Niraparib as maintenance therapy in a patient with ovarian cancer and brain metastases

Abstract

Ovarian cancer is the second the most common gynaecological malignancy in developed countries. 70% of patients relapse in the first 3 years following debulking surgery and first-line chemotherapy. Niraparib is a poly adenosine diphosphate ribose polymerase inhibitor which uses the concept of synthetic lethality in the presence of a mutation in the breast cancer susceptibility gene (BRCA), and is now recommended as maintenance treatment in patients with platinum-sensitive relapse of ovarian cancer. It has been shown to increase progression-free survival. We present a case of a 68-year-old woman with brain metastases from high-grade serous ovarian cancer who has remained free of disease progression for longer than 17 months with niraparib use as maintenance treatment after second-line chemotherapy.

Background

Ovarian cancer is the second most common gynaecological malignancy in developed countries and is the leading cause of death from gynaecological cancers worldwide. The UK’s 5-year survival for ovarian cancer has been approximately 50% in recent years, with 7300 new diagnoses in the UK in 2015.^{1 2}

Ovarian cancer is typically asymptomatic in its early stages, and its later stages may produce relatively non-specific symptoms such as abdominal bloating, early satiety, pelvic or abdominal pain and urinary frequency or urgency; diagnosis is therefore made at an advanced stage in the majority of patients. Brain metastases are relatively uncommon in ovarian cancer, with one study quoting a figure of 3.3%; metastases to within the peritoneal cavity and pleura are markedly more common.^3–5

Ninety per cent of ovarian cancers are of epithelial origin, with serous carcinoma being the the most common histological subtype. High-grade serous epithelial ovarian carcinoma (HGSOC) accounts for up to 80% of advanced ovarian cancer.⁴ High-grade serous epithelial ovarian carcinoma, fallopian tubal and peritoneal carcinoma are classified as a single clinical entity due to their shared clinical behaviour and treatment.

Initial treatment of patients with advanced ovarian cancer is typically with debulking surgery—this may take the form of laparotomy, total abdominal hysterectomy, bilateral salpingo-ophorectomy, omentectomy, resection of other tumour deposits, peritoneal biopsies and lymphadenectomy as appropriate. Chemotherapy follows, with a platinum-based compound (carboplatin or cisplatin) with or without the addition of paclitaxel as a first line.⁶ Following initial treatment, around 70% of patients experience a relapse in the first 3 years; second-line treatment of these patients is usually with further chemotherapy. Platinum is the most important agent in the chemotherapeutic management of ovarian cancer, with a significant deterioration in survival when patients become platinum-resistant.⁷ Poly adenosine diphosphate ribose polymerase (PARP) inhibitors such as niraparib can maintain the patient in remission following completion of platinum-based chemotherapy.^{4 6} Niraparib is recommended for use under the Cancer Drugs Fund for patients with recurrent disease who are platinum-sensitive and respond to second-line chemotherapy.⁸

We report a case of niraparib use in a 68-year-old woman who was diagnosed with HGSOC with BRCA1 gene mutation. She experienced recurrence of ovarian cancer, with cerebral metastases. The patient was commenced on niraparib following her second-line chemotherapy and remained in remission with good performance status. To our knowledge, at present, there are no published cases on the successful use of niraparib as maintenance therapy in a patient with cerebral parenchymal metastases from ovarian cancer.

Case presentation

A 68-year-old woman presented with extensive ascites in 2014. Her cancer antigen 125 was elevated at 4019 kU/L. CT scan showed diffuse peritoneal and omental disease and small volume retroperitoneal lymph nodes, with biopsy showing poorly differentiated serous cystadenocarcinoma. Genetic testing revealed a pathogenic germline mutation of BRCA1.

The patient underwent five cycles of carboplatin chemotherapy with interval debulking surgery in January 2015, with good treatment response. Paclitaxel was not used due to an adverse drug reaction.

However, she was found to have cerebral metastases in July 2016 in the absence of other disease recurrence. The patient received 30 Gy in 10 fractions of whole-brain palliative radiotherapy. She responded well to this treatment.

