Poly (ADP-ribose) polymerase inhibitors for the treatment of ovarian cancer

Case scenario

Mrs Jones, aged 59, is a regular patient at your pharmacy. For the last few weeks she has come in almost daily to purchase various over the counter gastrointestinal products to relieve lower abdominal pain and bloating, along with nausea and dyspepsia. Today she comes in to ask you for something stronger, as she is not getting any relief from the products she has tried and her discomfort is severe. She also requests some Hiprex tablets, because she frequently feels the need to urinate. As you know Mrs Jones quite well, you can see she has lost weight in the last few weeks, but her abdomen is bloated. Mrs Jones tells you she does not have much of an appetite and feels full after a few bites of her food.

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Introduction

Ovarian cancer (OC) refers to a malignant tumour in one or both of the ovaries. It is the sixth leading cause of cancer deaths among females in Australia.¹ Mean age at diagnosis is 63 years.² Despite recent advancements in ovarian cancer management, overall prognosis has remained poor, with a five-year survival rate of only 46% in Australia.¹ Poor prognosis is mainly attributed to presentation with advanced-stage disease due to the lack of an established screening approach and lack of symptoms at early stages.³

There are many types of OC, including epithelial, germ cell and stromal tumours. Epithelial ovarian cancer (EOC) is the most common type (90% of OCs are EOCs).³ EOC is a heterogeneous disease characterised by diverse clinicopathological features and therapy response. According to the World Health Organization, there are five major classes of EOC based on histopathology and immuno-molecular profiling: high-grade serous carcinoma, endometrioid carcinoma, clear cell carcinoma, low-grade serous carcinoma, and mucinous carcinoma.⁴

Primary peritoneal carcinoma (PPC) and fallopian tube cancer (FTC) are two other types of cancer that resemble EOC and are often treated with a similar approach.⁵

High-grade serous carcinoma is the most prevalent class of EOC, accounting for approximately 70% of cases.⁴  Due to a lack of successful screening techniques, approximately 80% of patients with high-grade serous carcinomas present with advanced-stage disease; and mostly with extra-ovarian tumour spread at the time of diagnosis.⁶

Molecular profiling completely separates the high-grade serous subtype from other classes of EOC. As defined by the Cancer Genome Atlas, BReast CAncer (BRCA) 1 and 2 genes germline and somatic mutations are the most common molecular alterations in this subtype.⁷

The current treatment strategy for EOC includes cytoreductive surgery, platinum and taxane-based chemotherapy, and targeted therapies. Targeted therapies, including angiogenesis inhibitors and poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors, have emerged as promising therapeutic agents in the last decade.

Symptoms and differential diagnosis

EOC mostly presents in the advanced stage of disease.⁸ However, studies have shown that even early-stage OC can produce similar symptoms, albeit with less frequent presentation.⁹ Symptoms of EOC are often vague and non-specific, such as pelvic or abdominal pain, abdominal bloating, nausea, dyspepsia (indicative of upper abdominal disease), anorexia, early satiety (suggestive of the presence of ascites and/or metastasis to omentum or bowel), urinary urgency or frequency, and dyspnoea (due to a pleural effusion).^9,10

Although these symptoms are non-specific and may be caused by other diseases such as gastrointestinal or urologic diseases, they are usually more common, severe and present more frequently in patients with EOC compared to patients with other conditions.^9-13

Patients who have these symptoms almost daily for more than a few weeks should be referred to a gynaecologist for further evaluation. Early referral and evaluation may lead to detection at early stages and improve prognosis.^9-13

Diagnosis

The evaluation of patients with EOC symptoms starts with obtaining a detailed medical history and assessment of risk factors, followed by complete physical examination. Imaging (transvaginal and transabdominal ultrasound) and laboratory studies are then performed to determine the presence of adnexal mass or elevated tumour markers. Once malignancy is confirmed, subsequent evaluation – including pelvic, abdominal and chest imaging (computed tomography and magnetic resonance imaging) and fluid or tissue sampling – is performed to assess the presence of metastatic disease. This evaluation will assist in decision making for treatment strategy. Staging laparotomy is an important step to obtain a specimen for histologic diagnosis and staging.¹⁴

