Patients with PROC face severe unmet needs for efficacious treatment options, as the platinum-free chemotherapies currently recommended by the National Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology (ESMO) guidelines only offer limited efficacy in terms of response rate (10–15%) and durability (3–4 months).20–22 The ANNIE study evaluated the niraparib-anlotinib combination in 40 patients with PROC. The primary analysis previously published showed promising antitumor activity of niraparib-anlotinib in this patient population, achieving an ITT ORR of 50% (including 1 case of complete response), together with encouraging results for median duration of response (6.9 months), platinum-free interval (13.2 months), progression-free survival (9.2 months), and OS (15.3 months).13 In this analysis, the updated median OS of 18.2 months (95% CI: 12.1–not evaluable) provided further evidence on the persistent clinical benefit of niraparib-anlotinib.
For PROC patients, the quest for more efficacious treatments is integrally related to drug safety and tolerability, as the latter is crucial for ensuring treatment adherence and sustainability and therefore, a prerequisite for optimally translating drug activity into clinical efficacy. Ovarian cancer patients are often at risk of chronic and metabolic comorbidities and face high levels of mental stress.1,6 For patients with PROC, the cumulative toxicities of multiple prior lines of platinum-based chemotherapy would have exacerbated their general health.23 Additionally, with an estimated overall survival of less than one year,24 maintaining the quality of life is considered an important principle in PROC care. Prior to ANNIE, olaparib plus cediranib is another combination of PARP inhibitor-antiangiogenic that has been studied for treating PROC.25–27 However, this combination faced the challenge of high toxicity. In two clinical studies of olaparib-cediranib, grade ≥ 3 adverse events occurred in over 70% of the patients, and safety concerns prevented the use of both agents at full clinical doses.25,26 In the ANNIE study, the safety results from both the primary analysis and the current update indicate that overall the niraparib-anlotinib combination can be safely used in PROC patients with both agents at usual clinical doses; TEAEs were well managed, and all death events were due to disease progression.
Hypertension is commonly observed in patients receiving VEGFR inhibitors, occurring in 30–80% of patients.28 With olaparib-cediranib, the incidence of hypertension was reported at 66.7%,25 mainly attributable to the VEGFR inhibitor cediranib. Among the major guideline-recommended classes of hypertension medication (CCB, ACEI, ARB, beta-blockers, and diuretics29), vasodilators such as CCB and renin-angiotensin-aldosterone system inhibitors such as ACEI and ARB would be suitable for relieving hypertension induced through VEGFR inhibitors’ on-target vasoconstriction effects.28,30 However, most CCBs are metabolized via the CYP3A pathway, interacting with most small-molecule tyrosine kinase inhibitors such as cediranib, anlotinib, and apatinib.31 For olaparib-cediranib, the situation is compounded by olaparib also being CYP3A-metabolized, making the management of blood pressure increasingly challenging. The use of CCBs would render the plasma concentrations of both olaparib and cediranib unpredictable, potentially causing uncertainty to both efficacy and safety.32,33
The design of the ANNIE study similarly anticipated a heightened need for blood pressure management, because in addition to anlotinib, which shares the hypertension-inducing class effect of VEGFR inhibitors,15,18 niraparib can also cause hypertension and increased heart rate due to inhibition of dopamine, norepinephrine, and serotonin receptors.16 In the NOVA trial, 19.3% patients reported hypertension, with grade ≥ 3 hypertension in 8.2% patients, and 10.4% patients reported palpitations.34 Upon adopting individualized starting dose for niraparib, the NORA study conducted in Chinese patients saw a lower rate of all-grade and grade ≥ 3 hypertension (11.3% and 1.1%, respectively), and 18.1% patients experienced palpitations.35 On the other hand, unlike olaparib, niraparib is not metabolized by CYP3A, and this would reduce the constraints on the choice of antihypertensives. Based on these considerations, the ANNIE study designed and implemented close monitoring and preventive/early interventive measures for blood pressure management, and the results were satisfactory: 22 patients experienced post-baseline clinical hypertension events, with increased heart rate and diastolic blood pressure being the predominant symptoms. As such, beta-blockers, a class of potent heart rate controllers, were adopted as the mainstay for blood pressure and heart rate management. Early interventions with beta-blocker-based monotherapy or combination therapy achieved effective blood pressure control in most patients, with only five patients requiring triple therapy. No intensive antihypertensive therapy (< 120/80 mmHg) was conducted. No cardiovascular events were recorded during the post-study treatment safety follow-up.
