Managing ovarian cancer patients on PARPi

PARP inhibitor side effects in ovarian cancer

In the video below, Professor Isabelle Ray-Coquard, Professor of Medical Oncology at the Clinical Science Institute in Lyon, France, outlines the main side effects of poly(ADP-ribose) polymerase (PARP) inhibitors, the differences between them, and how they impact on selection of treatment for women with ovarian cancer.

Professor Isabelle Ray-Coquard discusses the opportunity that healthcare professionals have to adapt PARP inhibitor treatment to the patient profile. She also highlights the importance of healthcare professionals and patients understanding the differences in the safety profile between the PARP inhibitors niraparib, olaparib and rucaparib so that treatment can be adapted as needed for patients.

While the PARP inhibitors niraparib, olaparib and rucaparib have been demonstrated as effective treatment for women with newly diagnosed advanced ovarian cancer, long-term dosing and differences in toxicity profiles highlight the importance of regular monitoring and consideration of treatment modification. By having a good understanding of adverse events and their management, improvements can be achieved in patient safety and treatment efficacy, and appropriate dose intensity can be maintained¹.

Many adverse events (AEs) associated with PARP inhibitors are class effects¹ such as haematological toxicities, which are a common side effect². PARP inhibitor adverse events can be associated with on-target and off-target effects¹.

It is also important to understand differences in the incidence of class effect AEs, drug-to-drug differences and non-class effect adverse events, because ovarian cancer patients being treated with PARP inhibitors will experience adverse events while on treatment¹.

While no clinical trial has yet investigated the PARP inhibitors niraparib, olaparib and rucaparib in a direct head-to-head comparison, a network meta-analysis was conducted, aiming to compare adverse events of these PARP inhibitors in ovarian cancer patients by analysing direct and indirect evidence as a means to compare them as maintenance therapy for platinum-sensitive ovarian cancer. The data was sourced from six randomised controlled trials involving a total of 2,270 women with ovarian cancer. No significant differences in overall survival and progression-free survival were observed. However, all three PARP inhibitors niraparib, olaparib and rucaparib were associated with a significantly higher risk for anaemia, fatigue, nausea, neutropenia, decreased appetite, dyspnoea, dizziness, and vomiting compared to placebo³.

The analysis found a higher risk of some adverse events for niraparib compared to olaparib and rucaparib: namely constipation (compared to olaparib), headaches (compared to rucaparib), and neutropenia and thrombocytopenia (compared to both olaparib and rucaparib)³.

In the same network meta-analysis, differences in the risk of AEs between the three PARP inhibitors were calculated using risk difference (RD). In the following AEs, there were no significant differences between the three PARP inhibitors in any grade: anaemia, fatigue, nausea, vomiting, arthralgia, diarrhoea, decreased appetite, cough, dizziness, back pain, dyspnoea, dysgeusia or dyspepsia. In addition, the results indicated no increased RD for the following AEs compared to placebo: arthralgia, diarrhoea, abdominal pain, and back pain³.

In a separate meta-analysis examining differences in adverse events between niraparib, olaparib and rucaparib, the following results were observed⁴:

• haematologic adverse events were significantly related to niraparib
• diarrhoea was significantly related to olaparib
• abdominal pain was significantly related to rucaparib

Recently, results from the phase III SOLO3, ARIEL4 and QUADRA clinical trials have led to voluntary manufacturer withdrawal of olaparib, rucaparib and niraparib for advanced ovarian cancer (AOC)^5-7.

In the phase III SOLO3 clinical trial, a subgroup analysis revealed that women with germ-line BRCA-mutated AOC who had prior treatment with 3 or more lines of chemotherapy showed a 33% increase in risk of death when compared with a chemotherapy-control group⁸.

Similarly, in the ARIEL4 clinical trial, women treated with rucaparib who had previously received 2 or more lines of chemotherapy had a 31.3% increase in the risk of death, compared with chemotherapy- controls⁹.
In light of the withdrawal of olaparib and rucaparib, niraparib was also voluntarily withdrawn because of a lack of comparative overall survival data, making it difficult to adequately assess its overall safety and efficacy in women with AOC treated with more than 3 lines of chemotherapy⁷.

These changes to the prescribing information only apply to patients with AOC who have received multiple lines of chemotherapy, and have no impact on indications for first-line and maintenance therapy.