Genetic risk evaluation and genetic testing should be performed on patients with a confirmed diagnosis of ovarian cancer (e.g. for BRCA1 and BRCA2 mutations).¹⁵

BRCA 1/2 gene mutations: EOC risk and implication in therapy

BRCA1 and BRCA2 tumour suppressor genes work together to protect the genome against pathogenic or harmful variations (mutations). These genes produce proteins that play an active role in deoxyribonucleic acid (DNA) repair. A harmful variant of BRCA1 or BRCA2 can be inherited from either parent (germline mutations). Harmful variations can also occur on normal inherited genes during lifetime (somatic mutations). The general population risk of BRCA1/2 mutations is approximately 1:150 to 1:200. The prevalance is higher in certain communities with about 1:40  risk in the Ashkenazi Jewish population.¹⁶ Cells harbouring mutated BRCA1/2 genes have an impaired genetic stability due to deficiency of a crucial repair pathway called homologous recombination (HR).¹⁷ HR deficiency triggers a phenotypic behaviour of cells resulting in the accumulation of genetic damage. Accumulation of DNA damage and resultant genetic modifications alter the cellular signalling pathway leading to malignant transformation.¹⁷

BRCA1/2 mutations are the most significant genetic aberrations in EOC. 15-25% of patients with EOC have a germline BRCA1/2 mutation.¹⁷ Besides BRCA1/2 mutations, other genetic alterations leading to genetic instability in the pattern of HR deficiency have been recognised in EOC. HR deficiency has been found in about 50% of high-grade serous carcinomas.⁷

BRCA1/2-mutated cancer cells are vulnerable to loss or inhibition of DNA repair proteins such as PARP-1. Thus, inhibition of PARP-1 promotes synthetic lethality in these cells and provides a therapeutic benefit to patients with BRCA1/2 mutations. Moreover, patients with BRCA1/2 wild-type tumours who are HR-deficiency positive also benefit moderately from PARP-1 inhibitors.¹⁸

Management

The current standard of care for treatment of most EOC patients includes debulking surgery to remove as much cancer as possible, followed by adjuvant chemotherapy. However, neoadjuvant chemotherapy prior to surgery can be considered for patients unsuitable for surgery or when surgery is unlikely to achieve optimal cytoreduction. The goal of neoadjuvant treatment is to decrease tumour burden or allow time for medical comorbidities to improve so the patient is suitable for surgery.^19,20 Preferred chemotherapy regimens in both the adjuvant and neoadjuvant settings include platinum- and taxane-based combinations. In patients with stage III or IV disease, the addition of the angiogenesis inhibitor bevacizumab may also be considered. However, in the neoadjuvant setting bevacizumab should be avoided in the cycle prior to surgery as it may interfere with wound healing following surgery.¹⁹

Stage II- IV patients with complete or partial response to initial treatment can be considered for maintenance therapy with bevacizumab and/or a PARP inhibitor.¹⁹

Despite advancement in treatment strategies, the chance of relapse is high in patients with advanced-stage EOC. Response to subsequent platinum-based chemotherapy in these patients depends on various factors. The role of surgery in recurrent disease is not identified yet. The role of radiation therapy is limited to pain management and palliation. Bevacizumab and/or PARP inhibitors have shown promising results in the management of recurrent EOC.²¹

PARP inhibitor therapies

PARP inhibitors have shown improved progression-free survival (PFS) in patients with EOC who have BRCA1/2-mutated²² or HR-deficiency-positive tumours.¹⁸ Mature overall survival (OS) data is not yet available for these agents. Currently two PARP inhibitors (olaparib and niraparib) have received Australian Therapeutic Goods Administration (TGA) approval for the treatment of EOC, PPC and FTC.

