer cell or enhancing PARP enzymatic activity or PARP trapping.
Several ongoing phase III studies are testing the benefit of PARP inhibitor and chemotherapy combinations vs chemotherapy alone, with at least three phase III studies reporting negative results. These studies include testing the addition of the PARP inhibitor veliparib to combination chemotherapy for either non–small cell lung cancer or breast cancer (ClinicalTrials.gov identifiers NCT02032277 and NCT02106546)3 and the addition of olaparib to weekly paclitaxel in advanced gastric cancer (NCT01924533).4 These negative trials suggest this development strategy either is flawed or will require much more clinical trial time and effort to establish combination doses and schedules that are superior to chemotherapy alone.
Combining PARP inhibitors with biologic agents is another strategy being tested and one that avoids the excessive myelotoxicity observed with PARP inhibitor and chemotherapy combinations. Our group at the Dana-Farber Cancer Institute, in close collaboration with colleagues from the National Cancer Institute, has tested the combination of olaparib with the investigational vascular endothelial growth factor receptor inhibitor cediranib, which showed promising phase II results against olaparib alone, especially in BRCA wild-type ovarian cancer.5 These results have led to phase III studies comparing olaparib plus cediranib to standard therapies in both platinum-resistant and platinum-sensitive ovarian cancer (NCT02502266 and NCT02446600); NCT02446600 completed accrual in November 2017.
Multiple other studies are testing PARP inhibitors with other biologic agents, including immunotherapy agents (eg, programmed cell death protein 1 [PD-1], programmed cell death ligand 1 [PD-L1], and cytotoxic T lymphocyte–associated protein 4 [CTLA-4] inhibitors) and other targeted agents such as ATR inhibitors, PI3 kinase inhibitors, and heat shock protein (HSP) 90 inhibitors. This is indeed an exciting, promising strategy that seeks to augment the homologous recombination deficiency of a cancer cell without introducing significant and overlapping myelosuppression and to possibly extend PARP inhibitor use to BRCA wild-type and homologous recombination–proficient cancers.
Current Regulatory Approvals
Three PARP inhibitors are now U.S. Food and Drug Administration (FDA) approved for recurrent ovarian cancer:
(1) Olaparib is indicated for patients with recurrent germline BRCA-mutated ovarian cancer who have received three or more prior lines of chemotherapy and, as of August 17, 2017, also as post-platinum maintenance therapy for patients with platinum-sensitive recurrence who have responded to platinum-based chemotherapy, regardless of BRCA or tumor homologous recombination status. With this recent FDA approval, the formulation and dosing of olaparib have changed, from capsules (400 mg twice daily, as originally approved by the FDA in 2014; 16 capsules per day) to tablets (300 mg twice daily; 4 tablets per day).
(2) Rucaparib is indicated for patients with BRCA-mutated ovarian cancer (either deleterious tumor or germline mutation) who have received at least two prior lines of chemotherapy. The dose of rucaparib is 600 mg twice daily orally. On October 9, 2017, a supplemental New Drug Application to the FDA was submitted for rucaparib as maintenance treatment of patients with recurrent ovarian cancer in response to platinum-based chemotherapy based on the ARIEL3 results.6
(3) Niraparib is indicated as maintenance therapy for patients with platinum-sensitive recurrent ovarian cancer who are in response to platinum-based chemotherapy, regardless of BRCA or tumor homologous recombination status—an indication similar to the olaparib maintenance approval. Niraparib’s dose is 300 mg once daily orally.
As germline and somatic testing for homologous recombination–related genes such as BRCA1, BRCA2, and others become more commonplace, … PARP inhibitor use is certain to increase.— Ursula A. Matulonis, MD
Thus, oncologists now have three agents that similarly trap PARP on DNA and inhibit the enzymatic activities of PARP, the two crucial functions of PARP inhibitors,2,7 as well as have overlapping indications. Yet, these agents have different mechanisms of metabolism, schedule and dosing, as well as some important toxicity differences, so oncologists need to familiarize themselves with each drug via the FDA-approved package inserts.
