**4.4. Niraparib**

Niraparib is a potent PARP1 and PARP2 inhibitor whose pharmacokinetics allows once daily dosing. A phase I dose escalation trial established the MTD as 300 mg/day. Dose-limiting toxicities included fatigue, reversible pneumonitis (in the context of recent chest wall irradiation) and reversible grade 4 thrombocytopenia. Of the 20 patients with gBRCA mutations and evaluable tumours the ORR (at doses between 80 and 400 mg) was 40% [58].

The pivotal phase III NOVA trial enrolled patients with platinum-sensitive disease who had received at least two prior lines of chemotherapy and who had measurable disease of <2 cm post-treatment [59]. Patients were randomised to niraparib 300 mg or placebo as maintenance till PD or unacceptable toxicity. Patients were stratified into gBRCA mutations vs. those without. Those without gBRCA mutations were further stratified into those with or without a positive HRD score (see below) and a predefined cut-off. PFS in the gBRCA mutated group was 21 vs. 5.5 months in the niraparib and control arms respectively (HR 0.30) and 12.9 vs. 3.8 months (HR 0.45) in the HRD positive cohort.

QUADRA is an ongoing single-arm phase II trial in patients pre-treated with 3–4 lines of chemotherapy and who were platinum sensitive at first recurrence regardless of BRCA mutation status. Patients who entered the trial underwent testing for homologous recombination deficiency (HRD) using a validated commercial assay. This assesses tumour samples for three SNP array-based 'signatures' of genomic instability (loss of heterozygosity, telomeric allelic imbalance and large scale transition) to derive an overall 'HRD score' that should predict sensitivity to PARP inhibition [NCT02354586].

PRIMA is an ongoing phase III of niraparib maintenance after 1st line chemotherapy. Unlike SOLO1, patients are enrolled on the basis of HRD score rather than gBRCA mutation status.

#### **4.5. Rucaparib**

Rucaparib is another orally bioavailable PARPi with both catalytic inhibitory and PARPtrapping activity, the potency of the latter being equivalent to olaparib [60].

Rucaparib was granted accelerated FDA approval largely based on composite data from 2 phase II studies. 106 patients with gBRCA mutations who had received at least 2 prior lines of chemotherapy received continuous rucaparib at 600 mg BD [61]. The confirmed ORR by RECIST was 54%. Toxicity at ≥ grade 3 included anaemia (27%), fatigue (15%), transient AST/ ALT elevation (13%), vomiting (6%) and nausea (4%).

Part 1 of the ARIEL2 trial (from which the gBRCA mutation data was pooled in the above analysis) enrolled 206 patients who had been received at least 1 prior platinum containing chemotherapy regimen and who had progressed after at least 6 months after their most recent course [62]. Patients were prospectively divided into three subgroups based on their HRD status: 1) germline or somatic BRCA mutations 2) BRCA wild-type and LOH-high 3) BRCA wild-type and LOH-low. LOH was assessed using a next generation sequencing assay and a cut-off of 14% was assigned using microarray and survival data from TCGA. Based on this pre-specified score, PFS was 12.8 months, 5.7 months and 5.2 months in the BRCA mutated, BRCA wild-type/LOH-high and BRCA wild-type/LOH-low subgroups. Although median PFS was similar in the latter groups, the HR for PFS was significantly in favour of the LOHhigh subgroup (0.62 95% CI 0.42–0.90), and ORR by RECIST (29% vs. 10%) and 1 year survival (28% vs. 10%) were also better for the LOH-high subgroup. Of note, LOH exists on a continuum and exploratory post-hoc analysis revealed that a cut-off of 16% provided better discrimination between the two subgroups [63]. Also importantly, there were patients in the LOH-negative group with very good partial and even complete responses (by ca125). In this single arm phase II study, it is not possible to exclude the possibility that LOH-high tumours simply have a better prognosis and that LOH is a prognostic rather than predictive marker. In order to address this question (in a maintenance setting at least) the NGS assay is being prospectively applied in the phase III Ariel 3 study which is investigating maintenance rucaparib in platinum-sensitive ovarian cancer. The phase III Ariel 4 study is will compare rucaparib as an active treatment vs. standard of care chemotherapy in platinum-sensitive disease after at least 2 prior lines.