Olaparib (Lynparza) is the first PARP inhibitor to receive TGA approval for platinum-sensitive advanced or recurrent high-grade serous, BRCA1/2-mutated EOC, PPC and FTC based on the SOLO1 and SOLO2 trials. The SOLO1 study demonstrated significant PFS benefits with olaparib maintenance treatment in patients with advanced disease who were in partial or complete response to first line platinum-based chemotherapy (PFS in the experimental arm was approximately three years longer than the placebo group, hazard ratio 0.30).²² In the SOLO2 trial, olaparib maintenance treatment demonstrated significant PFS benefits (13.6 months longer in the experimental arm, hazard ratio 0.30)  and OS benefits (12.9 months longer in the experimental arm, hazard ratio 0.74) in patients with recurrent disease who were in partial or complete response following  platinum-based regimens.²³ More recently, the combination of olaparib and bevacizumab was approved for the maintenance treatment of platinum-sensitive advanced high-grade serous HR deficient EOC, PPC and FTC. This indication is based on the outcomes of the PAOLA-1 study comparing bevacizumab alone with bevacizumab plus olaparib in the aforementioned patient population. Overall, PFS in the experimental arm was 5.5 months longer compared to the bevacizumab alone group (hazard ratio 0.59).²⁴

Niraparib (Zejula) is TGA approved for maintenance treatment of platinum-sensitive advanced or  recurrent high-grade serous EOC, PPC and FTC after completion of platinum-based chemotherapy, based on the NOVA and PRIMA trials. The NOVA trial showed a PFS improvement with niraparib maintenance treatment in patients with recurrent disease who were in partial or complete response following platinum-based chemotherapy. PFS advantage of the experimental arm was 15.5 months (hazard ratio 0.27) in the BRCA-mutated, 5.4 months in the BRCA wild-type, and 9.1 months (hazard ratio 0.38) in the HR deficient cohort compared to the placebo group.²⁵ In 2019, the US Food and Drug Administration (FDA) expanded this indication to include late-line treatment of the population mentioned above who are specifically HR-deficiency positive irrespective of sensitivity to platinum chemotherapy, based on the QUADRA trial.²⁶ The PRIMA study demonstrated PFS benefit with niraparib maintenance treatment in patients with advanced disease who were in partial or complete response to first line platinum-based chemotherapy, independent of HR-deficiency status.  PFS benefit obtained by the experimental treatment was 11 months in HR deficient population (hazard ratio 0.43), compared with 5.6 months (hazard ratio 0.62) in the overall population.¹⁸

Olaparib and niraparib in clinical practice

The earlier olaparib studies used a capsule formulation, which has now been replaced by a tablet formulation that has greater bioavailability, reducing the pill burden and improving adherence. The capsules and tablets are not interchangeable due to differences in pharmacokinetics, pharmacodynamics, dosing schedules and adverse effects.^27,28

The recommended starting dose of olaparib tablets is 300 mg orally twice a day continuously until disease progression or unacceptable toxicity.^22,23 Patients on maintenance treatment for advanced ovarian cancer who show a complete response at two years may stop treatment.

Niraparib is available in a capsule formulation. The recommended starting dose in recurrent disease is 300 mg orally once a day continuously until disease progression or unacceptable toxicity (25). A lower starting dose of 200 mg once a day is recommended for patients who weigh less than 77 kg or have a baseline platelet count less than 150 x 10⁹/L.²⁹ For first-line maintenance treatment of advanced disease, the recommended starting dose is 200 mg once a day. For patients who weigh ≥ 77 kg and have a baseline platelet count ≥ 150 x 10⁹/L, a starting dose of 300 mg once a day is recommended.³⁰

Patients taking these medicines require regular blood tests to monitor for treatment-related toxicity. Recommended tests for olaparib include full blood count (FBC), electrolytes, urea and creatinine (EUC) and liver function tests (LFTs) at baseline, monthly during the first year of treatment then as clinically indicated.^31,32 Recommended tests for niraparib include weekly FBC  for the first month, then monthly for the next 10 months, then as clinically indicated; EUC and LFTs at baseline, then monthly during the first year of treatment then as clinically indicated.^31,30