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PARP inhibitor treatment monitoring in ovarian cancer

In the video below, Professor Isabelle Ray-Coquard provides practical insights for healthcare professionals when monitoring PARP inhibitor treatment in women with ovarian cancer.

In this video, Professor Isabelle Ray-Coquard discusses monitoring ovarian cancer patients on PARP inhibitors. Firstly, Professor Isabelle Ray-Coquard outlines the consideration of timing of PARP inhibitor treatment in relation to the end of chemotherapy. Secondly, she discusses the tendency of issues arising at the beginning of PARP inhibitor administration, which is the opposite experience with chemotherapy (issues tend to arise towards the end of chemotherapy treatment). Professor Ray-Coquard also provides an overview of additional monitoring for patients taking PARP inhibitors, such as blood analyses.

In light of the adverse events experienced in phase III trials for PARP inhibitors, it is important that patients are routinely monitored for toxicity and other adverse experiences, especially considering those patients who will be receiving PARP inhibitor treatment for the long term⁴.

According to the label recommendations, a complete blood count should be conducted at least monthly to monitor haematological toxicity^10-15 These routine visits also provide an opportunity for healthcare professionals to consider dose reductions where toxicity may be an issue.

To learn more about dose modifications, navigate to section 3, PARP inhibitor treatment modification.

When monitoring ovarian cancer patients being treated with PARP inhibitors in first-line maintenance, it is recommended that healthcare professionals conduct regular assessments to monitor efficacy and toxicity. However, data do not exist to suggest a survival benefit in more intensive versus less intensive follow-up. This monitoring should also include assessment of any symptoms suggesting disease relapse. Review the relevant national guidelines for follow-up procedures, and conduct CA125 investigations and imaging as stipulated¹⁶.

Table 1 outlines key factors to monitor in ovarian patients being treated with PARP inhibitors.

Table 1. Key factors to monitor in ovarian cancer patients being treated with PARP inhibitors (Adapted^10-15).

Switch maintenance strategies have been evaluated in phase III ovarian cancer trials for niraparib, olaparib and rucaparib, demonstrating improvement to progression-free survival without negative impacts on quality of life. However, only limited overall survival data is available¹.

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PARPi treatment modifications in ovarian cancer

In the video below, Professor Isabelle Ray-Coquard outlines the goal of PARP inhibitor maintenance therapy, and highlights when dose modifications may be required.

Women with advanced ovarian cancer receiving PARP inhibitor therapy will experience adverse events (AEs). By closely monitoring patients, healthcare professionals can make treatment modifications to help ensure patients continue PARP inhibitor therapy. This may include counselling to emphasise the importance of therapy in order to prevent early discontinuation, which is especially important in the maintenance setting¹.

Maintaining a similar PARP inhibitor dose intensity to that which is approved is important, and during the initial months of treatment, brief treatment pauses may be appropriate¹

According to the National Comprehensive Cancer Network (NCCN), guidelines and expert opinion, the following PARP inhibitor dose modifications are recommended to manage general non-hematologic AEs.

Grade 1 AEs¹:

• Continue treatment
• Despite acceptable symptom management, consider dose interruptions or reductions if considered clinically intolerable

Grade 2 AEs¹:

• Continue treatment
• Consider dose interruptions or reductions if no improvement with symptom management, or considered clinically intolerable

Grade ≥3 AEs where prophylaxis is not feasible or AE persists despite treatment¹:

• Withhold up to 28 days or until AE resolution, then consider dose reduction

Grade ≥3 AEs lasting >28 days on the lowest dose-level¹:

• Permanently discontinue if AE persists despite adequate management

Consider dose reduction or treatment interruption for ovarian cancer patients who experience adverse reactions while on treatment with a PARP inhibitor. In some cases, discontinuation should be considered^10-15

For detailed EMA and FDA recommendations on dose adjustments for niraparib, olaparib and rucaparib in ovarian cancer treatment, review the tables below.

Table 2. Recommended PARP inhibitor dose adjustments for ovarian cancer patients treated with niraparib who experience adverse reactions (Adapted^10,11)

For niraparib there are specific dosing implications for haematological and non-haematological issues that are experienced. For more information refer to the label^10,11.

Table 3. Recommended PARP inhibitor dose adjustments for ovarian cancer patients treated with olaparib who experience adverse reactions (Adapted^12,13)

Table 4. Recommended PARP inhibitor dose adjustments for ovarian cancer patients treated with rucaparib who experience adverse reactions (Adapted^14,15).