#### **4.6. Veliparib**

improved from not reached vs. 18.4 months (HR 0.5) and OS data are immature. Although nausea (76% vs. 33%) and vomitting (37% vs. 19%) were higher in the olaparib arms, grade 3/4 events were infrequent (2.6% for both). Grade 3/4 anaemia occurred in 20%. Patient-reported

The phase III SOLO1 has completed accrual and randomised patients with BRCAm following

Niraparib is a potent PARP1 and PARP2 inhibitor whose pharmacokinetics allows once daily dosing. A phase I dose escalation trial established the MTD as 300 mg/day. Dose-limiting toxicities included fatigue, reversible pneumonitis (in the context of recent chest wall irradiation) and reversible grade 4 thrombocytopenia. Of the 20 patients with gBRCA mutations and

The pivotal phase III NOVA trial enrolled patients with platinum-sensitive disease who had received at least two prior lines of chemotherapy and who had measurable disease of <2 cm post-treatment [59]. Patients were randomised to niraparib 300 mg or placebo as maintenance till PD or unacceptable toxicity. Patients were stratified into gBRCA mutations vs. those without. Those without gBRCA mutations were further stratified into those with or without a positive HRD score (see below) and a predefined cut-off. PFS in the gBRCA mutated group was 21 vs. 5.5 months in the niraparib and control arms respectively (HR 0.30) and 12.9 vs.

QUADRA is an ongoing single-arm phase II trial in patients pre-treated with 3–4 lines of chemotherapy and who were platinum sensitive at first recurrence regardless of BRCA mutation status. Patients who entered the trial underwent testing for homologous recombination deficiency (HRD) using a validated commercial assay. This assesses tumour samples for three SNP array-based 'signatures' of genomic instability (loss of heterozygosity, telomeric allelic imbalance and large scale transition) to derive an overall 'HRD score' that should predict

PRIMA is an ongoing phase III of niraparib maintenance after 1st line chemotherapy. Unlike SOLO1, patients are enrolled on the basis of HRD score rather than gBRCA mutation status.

Rucaparib is another orally bioavailable PARPi with both catalytic inhibitory and PARP-

Rucaparib was granted accelerated FDA approval largely based on composite data from 2 phase II studies. 106 patients with gBRCA mutations who had received at least 2 prior lines of chemotherapy received continuous rucaparib at 600 mg BD [61]. The confirmed ORR by RECIST was 54%. Toxicity at ≥ grade 3 included anaemia (27%), fatigue (15%), transient AST/

trapping activity, the potency of the latter being equivalent to olaparib [60].

first-line platinum-based chemotherapy to either Olaparib 300 mg BD or placebo.

evaluable tumours the ORR (at doses between 80 and 400 mg) was 40% [58].

outcomes showed no detriment for olaparib [57].

340 Ovarian Cancer - From Pathogenesis to Treatment

3.8 months (HR 0.45) in the HRD positive cohort.

sensitivity to PARP inhibition [NCT02354586].

ALT elevation (13%), vomiting (6%) and nausea (4%).

**4.4. Niraparib**

**4.5. Rucaparib**

Another orally bioavailable PARP inhibitor, veliparib is far less potent at PARP-trapping than the previously mentioned agents although it is a more potent catalytic inhibitor than niraparib and has been shown to cross the blood–brain barrier [51]. In a phase I trial 40% of the 28 BRCAm positive evaluable patients had an ORR at the MTD (400 mg BD). Commonest toxicities were nausea, vomiting and lymphopenia and 2 patients had grade 2 seizures [NCT01472783].

In a phase II trial in patients with gBRCAm who had been treated with 3 or fewer prior regimens (median 2) and of whom 60% were platinum resistant, the ORR was 26% (35% in the platinum-sensitive cohort). Grade 3 fatigue, nausea and neutropenia occurred in 6%, 4% and 2% respectively with no other grade 3 toxicities. Veliparib is currently being explored in phase III trial concurrently with carboplatin/paclitaxel and then continued as maintenance (NCT02470585, see below).

#### **4.7. Talazoparib**

Talazoparib is a novel PARPi that traps PARP approximately 100-fold more efficiently than olaparib and rucaparib and exhibits cytotoxicity at nanomolar (compared to micromolar) concentrations) [60]. At an MTD of 1 mg/kg, 5/12 patients with BRCAm ovarian cancer achieved an ORR with a 24% and 18% rate of G3 anaemia and thrombocytopenia respectively [64]. Given its unique potency for trapping, there is hope that it may have efficacy as a second line agent for patients who have progressed on a previous PARPi [65].

were independent predictors of OS in multivariate analysis and BRCA mutated tumours had an increased TIL burden and PD-L1 expression. Lastly, tumour burden/volume is an important factor in predicting the response to immunotherapy [72]. Ovarian cancer is unusual as patients presenting *de novo* with bulky disease can be treated with radical surgery to no residual disease. Although the majority relapse, there is a window of time where disease remains undetectable. Given the data that exists on enhanced effectiveness of immunotherapy in patients with a low overall tumour burden, this may present a window of opportunity to maximise effectiveness of