Additionally, PARP inhibitors are being tested in other cancers besides ovarian cancer. In January 2016, olaparib was granted Breakthrough Therapy designation as a single agent for the treatment of BRCA or ATM gene–mutated metastatic castration-resistant prostate cancer in patients who have received a prior taxane-based chemotherapy and at least one newer hormonal agent. This designation was based on a 33% response rate observed in the TO-PARP study.8
More recently, the OlympiAD study tested olaparib in BRCA-mutated breast cancer and compared it to standard chemotherapy, and this study demonstrated a 4-month progression-free survival improvement of olaparib vs standard chemotherapy.9 On October 17, 2017, the FDA accepted and granted Priority Review for a supplemental New Drug Application for olaparib in patients with germline BRCA-mutated HER2-negative metastatic breast cancer previously treated with chemotherapy.
Patients with other BRCA-mutated cancers also have shown responses with PARP inhibitors, especially pancreatic cancer, prostate cancer, and melanoma. As germline and somatic testing for homologous recombination–related genes such as BRCA1, BRCA2, and others become more commonplace—and, thus, the number of cancers possessing underlying DNA repair defects are identified—PARP inhibitor use is certain to increase.
PARP inhibitor class–related toxicities include bone marrow suppression with neutropenia, anemia, and thrombocytopenia; gastrointestinal side effects; and fatigue. The degree of bone marrow suppression among the approved PARP inhibitors differs, likely due to each drug’s recommended starting doses, the extent of pretreatment, and drug metabolism.
Oncologists need to be mindful of the myelosuppression and follow patients’ complete blood cell counts—including white blood cells and neutrophils, platelets, and red blood cell counts—closely. For niraparib, the package insert recommends weekly blood cell counts for the first month of treatment and monthly checks thereafter; the rucaparib and olaparib package inserts recommend monthly complete blood cell counts. Clinicians may need to monitor blood cell counts more frequently depending on the patient’s baseline counts and the hematologic effects rendered by the PARP inhibitor.
An important but more rare hematologic toxicity of single-agent PARP inhibitors is a < 2% risk of acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS); randomized studies of PARP inhibitors vs placebo show comparable AML and MDS risks between the two arms, thus suggesting this risk is associated more with the treated patient population, their underlying genetics, and prior therapy than treatment with a PARP inhibitor. However, I do inform patients of the rare risk of AML or MDS regardless of PARP inhibitor choice. Other important toxicities observed with PARP inhibitors include fatigue and gastrointestinal toxicities such as nausea, vomiting, dyspepsia, anorexia, dysgeusia, decrease in appetite, and diarrhea. Olaparib data that followed gastrointestinal toxicities have suggested that these quality of life–impacting adverse events decrease over time, but patients still need to be monitored for them.
The future of PARP inhibitors is an exciting one, given their robust single-agent activity in cancers that have underlying defects in DNA repair, their manageable safety profile, and the fact that they are oral agents that patients can take at home.— Ursula A. Matulonis, MD
With both olaparib and rucaparib, a rise in creatinine is observed, likely due to their effect on renal transporter proteins such as OCT2, MATE1 (also hepatically expressed), and MATE2-K. Rucaparib use can also lead to liver function test elevation. Other toxicity differences among the PARP inhibitors include palpitations and a 10% risk of grade 3 or 4 hypertension with niraparib likely due to niraparib’s ability to bind to and thereby inhibit the dopamine transporter, the norepinephrine transporter, and the serotonin transporter.10 As a result, the niraparib package insert recommends close blood pressure and heart rate monitoring at least monthly for the first year. I have recommended that patients—especially those with an established hypertension diagnosis—check their blood pressure daily at home after starting niraparib and contact me if it rises higher than baseline.
Other unique toxicities include cholesterol rise with rucaparib, a 2% risk of pneumonitis with olaparib, and an increased risk of infections with some of these agents. For example, the olaparib package insert reports a > 20% risk of nasopharyngitis and upper respiratory infection.
The financial burden of PARP inhibitors on patients is an important and timely topic, and I do think oncologists need to communicate the benefit derived by a specific patient vs the financial costs of prescribing the PARP inhibitor. Patients will derive different levels of benefit from PARP inhibitors based on how homologous recombination–proficient or –deficient their cancer is, and also depending on this status, will remain on the drug for varying amounts of time. And because the available PARP inhibitors have very similar FDA indications for ovarian cancer treatment and comparable efficacy levels, decisions about the choice of a PARP inhibitor may be influenced by cost.