In May 2017, surveillance CT scanning showed disease progression with multiple brain metastases in the absence of extracranial disease (figure 1). The patient’s brain metastases were considered unsuitable for stereotactic radiotherapy due to their size and number. She then underwent second-line chemotherapy composed of six cycles of carboplatin and gemcitabine. CT in September 2017 showed a good partial response (figure 2), attributed to her chemotherapy, and clinically she remained stable between May and September. We accept as a limitation of our case that the patient’s brain lesions were not biopsied; we felt this invasive surgery was not clinically justifiable.

Figure 1.

CT head: May 2017 (coronal view) showing the largest metastatic brain lesion in the left centrum semiovale prior to commencing on second-line chemotherapy.

Figure 2.

CT head: September 2017 (coronal view) showing the residual metastatic brain lesion in the left centrum semiovale which has markedly reduced in size after second-line chemotherapy, before niraparib use.

Following the carboplatin-gemcitabine chemotherapy, she was eligible for maintenance treatment with niraparib which was accessed under an Early Access to Medicines programme. She commenced on niraparib 300 mg daily in November 2017 and was monitored with weekly full blood count testing as per niraparib’s summary of product characteristics.

She developed severe thrombocytopaenia after 23 days of niraparib treatment, with a platelet count of 19×10⁹/L. As a result, niraparib was withheld for 3 weeks to allow haematological recovery. It was restarted at a reduced dose of 100 mg daily and then retitrated upwards. On retitration to 200 mg daily, she had two further episodes of significant thrombocytopaenia. Further dosage adjustment to 200 and 100 mg on alternate days was completed in September which has for the last 7 months maintained a platelet count of >100×10⁹/L, having started niraparib 17 months ago.

Outcome and follow-up

This 68-year-old woman has otherwise tolerated niraparib very well. Her current performance status is 0, enjoying a full and normal good quality life. Her cerebral metastatic disease has remained stable, as shown in a recent CT head (figure 3).

Figure 3.

CT head: February 2019 (coronal view) showing stable disease appearance of the brain metastasis (which is now calcified) in the left centrum semiovale with no new metastases.

Discussion

Synthetic lethality: BRCA mutation and PARP inhibition

Synthetic lethality describes a situation in which a combination of deficiencies in gene expression results in cell death; in this case, BRCA-mutated cancer cells are targeted with inhibition of PARP, as both BRCA and PARP are involved in the DNA damage response and the loss of both DNA repair mechanisms typically results in cell death. PARP inhibitors are the first treatment developed to use the concept of synthetic lethality.⁹

BRCA is a tumour suppressor gene whose expressed protein is involved in the repair of DNA double-strand breaks by a process of homologous recombination, which involves the exchange of nucleotide sequences between molecules of DNA to effectively repair double-stranded DNA breaks. This function is lost in patients with BRCA mutation which increases genomic instability, causing a significantly increased risk of breast, ovarian and other cancers.¹⁰ BRCA-mutated cells are therefore considered to have homologous recombination deficiency (HRD), though BRCA mutation is not the only means of acquiring HRD. HRD can also be manifested through the loss of heterozygosity (LOH), which is due to a cross-chromosomal event resulting in complete loss of a gene and its surrounding chromosomal region.¹¹

BRCA1 and BRCA2 germline mutations have been found in 15% of patients with HGSOC, and presence of the mutation in this group actually confers a response benefit due to greater sensitivity to platinum-based chemotherapy in both primary and recurrent disease. BRCA mutation also works synergistically with PARP inhibitors via the mechanism of synthetic lethality.⁹

PARP enzymes play an important role in repairing single-strand DNA breaks; PARP inhibition therefore results in an accumulation of single-stranded DNA breaks. PARP inhibitors also seem to act by trapping PARP enzymes on DNA—these PARP–DNA complexes are shown to be more cytotoxic than single-strand breaks alone. By impeding DNA uncoiling during cell replication, PARP–DNA complexes cause stalling of the replication fork, which produces double-stranded DNA breaks. In BRCA-mutated cells, these double-stranded breaks are then not repaired appropriately; DNA damage thus accumulates and cell death results.¹²