Dose modifications are recommended for olaparib in moderate renal impairment.^31,32 The use of olaparib or niraparib in severe renal or hepatic impairment is not recommended.^31,32,30

Adverse events

Both olaparib and niraparib are associated with haematological toxicity, including neutropenia, thrombocytopenia and anaemia, which can lead to life-threatening infections or bleeding. Blood test results must be reviewed regularly by the medical oncologist to determine whether a treatment delay or dose reduction is required, particularly for toxicities ≥ grade 3. Patients should be advised to monitor for signs of toxicity and to present to their nearest emergency department if they develop a temperature ≥38°C, chills, shivers, sweating or shakes, overt bleeding or bruising, shortness of breath or chest pain.^22,25,31

Nausea and vomiting are common during the first few weeks and months of treatment with both olaparib and niraparib, however symptoms usually resolve and dose reductions are not usually required. Taking doses with food, or taking niraparib at bedtime, may help to reduce symptoms. Pharmacists should advise on supportive care measures to manage nausea and vomiting, for example  eating smaller meals more frequently throughout the day, avoiding foods with a strong smell, and trying ginger or peppermint food/drinks. Also should check that patients have a supply of appropriate antiemetics (e.g. metoclopramide) and are aware of how to take them.³¹

Olaparib can cause diarrhoea so patients should be educated on how to take antidiarrhoeals (e.g. loperamide) and to ensure adequate fluid intake to maintain hydration. Non-pharmacological measures such as avoiding fatty, spicy or high-fibre foods, dairy products, caffeine and alcohol may be helpful. Patients should monitor and report their diarrhoea symptoms as a treatment delay and dose reduction may be required depending on the severity of diarrhoea.³¹

Niraparib can cause both constipation and diarrhoea but constipation is more common. Patients should be educated on the management of constipation or diarrhoea as clinically appropriate.²⁵

Hypertension, including hypertensive crisis, has been reported with niraparib. Pre-existing hypertension should be adequately controlled prior to commencing treatment. Blood pressure and heart rate should be monitored regularly at least weekly for the first two months, then monthly during the first year of treatment and then as clinically indicated.³⁰

Fatigue is a common adverse event associated with both olaparib and niraparib. Strategies to manage fatigue include exercise, massage therapy, and cognitive behavioural therapy, as well as treating any underlying causes (e.g. anaemia).²⁸

Pneumonitis is a rare but serious adverse event which may occur during or after treatment with olaparib. Patients should be counseled to monitor for respiratory signs and symptoms, such as dyspnoea, cough or fever. Patients should advise their treating team immediately if symptoms occur as olaparib may need to be discontinued.³²

There is a small risk of developing myelodysplastic syndrome and acute myeloid leukaemia as a result of olaparib or niraparib treatment. Use should be avoided in patients with a history of bone marrow dysplasia. Full blood examinations, including blood film, is recommended whilst on treatment.^30,32

Drug interactions

Concomitant use of strong or moderate CYP3A inhibitors with olaparib is not recommended as they may increase the toxicity of olaparib. If concomitant use of a strong CYP3A inhibitor (e.g. azole antifungals, antiviral agents) is necessary, the olaparib dose should be reduced to 100 mg twice a day. If concomitant use of a moderate CYP3A inhibitor is necessary, the olaparib dose should be reduced to 150 mg twice a day. Grapefruit and Seville oranges should also be avoided whilst on olaparib treatment.³²

Concomitant use of a strong or moderate CYP3A inducers (e.g. phenytoin, carbamazepine, rifampicin) is not recommended as they may reduce the efficacy of olaparib.³²

Olaparib may reduce the efficacy of CYP3A and P-gp substrates so these medicines should be used with caution if taken concomitantly.³²

There is an increased risk of myelosuppression and/or bleeding if olaparib or niraparib are used concomitantly with other medicines that have an additive effect (e.g. other anticancer agents, anticoagulants, antiplatelets).^32,30

The product information for niraparib recommends caution if using in combination with CYP3A4, CYP1A2, BCRP, MATE1/2, OCT1 substrates, however the clinical relevance is unknown.³⁰

Patients should be advised to inform their doctor or pharmacist about any medications they are taking before starting treatment, including vitamins or herbal supplements and to check with their doctor or pharmacist before stopping or starting any other medications during treatment.³⁰

Knowledge to practice

Pharmacists play an important role in the management of patients with ovarian cancer. As the presentation usually involves non-specific gastrointestinal or urinary symptoms, it is important to keep this in mind and recommend early referral to a doctor for investigation if the symptoms are ongoing.