Lipid metabolism should be another focus in managing ovarian cancer patients, who are subject to multiple dyslipidemia risk factors including aging, hormonal alterations due to natural or ovariectomy-induced mesopause, and elevated cardiovascular risks.9 TEAEs of increases in triglycerides and cholesterol have been reported in studies of anlotinib, occurring in approximately 20–60% of patients.36–38 In this study, patient lipid levels were closely monitored. Hypertriglyceridemia occurred in 12 patients, including grade ≥ 3 hypertriglyceridemia in three. Five patients experienced hypercholesterolemia, all of which were of grade 1–2. In standard clinical practice, the choice of therapeutic modalities for blood lipid management depends on the patient’s profile: lifestyle therapies constitute the primary treatment for patients with mild blood lipid elevation and without other cardiovascular or metabolic risk factors, while lipid-lowering medications are used for patients with persistently elevated blood lipid levels despite lifestyle therapies and patients with multiple other risk factors. However, for the middle-aged and elderly post-operative PROC patients in this study, lifestyle therapies such as weight control and physical activities would be unrealistic and might increase the patients’ physical burdens. As such, blood lipid TEAEs were primarily managed using lipid-lowering medications, which were prescribed based on physicians’ instruction and immediately upon detecting a trend of blood lipid elevation in any patient. Ten patients received immediate lipid-lowering medications, mostly using atorvastatin and simvastatin. One patient experiencing grade ≥ 3 hypertriglyceridemia received fenofibrate. These management measures successfully maintained patients’ blood lipid levels at normal or CTCAE grade 1–2 level. No pancreatitis or cardio-cerebrovascular events occurred.
Hematologic toxicities have always been noted as a common class effect of PARP inhibitors and with niraparib, the incidence of hematologic TEAEs reported in clinical trials is approximately 60%.34,35,39 Notably, myelodysplastic syndrome has been reported in patients receiving niraparib, with an incidence of 0.2–1.4%.14 Once this occurs, patients would face severe hematological damage and need to permanently stop using PARP inhibitors, leaving them with restricted treatment options. Some studies of anlotinib also reported hematologic adverse events.37,38 As such, it was crucial to conduct comprehensive tracking of blood system indicators when these two drugs that could cause hematologic adverse events were administered in combination. In this study, patients’ CBC was closely monitored, with focused follow-up for leukocyte, red blood cell, hemoglobin, and platelet levels. Overall, the hematological adverse events were manageable, without new signals identified.
This study had several limitations. Firstly, information was incomplete on patients’ treatment history for pre-existing hypertension and the use of other concomitant medications. While timely and effective interventions were implemented during the study for hypertension TEAEs, it was difficult to determine whether prior medications influenced the efficacy of these interventions. Secondly, the study did not assess the quality of life or patient-reported outcomes (PRO), which are important parameters for late-stage ovarian cancer patients in addition to survival. While the study provided multidisciplinary interventions for controlling patients’ somatic symptoms, the effectiveness of this management process could not be evaluated in a more intuitive or in-depth manner due to the lack of PRO data. Thirdly, insomnia should have been pre-specified as a key TEAE for investigation in addition to the vascular, metabolic, and hematologic TEAEs discussed above. Later in the study, it was found that five patients used sleep aids and four patients experienced insomnia events. This incidence of insomnia at 10% is lower than that in the general population (33%),40 suggesting possible under-reporting of insomnia TEAEs and by extension, possible under-recording of the use of sleep aids.