For full details about recommended PARP inhibitor dose modifications for patients with ovarian cancer, refer to the relevant Summary of Product Characteristics (SmPC) and Product Information for use in your geographical region.

Management of specific adverse events

Fatigue

Fatigue is a common class effect AE related to PARP inhibitor therapy in women with ovarian cancer. In patients treated with maintenance niraparib in platinum-sensitive recurrence, their perceived lack of energy was more pronounced at treatment initiation, improving over time¹.

While physical activity is recommended for fatigue management, the level of activity prescribed should be carefully considered, particularly if the patient is also experiencing anaemia or thrombocytopenia related to PARP inhibitor treatment. Psychosocial techniques and massage therapy are also recommended for management of fatigue, and it may be worth considering treatment optimisation for nutritional imbalance or deficit, and for sleep dysfunction¹

Haematologic toxicity

Haematologic AEs are common class effects related to PARP inhibitor treatment and are associated with its mechanism of action. These AEs tend to occur more frequently in the first months of treatment and reduce over time, and dose interruptions or reductions may be required. Late-onset haematologic AEs may occur however, so it is important to monitor for haematologic toxicity over time¹

Management of specific haematologic AEs:

Anaemia

• If haemoglobin (Hb) levels fall below 8 g/dL, dose interruptions may be required, with weekly monitoring until levels reach or exceed 9 g/dL. After recovery, PARP inhibitor treatment may be resumed at the same level as first occurrence or a lower dose
• For grade 1–2 symptomatic anaemia, management can include short dose interruptions at the same dose level
• Transfusion may be appropriate in patients with Hb levels below 7g/dL, or if their levels are higher and there are symptoms or significant comorbidities such as cerebral vascular, cardiac or chronic pulmonary disease
• Other causes should be ruled out including hypothyroidism and vitamin B12, folate or iron deficiencies¹

Thrombocytopenia

• More commonly associated with niraparib
• If platelet counts are under 100x10⁹ cells/L, withhold PARP inhibitor treatment and monitor weekly until the counts return to at least 100x10⁹ cells/L. After recovery PARP inhibitor treatment can resume at the same level or a lower dose. Dose reduction should be considered however, if platelets remain under 75x10⁹ cells/L or if there is a second occurrence.
• Prophylactic platelet transfusion is recommended if platelet counts are under 10x10⁹ cells/L, or if counts are higher and invasive procedures are required or there is active bleeding. Transfusion at a higher threshold can be considered, given that there may be bleeding from necrotic tumour sites
• PARP inhibitor interruption +/- transfusion at a higher platelet count may be appropriate for patients receiving antiplatelet drugs or anticoagulants¹

Neutropenia

• If neutrophil levels are below 1000/μL, PARP inhibitor treatment should be discontinued, with weekly monitoring. Treatment may resume when neutrophils return to over 1500/μL, and a lower dose level can be considered. Resumption of treatment can be considered once neutrophils resolve to grade 2 (≥1000/µL)
• Short interruptions of PARP inhibitor treatment without dose reduction can be considered in particular cases, for asymptomatic grade 3 neutropenia¹

Gastrointestinal disorders

Nausea and vomiting

• Vomiting and nausea are commonly associated with PARP inhibitor treatment
• Nausea tends to occur earlier on in treatment, becoming less frequent and approaching baseline with time
• Consider administering metoclopramide, prochlorperazine, or promethazine 30 minutes before PARP inhibitor treatment, especially at its commencement
• Food taken 30–60 minutes before a PARP inhibitor may prevent vomiting
• Benzodiazepines may be appropriate for patients who experience anticipatory nausea and vomiting
• Steroids, dronabinol, haloperidol, olanzapine, domperidone, or scopolamine transdermal patch may also help manage nausea and vomiting. However, long-term steroid use for this purpose should be avoided
• If nausea and/or vomiting are severe (grade 3 or higher), withhold PARP inhibitor (PARPi) treatment until symptoms recover, and then restart the PARPi at a lower dose
• Due to drug interactions, avoid a neurokinine-1 receptor antagonist such as aprepitant, in patients being treated with Olaparib¹

