Olaparib-induced cutaneous side effects in a patient with recurrent ovarian cancer

Abstract

Over the past decade, the treatment of ovarian cancer has been revolutionised by poly(ADP-ribose polymerase (PARP)) inhibitors. Based on the results from clinical trials, olaparib, a PARP inhibitor, is indicated for use in the first-line treatment for patients with BRCA gene mutations, and as a maintenance treatment in platinum‐sensitive relapsed ovarian cancer after a complete or partial response to platinum‐based chemotherapy. Although PARP inhibitors have been shown to be well tolerated, adverse side effects can affect the quality of life of patients and lead to the discontinuation of therapy. Here, we report a case of dermatosis of the left dorsal hand as a rare adverse side effect of olaparib. Dermatological adverse side effects may become the crux of a clinical problem that requires the cooperation of professionals in many fields.

Background

The standard treatment for ovarian cancer is a combination of maximal debulking surgery and six cycles of platinum doublet chemotherapy. Although most patients respond to multimodal treatment, relapse is common. The 5 year overall survival rate in patients with advanced stage disease (corresponding to stages III and IV) is 26%–42%.¹

Poly(ADP-ribose polymerase) (PARP) inhibitors play important roles in DNA repair and genome integrity maintenance.² The activity of PARP inhibitors is based on the concept of synthetic lethality, where an underlying homologous recombination repair deficiency in tumour cells renders cells highly susceptible to PARP inhibition.³ Patients with germline mutations in either BRCA1 or BRCA2 are sensitive to PARP inhibitors because they have a specific DNA repair defect. Evidence from clinical trials has demonstrated that patients with BRCA gene mutations (BRCAm) obtain a great benefit from PARP inhibitors. However, clinical studies have also shown that PARP inhibitors are beneficial in patients with ovarian cancer who do not have BRCAm. Long-term tolerability and efficacy of olaparib have been demonstrated in patients with and without BRCAm.⁴

Olaparib has been approved as a maintenance treatment for patients with platinum-sensitive relapsed ovarian cancer after a complete or partial response to platinum‐based chemotherapy. The most common adverse events associated with olaparib included nausea, fatigue or asthenia, vomiting, abdominal pain and diarrhoea. Moreover, the incidence of adverse cutaneous side effects was <5%.⁵ As cutaneous toxicities are associated with a significant impact on quality of life (QoL) and treatment adherence, the management of dermatological adverse side effects (dAEs) is essential for anticancer therapy. Here, we describe the case of a patient with cutaneous side effects from olaparib treatment for relapsed ovarian cancer.

Case presentation

A woman in her early 70s presented with a 1 week history of a painful rash on her left hand. Her medical history included ovarian serous adenocarcinoma (Federation International Gynecology and Obstetrics (FIGO) Stage IIIc), treated with platinum doublet chemotherapy and interval debulking surgery (abdominal hysterectomy, bilateral salpingo-oophorectomy, partial omentectomy and low anterior resection) approximately 6 years prior. After surgery, she underwent six cycles of paclitaxel and carboplatin with bevacizumab chemotherapy.

However, approximately 4 years prior, a systemic CT scan showed peritoneal dissemination and liver metastases. The patient was diagnosed with platinum-sensitive recurrent ovarian cancer. Considering her history of advanced ovarian cancer, she received oral olaparib maintenance monotherapy (600 mg/day) after achieving a complete response to 12 cycles of paclitaxel and carboplatin with bevacizumab chemotherapy. The patient did not take any other medication during olaparib maintenance monotherapy.

After treatment with olaparib for 11 months, she sought care for a rash and swelling on the left dorsal hand. Hand and finger movements were restricted because of pain. The patient was in general good condition with a normal body temperature. She had no medical history or family history of autoimmune diseases and inherited skin disorders.

Physical examination revealed several tender erythematous ulcerated plaques on the dorsum of the left hand, especially around the joints of the finger (figure 1). Blood examinations revealed Grade 2 anaemia (haemoglobin: 93 g/L) and Grade 3 neutropenia (neutrophils: 800 cells/µL), and erythrocyte sedimentation rate, serum C reactive protein level, platelet counts and thyroid hormones were within normal limits. Immunological serum test revealed that antinuclear antibody, serum C3 levels, serum C4 levels were all with normal ranges. Rheumatoid factor, matrix metalloproteinase-3, anti-ds-DNA immunoglobulin G, anti-cyclic citrullinated peptide and anti-RO/SSA antibodies were negative. No other signs or symptoms of a systemic autoimmune disease were evident. The systemic CT scan showed no signs of ovarian cancer recurrence. Although skin biopsy is a helpful diagnostic method, our patient declined an invasive provocation test. After consultation with rheumatology and dermatology specialists, the patient was diagnosed with olaparib-induced dermatosis. dAEs were classified as Grade 2 in accordance with the Common Terminology Criteria for Adverse Events (CTCAE).