Novel Systemic Treatments in High Grade Ovarian Cancer

http://dx.doi.org/10.5772/intechopen.71583

343

Co-inhibitory checkpoints usually act to minimize collateral tissue damage during immuneactivation. Upregulation of these checkpoints can subvert anti-tumour immunity. The binding of CTLA-4 to B7.1/B7.2 is one such inhibitory interaction that can be prevented by the anti

In a phase I study including 2 patients with ovarian cancer, one patient had a 43% reduction in ca125 levels while the other developed a plateau in ca125 levels despite rapidly rising levels before treatment [73]. In a follow-up study of 9 patients one developed a radiologic PR with complete resolution of mesenteric lymphadenopathy. Three others achieved radiographic and ca125-defined stable disease of 2, 4 and >6 months duration. In a phase II study of 40 patients with recurrent platinum-sensitive EOC (NCT01611558), 50% developed at least G3 toxicity and the ORR was 10.9% by RECIST. A phase II trial testing a combination of nivolumab and

A trial using another CTLA4 antagonist, tremelimumab, is currently enrolling patients for

Another inhibitory checkpoint interaction is between PD-1 (on T-cells) and PD-L1 (that may be upregulated on tumour cells and their microenvironment). Avelumab, a fully humanised IgG1 anti-PD-L1 antibody, was tested in a phase Ib trial in 124 patients with platinum resistant/refractory disease after a median of 4 lines of therapy [73, 74]. The drug was well tolerated with a grade 3/4 adverse event rate of 6.4%. ORR in this heavily pre-treated population was 9.7% and the relationship between germline BRCA status and probability of response is being investigated. Avelumab is currently being tested in two randomised phase III trials. The three-arm JAVELIN Ovarian 200 study (NCT02580058)I is recruiting patients with their first platinum resistant/refractory relapse and randomising to either Avelumab or PLD alone or in combination. In JAVELIN Ovarian 100 (NCT02718417) patients with previously untreated III/ IV ovarian cancer are randomised to carboplatin and paclitaxel followed by placebo or avelumab maintenance or carboplatin and paclitaxel with concurrent *and* maintenance avelumab. Atezolizumab is also a fully humanized IgG1 anti-PD-L1 antibody. In the phase III ATALANTE trial (NCT02891824) patients with platinum-sensitive relapse are being randomised to platinum-based chemotherapy with concurrent and maintenance bevacizumab + placebo (control arm) or bevacizumab + avelumab (experimental arm). The combination of bevacizumab and avelumab is a rational one based on evidence that endogenous VEGF signalling has a variety

ipilimumab for recurrent ovarian cancer is currently underway (NCT02498600).

phase I trials in combination with olaparib (NCT02571725, NCT02485990).

this therapeutic approach.

**5.1. Checkpoint blockade**

CTLA-4 monoclonal antibody ipilimumab.

#### **4.8. Combination therapy with PARP inhibitors**

PARPi were originally developed as potential chemo/radiosensitizers. There is obvious rationale in combining PARPi with other agents, especially in tumours that are HR proficient. When combining PARPi with chemotherapy, rational combination necessitates consideration of the mechanism of action of the chemotherapy plus the relative catalytic inhibitory/trapping properties of the PARPi. For example, PARPi combination with topo-1 inhibitors is synergistic primarily because of catalytic PARP inhibition whereas synergy with alkylating agents relies on trapping too [66]. Several PARPi/chemotherapy combinations are in trials, reviewed here [67]. Synergistic toxicity (e.g. myelotoxicity) will have to be borne in mind. PARPi/VEGFR targeting combinations have previously been discussed. Other targeted combinations include PI3K/MTOR pathway inhibitors, HSP90 and CHK1/2 inhibitors [67]. Finally, talazoparib had immunomodulatory effects in a pre-clinical mouse model; studies looking at immunotherapy with PARPi are underway (NCT0257172).

#### **4.9. Resistance to PARP inhibitors**

Several putative mechanisms of resistance have been described. These include a secondary mutation in BRCA which either restores the correct open reading frame (i.e. where the original mutation caused a frameshift) or which fully reverts the original mutation to wild-type. This also causes platinum resistance and in one study of platinum resistance in BRCAm patients, 46% had acquired a secondary BRCA mutation [68]. Other mechanisms include upregulation of P-glycoprotein and loss of 53BP1 (which usually promotes NHEJ and prevents HR). Knowledge of the specific resistance mechanism may have clinical relevance as some (e.g. secondary mutations) cause platinum resistance too whereas others do not. Also, 53BP1 loss causes resistance in BRCA1 but not BRAC2 deficient tumours.
