Libin Philip, PharmD

Ovarian cancer ranks fifth in cancer-related deaths among women.

 Ovarian cancer was originally thought to only began in the ovaries, but recent evidence shows that many ovarian cancers may start in the cells of the far end of the fallopian tubes.

 Because the ovaries are composed of different cell types, various tumors can develop. Epithelial tumors start from the cells that cover the outer surface of the ovary, making up most ovarian tumors. Germ cell tumors start from the ova, which are the cells that produce eggs. Stromal tumors start from the structural tissue cells that hold the ovaries together and produce estrogen and progesterone.

 Each type of tumor has different subtypes and grades based on tumor differentiation.

Risk factors for ovarian cancer include being overweight or obese, having children after age 35 or never having a full-term pregnancy, fertility treatment, and having a family history of ovarian, breast, or colorectal cancer.

 Factors that can lower the risk of ovarian cancer include full-term pregnancy before 26 years of age, breastfeeding, and birth control.

Common symptoms of ovarian cancer include bloating, pelvic or abdominal pain, trouble eating or feeling full quickly, and urinary symptoms, such as urgency or frequency.

 Treatment typically involves surgical removal of the tumor and chemotherapy, radiation, hormone therapy, or targeted therapy with poly (ADP-ribose) polymerase (PARP) inhibitors.

The National Comprehensive Cancer Network (NCCN) guidelines for ovarian cancer recommend several clinical options, including salpingo-oopherectomy, which is removal of the ovaries and fallopian tubes, plus comprehensive surgical staging.

 Comprehensive surgical staging considers whether future female fertility is desired and recommends that every effort be made during a primary procedure to achieve maximum cytoreduction (ie, removing as much visible cancer as possible).

 For poor surgical candidates or those with a low likelihood of optimal cytoreduction, neoadjuvant therapy is recommended as primary treatment, which can include chemotherapy, radiation, and other treatments.

Adjuvant therapy is used to decrease the risk of disease recurrence or to primarily treat residual disease.

 Adjuvant and neoadjuvant therapy for ovarian cancer include paclitaxel, carboplatin, liposomal doxorubicin, and docetaxel.

 Bevacizumab also can be used as a single agent, after combination with carboplatin/paclitaxel, for stage III or IV disease following initial surgical resection.

 Agents used for recurrence therapy are very similar to those that are used for adjuvant and neoadjuvant treatments.

Although there are several chemotherapy options, PARP inhibitors are a newer, targeted approach for patients with ovarian cancer who are in complete or partial response to first-line chemotherapy.

PARP inhibitors are responsible for preventing DNA restoration, killing cancer cells in the process. These agents predominately work with breast cancer (BRCA) gene mutations, as they also impair DNA repair, resulting in multiple modes of attack.

 The mechanism of action of PARP inhibitors is a novel approach to treating ovarian cancer. PARP is involved in the cell survival pathway by recruiting repair proteins to correct dysfunctional DNA. Inhibiting this process leads to cell death in the presence of a BRCA mutation. If BRCA is working correctly, then PARP inhibitors are ineffective, as the BRCA-proficient cell will repair the DNA mutation, leading to cell survival.

There are 3 available PARP inhibitors approved by the FDA to treat ovarian cancer (Table 1).

 These products can be used for fallopian tube and primary peritoneal cancers; however, their clinical settings may be different. For example, niraparib is used when olaparib and rucaparib have failed.

 Additionally, talazoparib is the first PARP inhibitor used for human epidermal growth factor receptor 2 breast cancer in patients with a BRCA mutation.

Adverse Events and Drug Interactions of PARP Inhibitors

Adverse events (AEs) are attributable to all cancer agents, and PARP inhibitors are not an exclusion. Gastrointestinal (GI) toxicities, such as nausea and vomiting, are present with all PARP inhibitors, but certain antiemetics should be avoided. Cytochrome (CYP) P450 3A4 inhibitors, such as aprepitant, interact with olaparib and rucaparib by increasing its plasma concentrations.

 However, niraparib is an exception, as it has no significant CYP interactions because it is metabolized by carboxylesterases.

 Because PARP inhibitors are classified under the moderate- to high-emetic risk category, the NCCN guidelines recommend patients be initiated on a serotonin (5-HT3) receptor antagonist 30 minutes prior to a PARP inhibitor.