The PARP inhibitors

Niraparib, olaparib and rucaparib are PARP inhibitors which are currently being used as maintenance therapy in platinum-sensitive recurrence of ovarian cancer. The SOLO2, NOVA and ARIEL3 studies revealed that the PARP inhibitors are beneficial in terms of progression free survival (PFS) following second-line or subsequent chemotherapy, especially in patients with BRCA gene mutation (see table 1).^13–15 Preclinical tumour models have demonstrated that niraparib crosses the blood–brain barrier, which was not seen with olaparib.¹⁶

Table 1.

Phase III trials of PARP inhibitors as maintenance treatment of relapsed ovarian carcinoma responsive to second-line platinum-based chemotherapy

	SOLO2 study Olaparib vs placebo (N=295)	NOVA study Niraparib vs placebo (N=533)	ARIEL3 study Rucaparib vs placebo (N=564)
Median PFS in months (HR)	BRCA mutation: 19.1 vs 5.5 (HR: 0.30)	BRCA mutation: 21 vs 5.5 (HR: 0.27) Patients with HRD (no BRCA mutation): 12.9 vs 3.8 (HR: 0.38) No BRCA mutation: 9.3 vs 3.9 (HR: 0.45)	BRCA mutation: 16.6 vs 5.4 (HR: 0.23) Patients with HRD (including BRCA mutation): 13.6 vs 5.4 (HR: 0.32) All patients: 10.8 vs 5.4 (HR: 0.36)

All trials assigned patients 2:1 to drug and placebo, respectively.

BRCA, breast cancer susceptibility gene; HRD, homologous recombination deficiency; PARP, poly adenosine diphosphate ribose polymerase; PFS, progression-free survival.

Niraparib

Niraparib is now recommended for use within the Cancer Drugs Fund as maintenance treatment for relapsed, platinum-sensitive ovarian, fallopian tube and peritoneal cancer in patients who have had 2 courses of platinum-based chemotherapy, regardless of BRCA mutation status. There is a paucity of data regarding the treatment of brain metastases with niraparib in ovarian cancer. The recommended dose of niraparib is 300 mg once daily, or an initial dose of 200 mg in patients weighing under 58 kg; it may be taken with or without food.⁸ In the first year, full blood counts and blood pressure are monitored monthly, with weekly full blood counts for the first month. Dose modification and short-term treatment interruption are options when managing reactions which do not require treatment discontinuation, as in the case we present.

NOVA is a randomised, double-blinded, phase III trial study with the primary endpoint of assessing PFS in patients who received niraparib as maintenance treatment for platinum-sensitive recurrent ovarian cancer. Patients who received niraparib had a statistically significant longer median PFS compared with placebo. This difference was most pronounced in patients with BRCA mutation, who had a PFS of 21 months vs 5.5 months (HR: 0.27; 95% CI: 0.17 to 0.41); in addition, patients found to have non-BRCA HRD saw significant benefit, with PFS of 12.9 vs 3.8 months (HR: 0.38; 95% CI: 0.24 to 0.59). Non-HRD patients also received some benefit, with PFS of 9.3 vs 3.9 months (HR: 0.45; 95% CI: 0.34 to 0.61).¹³

The NOVA study also examined niraparib’s safety profile; haematological side effects such as thrombocytopaenia (34% of patients), neutropenia (20%) and anaemia (25%) were particularly common at grade 3–4. Myelodysplastic syndrome and/or acute myeloid leukaemia were seen in 1.4% (n=5) of patients taking niraparib versus 1.1% of patients (n=2) in the placebo group. Treatment was discontinued due to adverse effects in 14.7% of patients taking niraparib, compared with 2.2% in the placebo group.¹³ Patient-reported quality of life outcomes were similar between the two groups.¹⁷