Dyspepsia

• Small meals should be considered, and potential dietary triggers assessed
• In uncontrolled dyspepsia proton pump inhibitor therapy may be appropriate, and if ineffective, tricyclic antidepressants or prokinetics can be considered
• Upper endoscopy or non-invasive Helicobacter pylori test can rule out other causes
• The effect of omeprazole may be enhanced with rucaparib treatment¹

Dysgeusia

• Good oral hygiene can assist with management¹

Diarrhoea

• Weight loss monitoring, evaluation of potential endocrine dysfunction such as thyroid, and patient and family education may be appropriate¹

Hepatic and renal function abnormalities

• During initial cycles of rucaparib treatment, transient transaminase elevation is common
• Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) have been associated with platinum-sensitive patients treated with maintenance rucaparib, however these AEs tend to be self-limiting, they return to normal limits within 3–4 treatment cycles, and are not associated with other signs of liver toxicity. If elevation of ALT/AST reaches grade 4, rucaparib treatment should be held until values return to grade 2 or under. Treatment may then resume at a reduced dose and with weekly monitoring for three or more weeks. In elevation of ALT/AST to grade 3, individualised treatment is recommended with careful monitoring if bilirubin is normal and alkaline phosphatase is below 3 of institutional normal limit. Within two weeks if levels have not declined, treatment interruption should be considered until the AE resolves to grade 2 or below, at which case treatment can resume at the same dose or lower
• If creatine elevation is significant, a renal scan may be considered and other causes should be ruled out. Dose modifications or treatment interruptions can be avoided if the glomerular filtration rate is maintained¹

Respiratory disorders

Dyspnoea/cough

• Rigorous assessment of symptoms should be conducted
• Other potential reversible co-morbidities should be treated
• Withhold treatment in the presence of new or worsening pulmonary symptoms, and conduct a diagnostic workup including a high-resolution computed tomography (CT) scan to rule out pneumonitis
• PARPi treatment may recommence if symptoms resolve and no abnormalities are found¹

Pneumonitis

• <1% of patients treated with olaparib have experienced this AE
• Treatment should be held in patients who exhibit symptoms and radiographic findings of pneumonitis. In these cases, investigations including bronchoscopy and pulmonary function tests should be considered, along with initiation of corticosteroid treatment and antibiotics as required¹

Nasopharyngitis

• For management, decongestants can be used to manage this AE, and if patients are very symptomatic, fluticasone nasal spray may also be appropriate¹

Nervous system and psychiatric

Insomnia

• Cognitive behavioural therapy, pharmacologic and/or sleep hygiene education should be considered¹

Headache

• Characterisation according to frequency and intensity should be considered, and pharmacological treatment may be appropriate¹

Neurologic

• Dizziness was experienced by approximately 15% of patients across maintenance PARPi treatments
• Consider ruling out other causes such as endocrine, central nervous system involvement or other laboratory abnormalities¹

Dermatologic Toxicity

• Instruct patients to use sun protection
• Consider referral to a dermatologist if required¹

Cardiovascular Toxicity

• Reported as AEs mainly in conjunction with niraparib treatment
• Includes hypertension, tachycardia, palpitation, and hypertensive crisis
• In patients being treated with niraparib, regularly monitor blood pressure – especially in those with prior history of cardiovascular disease. Consider non-pharmacologic and pharmacologic therapy if hypertension is diagnosed¹

Rare adverse events

Myelodysplastic syndrome/acute myeloid leukemia

• Associated with PARPi treatment
• Present in approximately 1% of patients
• Added risk factors: prior platinum therapy and other DNA-damaging agents; presence of germline BRCA mutation
• Refer patients to a haematologist to consider bone marrow aspiration if unexplained or prolonged pancytopenia is present
• Permanently discontinue PARPi treatment if myelodysplastic syndrome/acute myeloid leukemia is diagnosed¹

The future of ovarian cancer treatment

With the improved understanding of the mechanisms of ovarian cancer and its biological features, treatment has moved away from the outdated classification of platinum-sensitive versus platinum-resistant, and into an era in which there are more targeted options for ovarian cancer treatment, such as PARP inhibitors. HRD status and the presence of BRCA alterations may serve as predictive biomarkers for the response to chemotherapy and PARP inhibitor treatment¹⁷.

As advances in molecular profiling and treatment targeting continue, there appears to be a bright future ahead for further individualised treatment for women with ovarian cancer¹⁸.

Quiz

References

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