 Additionally, consuming food with these products can ameliorate additional GI issues. Other notable AEs of PARP inhibitors include anemia, neutropenia, and fatigue, which can be mitigated with both pharmacologic and nonpharmacologic strategies (Table 2).

PARP inhibitors are novel therapies with indications focused on ovarian cancer; however, new agents are being studied for other cancers as well. Veliparib is a PARP inhibitor in clinical trials for the treatment of non-small cell lung cancer.

 Likewise, pamiparib is studied as a combination regimen to treat advanced solid tumors.

 As more PARP inhibitors enter the market, it is important to recognize where they fall in therapy.

AEs are certainly legitimate concerns, but they are manageable, often only requiring dose modification. These agents have limited distribution channels, being dispensed only at specialty pharmacies. However, patients may reach out to their local pharmacist for questions or concerns. Consequently, it is important to understand PARP inhibitors and their implications for treating cancer. Future trials will tell if PARP inhibitors can extend their benefit beyond treating breast and ovarian cancers.

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Articles

PARP inhibitors are novel therapies with indication focused on ovarian cancer; however, new agents are being studied for other cancers as well.

PARP Inhibitors: A Novel Approach to Treating Ovarian Cancer

Cancer treatment has made significant advances through the years. Once dominated by chemotherapy agents, targeted therapy is now a better option, with less-taxing adverse effects (AEs). Chemotherapy agents, such as alkylating agents, antimetabolites, and plant alkaloids affect dividing cells, both cancerous and noncancerous. This leads to many AEs, such as hair loss, diarrhea, and vomiting. Conversely, targeted therapy is designed to reach cancer cells only, using molecular targets such as kinases or growth factors. With this approach, there are fewer AEs, and this results in better tolerability and continuance of therapy. However, it is impossible to assert that patients will not experience any AEs while on targeted therapy. Communicating and addressing effective mitigation strategies to ameliorate these AEs can lead to improved clinical outcomes.

One unique toxicity associated with tyrosine kinase inhibitors (TKIs), which target the epidermal growth factor receptor (EGFR), is a rash. Because the EGFR is present in epithelial cells lining the skin, inhibiting it with certain TKIs, such as erlotinib and gefitinib, can produce acneiform rash.

 The same is true for mitogen-activated protein kinase inhibitors (MEKIs), such as trametinib. Importantly, clinicians should note that in patients taking MEKIs, the rash presents as papules and pustules on the front torso and the face at a higher incidence than with traditional chemotherapy.

 Prophylactic treatment modalities for rash include corticosteroids, moisturizers, and sunscreen. Other therapies include dapsone gel and oral doxycycline. When a bacterial skin infection is suspected, clinicians should initiate antibiotics.

Angiogenesis is a pathway for cancers to grow with the vascular endothelial growth factor (VEGF). Several TKIs target the VEGF pathway, including sunitinib, sorafenib, and cabozantinib.

 These therapies are used in the first line in metastatic renal cell carcinoma and have been associated with hypertension. This is primarily due to impaired nitric oxide signaling and reduced prostacyclin production when VEGF is inhibited.

 The treatment for VEGF-induced hypertension is combination therapy consisting of angiotensin-converting enzyme inhibitors and dihydropyridine calcium channel blockers.

 In more severe cases, dose reduction of therapy may be warranted. 

Stomatitis is a very painful AE characterized by ulcers around the mucosa of the mouth, making swallowing difficult. The agents that cause most cases of stomatitis are the mammalian target of rapamycin (mTOR) inhibitors. Everolimus, temsirolimus, and sirolimus are linked to the development of stomatitis in 30% of patients.

 The SWISH trial results showed that after 8 weeks of treatment, the incidence of stomatitis was reduced to 2% among those who used a steroid mouthwash.

 Clinicians should educate patients on proper hygiene, such as washing their mouth with sterile water or sodium bicarbonate. For patients who are about to start therapy with everolimus, the initiation of a dexamethasone-based mouthwash has shown promising results.4 Multikinase inhibitors and EGFR inhibitors can also cause stomatitis, although it gradually disappears over time.

Hair loss, or alopecia, has been reported in more than half of patients who have breast cancer. This AE is associated primarily with hormone therapy, especially selective estrogen receptor modulators, which accounted for 25% of cases.

Inhibiting estrogen production is associated with a decrease in hair follicles, causing hair to become brittle and break easily. One way to reduce this AE is to apply topical minoxidil, which has shown efficacy in 80% of treated patients.