Other common side effects of niraparib (>10% of patients) include palpitations, nausea, vomiting, constipation, dyspepsia, diarrhoea, abdominal pain/distension, mucositis/stomatitis, dry mouth, fatigue, decreased appetite, urinary tract infection, transaminase elevation, myalgia, back pain, arthralgia, headache, dizziness, dysgeusia, insomnia, anxiety, nasopharyngitis, dyspnoea, cough, rash and hypertension.¹³

Olaparib and rucaparib

Olaparib and rucaparib are both FDA-approved as monotherapy to prolong PFS in patients with advanced ovarian cancer and BRCA mutation after multiple lines of chemotherapy; the National Institute for Health and Care Excellence has approved olaparib and are developing guidance on rucaparib at present. We are aware of two case reports showing intracranial responses to olaparib in these cancers—one for leptomeningeal metastases in a BRCA2-mutated patient with HGSOC and another for cerebral parenchymal metastases in a BRCA1-mutated patient with primary peritoneal cancer.^{18 19}

SOLO2 was a phase III study of olaparib as maintenance therapy in BRCA-mutated patients with platinum-sensitive relapsed ovarian high-grade serous or high-grade endometrioid malignancy. Olaparib conferred an improved PFS, of 19.1 vs 5.5 months (HR: 0.30; 95% CI: 0.22 to 0.41). Olaparib maintenance therapy did not have a detrimental effect on health-related quality of life outcomes compared with placebo. There was a low rate of serious (grade 3–4) toxicity; adverse events reported more commonly with olaparib than placebo included nausea (68% vs 35%), fatigue (49% vs 38%), vomiting (32% vs 14%) and anaemia (17% vs 5%).^{14 20}

The ARIEL2 part 1 phase II trial studied the role of rucaparib monotherapy in 204 patients with recurrent, platinum-sensitive, high-grade ovarian carcinoma. Those with BRCA mutations or high LOH experienced longer PFS with rucaparib monotherapy relative to those with low LOH.²¹

The ARIEL3 phase III trial studied 564 patients with relapsed high-grade serous or endometrioid ovarian carcinoma, all of whom had received ≥2 previous platinum-based chemotherapies and responded to their last platinum-based chemotherapy course. In contrast to other studies of PARP inhibitors, women were permitted to enrol in this study even if they had the residual bulky disease (≥2 cm). The most common grade 3–4 toxicities were anaemia (22%) and transaminitis (25%).¹⁵

Rucaparib demonstrated efficacy as maintenance therapy, improving PFS:

• In patients with a known genomic or somatic BRCA mutation (16.6 vs 5.4 months; HR: 0.23; 95% CI: 0.16 to 0.34).

• In patients with HRD, defined as BRCA-mutated or BRCA-wild-type with high LOH (13.6 vs 5.4 months; HR: 0.32; 95% CI: 0.24 to 0.42).

• In the intention-to-treat population (10.8 vs 5.4 months; HR: 0.36; 95% CI: 0.30 to 0.45).

All studies mentioned here used sensitivity to platinum-based chemotherapy as a selection criterion for patients; the primary target of these drugs is DNA, and the most platinum chemosensitive tumours will be those with the most compromised DNA damage response mechanisms. Such tumours would therefore be prime targets for PARP inhibition. Hence, platinum sensitivity was used as a surrogate predictive marker of response to PARP inhibitors in these trials.⁷

Conclusions

Cerebral metastases from ovarian cancer can have a significant impact on a patient’s quality of life. Niraparib use in this case has maintained our patient in remission for over 17 months; she enjoys a good quality of life and has maintained a very good functional status. This is an example of successful individualised treatment conferring a favourable clinical outcome in metastatic disease control.

Learning points.

• Poly adenosine diphosphate ribose polymerase inhibitors are effective maintenance therapies for relapsed, platinum-sensitive ovarian carcinoma.

• They are the first treatments that clinically harness the concept of synthetic lethality; accordingly, longer responses are seen among patients with BRCA mutations.

• In the case we present, brain metastases from ovarian cancer were controlled using niraparib for over 17 months in a patient with BRCA1 mutation.