Verification of anticancer prescriptions by pharmacists is vital to ensure optimal and safe medication use. It is recommended that pharmacists familiarise themselves with common anticancer medicines and treatment protocols for ovarian cancer, available at www.eviQ.org.au. A thorough medication history should be taken to check for drug interactions. Pharmacists should review patient comorbidities, adverse events and laboratory results if available to identify whether dose modifications or supportive therapies may be required.

Pharmacists are well placed to provide effective patient education. Protocol specific patient information is available for each eviQ treatment protocol, including olaparib and niraparib. They should be used in conjunction with verbal counselling to cover the treatment schedule, side effects, required monitoring (such as blood test and temperature), and lifestyle advice (such as the importance of a healthy diet, exercise and smoking cessation). eviQ general patient information sheets are also available on relevant topics, such as management of infection, nausea and vomiting, fatigue, diarrhoea, and constipation. Regular follow up and assessment of patients will ensure that any issues with treatment or adherence are identified and addressed promptly.

Useful resources

eviQ cancer treatments online  (www.eviQ.org.au)

eviQ is a free resource of evidence-based, consensus-driven cancer treatment protocols and information for use at the point of care. eviQ is developed for the Australian context and supports health professionals in the delivery of cancer treatments. Useful resources include:

• eviQ treatment protocols and patient information
• eviQ Pharmacist fact sheets
• eviQ Clinical resources
• eviQ Patient information sheets

eviQ Education www.education.eviQ.org.au

eviQ Education provides free online learning resources for health professionals. All resources aim to standardise and promote evidence based best practice when caring for patients with a cancer diagnosis.

Cancer Council Australia (www.cancer.org.au)

Ovarian Cancer Australia (www.ovariancancer.net.au)

A list of cancer-specific support groups are also available at:

• https://www.canceraustralia.gov.au/affected-cancer/cancer-support-organisations

Case scenario continued

You immediately refer Mrs Jones to her GP for assessment. 6 months later Mrs Jones calls to Dr Parvin Ataie-Kachoie (BPharm, PhD) and Jenny Tran (BPharm)

thank you as your referral led her to being promptly diagnosed with advanced (stage III) high-grade serous ovarian cancer. Genetic testing identified a BRCA1/2 mutation. She underwent a total abdominal hysterectomy with bilateral salpingo-oophorectomy, then completed 6 cycles of adjuvant carboplatin and paclitaxel chemotherapy. A positron emission tomography (PET) scan post chemotherapy showed she was in partial remission. Mrs Jones will now begin olaparib maintenance therapy.

Key points

• Poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors are effective in the treatment of advanced or recurrent high-grade serous epithelial ovarian cancer.
• Currently available PARP inhibitors in Australia include olaparib and niraparib, which are taken orally daily continuously until disease progression or unacceptable toxicity.
• Treatment delays or dose reductions may be required if toxicities occur as a result of PARP inhibitor therapy.
• Pharmacists have an important role in ensuring the safe use of anticancer therapies, including prescription verification and drug interaction checks. Pharmacists are ideally placed to educate patients on dosing, monitoring, and adverse effects.

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References

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DR PARVIN ATAIE-KACHOIE BPharm, PhD is a pharmacist and content author for Cancer Institute NSW’s eviQ website, which provides cancer treatment protocols and information for use at the point of care.

JENNY TRAN BPharm is a pharmacist and content author for Cancer Institute NSW’s eviQ website.