Both chemotherapy and targeted agents are associated with nail toxicities. Paronychia is a type of skin infection surrounding the toenail or fingernail and is characterized by inflammation, swelling, and general discomfort. A complication of paronychia is periungual granulomas, which are vascular tumors of the capillaries.

 The development of lesions is also common and can lead to brittle nails and onycholysis. Many targeted therapies, such as EGFR, MEK, and mTOR inhibitors, are associated with these nail toxicities.

 Preventive strategies include educating patients to avoid friction, wearing gloves or socks to protect the nails, and limiting pressure on the nails. Treatments include topical corticosteroids, antibiotics, and silver nitrate. Topical timolol has also been effective in periungual granulomas.

Hypothyroidism is more common than hyperthyroidism. TKIs are associated mainly with hypothyroidism as they change the blood flow to the thyroid, which causes destructive thyroiditis. Many of the symptoms can be confused with the symptoms of the cancer

; these include, fatigue, constipation, muscle weakness, and thinning of hair. Clinicians should monitor the thyroid stimulating hormone (TSH) levels of patients who are not on thyroid replacement therapy. Treatment with replacement therapy is warranted in patients who are symptomatic and have severe hypothyroidism. For patients on levothyroxine who are starting imatinib, sorafenib, or sunitinib, TSH monitoring every 4 weeks is recommended.

Dyslipidemia is an often-overlooked AE in cancer therapy that sometimes leads to cardiovascular complications. The prevalence of dyslipidemia from using mTOR inhibitors is as high as 81% because they impair lipid clearance from the bloodstream.

 Clinicians should obtain a lipid profile before the start of an mTOR inhibitor and repeat it every 6 weeks while the patient is on treatment. Although grade 1 and 2 toxicities do not require any interventions, grade 3 toxicity requires interruption of therapy and restarting the mTOR inhibitor at 50% of the dose.5 Discontinue therapy if grade 4 toxicity occurs. Importantly, patients with elevated cholesterol should start treatment with lipid-lowering agents. However, please note that cytochrome P450 3A4—substrate statins—simvastatin and atorvastatin&mdash;are associated with drug interactions that must be evaluated prior to first use.

The disruption of glucose metabolism has been associated with several targeted therapies. Hyperglycemia is associated with phosphoinositide 3-kinases, AKT, and mTOR inhibitors, as they help to regulate insulin signaling.

 Common symptoms of hyperglycemia include polyuria, polydipsia, and fatigue. Clinicians must monitor patients for their fasting serum glucose prior to therapy initiation and ensure they achieve optimal glycemic control. Treatment should be initiated with antidiabetic agents for grade 2 hyperglycemia, and treatment should be interrupted or discontinued for grades 3 and 4.5 In the case of hypoglycemia, TKIs—particularly imatinib, dasatinib, sorafenib, and sunitinib&mdash;have been shown to decrease glucose levels. Notably, sunitinib and pazopanib have induced hypoglycemia in patients on antidiabetic agents.

 Patients on targeted therapy must maintain glycemic control and understand the risks of severe hypoglycemia. 

Many targeted therapies are associated with electrolyte imbalances (

), so it is important to monitor electrolyte levels throughout therapy. For these disorders, treatment is primarily symptomatic management without interruption of the oncology agent. Most attributable agents associated with electrolyte disorders are TKIs and mTOR inhibitors. A bimonthly chemistry profile should be initiated in the first 3 months of treatment and then repeated monthly thereafter.

Table: Electrolyte Disorders with Targeted Therapies

Every patient will experience AEs differently while on oral targeted therapy. Many of the AEs previously mentioned are unique to certain classes of medications. Informing patients of the mitigation strategies prior to therapy will help reduce the risk of complications. Additionally, health care professionals and patients should recognize, monitor, and communicate AEs so they can be resolved in a timely manner. 

, is a clinical pharmacist educator at Diplomat. He makes sure Diplomat pharmacists, nurses, and technicians have the training and resources they need to provide safe and effective patient care. Philip earned his doctor of pharmacy degree from Wayne State University. He’s pursuing his master of business administration and master of science in leadership degrees from the University of Michigan-Flint. Philip also sits on the board of directors for the Wayne County Pharmacists Association and the nonprofit Fighting AIDS with Nutrition.

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It is impossible to assert that patients will not experience any adverse events while on targeted therapy. Communicating and addressing effective mitigation strategies to ameliorate these adverse events can lead to improved clinical outcomes.