Figure 1.

Tender, erythematous, ulcerated plaques over the dorsum of the left hand.

Treatment

Olaparib therapy was discontinued. The patient was started on topical steroid ointment and oral antihistamines. After 2 weeks, dermatosis showed a significant improvement (figure 2). However, when olaparib was resumed, the dermatosis relapsed, with a worsening of pain and swelling in both hands. The patient refused to continue treatment because dAEs limited her self-care and domestic life. Once the treatment was discontinued, the cutaneous symptoms abated.

Figure 2.

Significant improvement, with minimal residual erosions and erythema over the left dorsal hand, after 2 weeks of treatment with a topical steroid ointment.

Outcome and follow-up

The CT scan showed peritoneal dissemination in <6 months after discontinuation of olaparib. The patient was diagnosed with platinum-sensitive recurrent ovarian cancer and received chemotherapy with paclitaxel and carboplatin with bevacizumab. The chemotherapy was effective, and during a follow-up visit, the patient mentioned that she regretted the discontinuation of olaparib when the physicians advised her to continue the treatment by using a desensitisation protocol. To date, the patient is alive without signs of re-recurrence.

Discussion

PARP engages in DNA base excision repair by inducing poly-ADP-ribosylation of itself and other target proteins. The activity of PARP inhibitors is based on the concept of synthetic lethality. The mechanisms of action affect both malignant and normal cells, including epidermal and dermal homeostatic function.

In our case, exanthematous skin eruption under olaparib therapy resulted in a diagnosis challenge because the patient declined skin biopsy. If olaparib therapy-associated exanthema is suspected, the first diagnostic step is to exclude alternative causes such as medication related rashes, or inflammatory disorders, systematic diseases, reactive erythema and vasculitis. In the present case, the laboratory evaluation revealed anaemia and neutropenia, while the erythrocyte sedimentation rate, serum C reactive protein level, platelet counts and thyroid hormones were within normal limits. The immunological serum test results were negative. Erythematous ulcerated plaques were not well-demarcated and localised on the left dorsal hand. In addition, no other extracutaneous manifestations were evident. The patient had no family history of disseminated superficial actinic porokeratosis. Based on the above results, the patient was eventually diagnosed with olaparib-induced dermatosis.

The incidence of olaparib-induced cutaneous side effects is <5%. In the SOLO2 phase-3 trial, only 2 of 295 patients (0.7%) had reported cutaneous side effects. The dose had to be reduced for one patient (0.3%) because of a rash, and the other patient (0.3%) had to discontinue treatment due to dermatosis.⁵ Although rare, allergic reactions to PARP inhibitors, consisting of urticaria, have been reported.⁶ The pathophysiology of PARP inhibitor-induced cutaneous side effects remains poorly understood. The female sex is an independent risk factor in some specific dAEs due to targeted therapies.⁷

For a differential diagnosis, bevacizumab, a vascular endothelial growth factor inhibitor-induced erythematous skin eruption should be considered. Bevacizumab has a low clearance and long elimination half-life of 20 days, supporting a convenient 2-weekly or 3-weekly dosing schedule. Although the incidence of cutaneous side effects is very rare, bullous and psoriasiform dermatosis has been reported in 1 of 128 patients as a side effect of bevacizumab.⁸ A combination of bevacizumab with olaparib did not increase the known toxic effects of olaparib. As the exanthematous skin eruption occurred after olaparib treatment for 11 months, the possibility of dAE induced by bevacizumab is very low.

In the present case, cutaneous side effects negatively affected QoL of the patient and led to the discontinuation of therapy. Even if physicians’ grade dAE as 1 or 2 as per the CTCAE, the chronicity, associated pain and pruritus results in a negative impact on QoL. Patients may be managed with topical or oral corticosteroids and antihistamines. In severe cases, a desensitisation protocol for olaparib can be used to prevent discontinuation of treatment.⁶

This case report highlights the rare occurrence of adverse cutaneous side effects of olaparib. As the number of patients undergoing olaparib treatment increases, the risk of cutaneous side effects is also expected to increase. In some cases, cutaneous adverse side effects become the crux of a clinical problem that requires the cooperation of professionals from many fields. Knowledge of possible skin complications and their treatment may significantly improve the effectiveness of oncology therapies.

Learning points.

• Cutaneous side effects are associated with a significant impact on quality of life and treatment adherence; the management of dermatological adverse side effects is essential for anticancer therapy.

• Dermatological adverse side effects may become a clinical problem that requires the cooperation of professionals in many fields.

• Discontinuation of poly(ADP-ribose polymerase) inhibitors and initiation of treatment with topical or oral corticosteroids are crucial for the management of adverse cutaneous side effects.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).