The Institute for Clinical and Economic Review recently released its final results of an economic and effectiveness report in September 2017, which tried to quantitatively investigate the cost-effectiveness of PARP inhibitors used as treatment for BRCA‑mutated ovarian cancer (olaparib, rucaparib) and as maintenance post-platinum in the recurrent setting. Given that PARP inhibitors are a new class of agent, finding comparators for cost analysis is difficult and sometimes impossible, making these types of economic analyses for PARP inhibitor use flawed.
Nonetheless, the financial costs of PARP inhibitors are a critical and real-world consideration for both patients and clinicians. Based on my own practice, several of my patients have had to pay several thousands of dollars out of pocket per month for a copay, and this is unacceptable and unfortunate.
The future of PARP inhibitors is an exciting one, given their robust single-agent activity in cancers that have underlying defects in DNA repair, their manageable safety profile, and the fact that they are oral agents that patients can take at home, away from an oncology clinic. To date, it has been challenging to combine PARP inhibitors with chemotherapy, and phase III trials of such combinations have thus far been negative; others are in progress, and we await their results.
Other approaches using combinations of PARP inhibitors and biologic agents that avoid overlapping myelosuppression and, thus, the need for dose and schedule reductions look more promising than PARP inhibitor and chemotherapy combinations. These strategies are designed to induce homologous recombination deficiency and thus increase the susceptibility of cancer cells to a PARP inhibitor regardless of their homologous recombination state or to overcome potential PARP inhibitor resistance mechanisms.
Many studies are underway combining PARP inhibitors with antiangiogenic agents, immunotherapies, and other targeted agents such as PI3 kinase, ATR, and HSP90 inhibitors. A better understanding of PARP inhibitor resistance mechanisms should lead to the development of post–PARP inhibitor strategies and their translation into clinical practice. ■
DISCLOSURE: Dr. Matulonis is the North American primary investigator for Study 19 and the NOVA study; is on the scientific advisory board of 2X Oncology and the Clearity Foundation; and has been a consultant for Eli Lilly, Clovis Oncology, Merck, Myriad, Fujifilm, and Geneos Therapeutics.
Dr. Matulonis is Medical Director and Program Leader of the Medical Gynecologic Oncology Program at Dana-Farber Cancer Institute and Professor of Medicine at Harvard Medical School, Boston.
1. Konstantinopoulos PA, Ceccaldi R, Shapiro GI, et al: Homologous recombination deficiency: Exploiting the fundamental vulnerability of ovarian cancer. Cancer Discov 5:1137-1154, 2015.
2. Lord CJ, Ashworth A: PARP inhibitors: Synthetic lethality in the clinic. Science 355:1152-1158, 2017.
3. AbbVie announces topline results from two phase 3 studies investigating veliparib in combination with chemotherapy for the treatment of patients with advanced or metastatic squamous non-small cell lung cancer and early-stage triple-negative breast cancer. AbbVie press release, April 19, 2017. Available at news.abbvie.com. Accessed September 7, 2017.
4. AstraZeneca provides top-line results from Lynparza GOLD trial in advanced gastric cancer. AstraZeneca press release, May 18, 2016. Available at www.astrazeneca.com. Accessed September 7, 2017.
5. Liu JF, Barry WT, Birrer M, et al: Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: A randomised phase 2 study. Lancet Oncol 15:1207-1214 2014.
6. Coleman RL, Oza AM, Lorusso D, et al: Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 390:1949-1961, 2017.
7. Konecny GE, Kristeleit RS: PARP inhibitors for BRCA1/2-mutated and sporadic ovarian cancer: Current practice and future directions. Br J Cancer 115:1157-1173, 2016.
8. Mateo J, Carreira S, Sandhu S, et al: DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med 373:1697-1708, 2015.
9. Robson M, Im SA, Senkus E, et al: Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med 377:523-533, 2017.
10. U.S. Food and Drug Administration: Niraparib (Zejula). Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208447lbl.pdf. Accessed November 14, 2017.