“We have made a tremendous difference in the treatment of ovarian cancer”

Ovarian cancer remains one of the most lethal gynecologic tumors in women [1]. However, the approval of new treatment options has led to significant advances in therapy in recent years [2]. Dr. Mansoor Raza Mirza and Prof. Martin Heubner talk about the status quo and the future of treatment for patients with ovarian cancer.

Mansoor Raza Mirza, M.D.
Head of Oncology Department at Rigshospitalet – Copenhagen University Hospital, Denmark, Chairmen of ENGOT (European Network of Gynaecological Oncological Trial Groups), Faculty of ESMO and ESGO

Prof. Dr. med. Martin Heubner
Head Physician Gynecology of the Department of Women and Children – Kantonsspital Baden, Switzerland

1. as of April 1, 2021, niraparib is the only PARP inhibitor (PARPi) approved for first-line monotherapy of advanced platinum-sensitive ovarian cancer with homologous recombination deficiency (HRD) regardless of BRCA status [4]. What does this mean for the treatment of these patients?

Dr. Mirza: With the data from the PRIMA trial, we have solid evidence for the efficacy of niraparib maintenance therapy in patients with ovarian cancer [siehe Wichtige Fakten zur PRIMA-Studie] [3]. One of the primary endpoints of the study was progression-free survival (PFS) of patients with HRD. In this group, we distinguished between patients with BRCA mutation (BRCAmut) and without BRCA mutation (BRCAwt). We are pleased to report that in terms of PFS, regardless of subgroup, we observed a significant benefit with niraparib compared to placebo. Two years after study initiation, we found that short-term PARPi administration conferred a real long-term benefit-with similar efficacy profiles in HRD/BRCAmut and HRD/BRCAwt patients [3].

Prof. Heubner: Before the PRIMA trial, it was already clear to us that PARPi are an effective therapy for BRCAmut patients [5]. However, only 10% to 20% of patients have a BRCA mutation, whereas a much larger proportion of ovarian cancer patients have HRD [6].

Dr. Mirza: In the PRIMA study population, 50.9% of patients had HRD [3].

Prof. Heubner: That’s how it is. This means that, based on these data and the new label of niraparib, we can now offer a large proportion of patients with advanced ovarian cancer an innovative routine treatment and a new perspective.

2. the most recent ESMO guidelines recommend the use of niraparib for the treatment of patients with BRCA mutation or other HRD [7]. What do you think about maintenance therapy with niraparib in light of the existing treatment landscape?

Prof. Heubner: In the last 20 years, there has been very little progress in the treatment of ovarian cancer. For years we relied only on standard chemotherapy, and later we were able to add bevacizumab. Angiogenesis inhibitors act as chemotherapy boosters, especially in individuals with high tumor burden [8, 9]. However, despite an advantage in terms of PFS, they appear to be effective only over a very short period of time. Now we have an additional option in the form of PARPi – and a very effective one at that. I think that we could possibly cure even more patients than before, and that is ultimately the decisive criterion.

Dr. Mirza: The fact that we are confident that we can cure more people is a strong statement that would not have been possible just a few years ago. Although we still have to wait for an observation period of 10 to 15 years, we can already say that the gradually available data are convincing. In patients who received niraparib for 2 to 3 years as first-line treatment, PFS stabilized at a certain level, although they all discontinued treatment some time ago [3]. That is why I believe that we can cure some of these patients.

Prof. Heubner: Or at least be able to offer them a noticeably longer life expectancy.

3, How do you estimate a potential synergistic effect of combining a PARPi with an angiogenesis inhibitor?

Prof. Heubner: We know that each of these treatments is effective on its own. We also know that the combination is effective, feasible, and safe [3, 5, 10]. What we don’t know yet is whether the combination treatment is more effective than PARP inhibition alone. Previous clinical trials lacked either the PARPi monotherapy or the bevacizumab monotherapy arm [10]. Overall, I do not expect significant additional benefit in individuals who already respond well to a PARPi, as the PARPi may outweigh the effect of the angiogenesis inhibitor. A future challenge will be to determine which patients will benefit from the combination and which will not.

Dr. Mirza: The main problem would be that by combining the two agents in first-line therapy, we would no longer have options for second-line therapy. Regardless of any benefits, sequential application is probably the better option.

Prof. Heubner: This leads us to a very important question: Do angiogenesis inhibitors have a place in first-line therapy? We now have sufficient evidence that PARPi are more effective than angiogenesis inhibitors in the appropriate patients [3, 5, 8-10]. Due to the country-specific restriction on the use of bevacizumab in first-line therapy, angiogenesis inhibitors could move to second-line therapy in a substantial proportion of our patients. However, in individuals with high tumor burden, angiogenesis inhibitors may still be a very good option in the first-line setting [8, 9].

4. How can niraparib as once-daily oral monotherapy help improve quality of life during maintenance therapy?

Dr. Mirza: Once-daily dosing certainly contributes to better compliance, and evening dosing may also reduce side effects such as fatigue and nausea [4].

Prof. Heubner: Most patients tolerate niraparib well, which makes it ideal for maintenance therapy with good quality of life [3]. Overall, the side effects in the context of PARPi treatment are very diverse. Some patients barely notice and virtually no hematologic toxicity is observed, especially when the initial dose is individualized to body weight and platelet count1. Others, however, experience nausea, headache, insomnia, arthralgia, and fatigue, in addition to the hematologic reactions we regularly observe. Usually, these side effects are well manageable [3].

Dr. Mirza: The cause of these side effects is difficult to determine, but overall PARPi are well tolerated. We achieved good compliance in all PARPi trials, with only 10% to 15% of participants dropping out due to toxicity. This is a very small proportion for a drug that is administered daily [3].

¹ Niraparib should be administered at this initial dose: 200 mg in patients with a body weight < 77 kg or platelet count < 150,000/µl or 300 mg in patients with a body weight ≥ 77 kg and platelet count ≥ 150,000/µl [4].

5 In the PRIMA study, good patient management contributed to a large proportion of participants (88%) continuing treatment [3]. What is your experience with the safety profile of niraparib in clinical practice?

Prof. Heubner: In the first weeks and months, strict monitoring of the therapy is of central importance. It is very important to monitor the patients’ condition, to examine them personally on a regular basis, to talk about side effects and to check the blood count. When we respond quickly to side effects, we support patients to stay on therapy.

Dr. Mirza: Hemotoxicity, that is, thrombocytopenia and leukopenia, already occurs in the first weeks of treatment [11]. Also, nausea and vomiting usually manifest in the first month or not at all [12]. Therefore, it is especially important to examine patients weekly during the first weeks and to watch for any side effects. The hemoglobin concentration, on the other hand, can also drop suddenly and unexpectedly at a later time, which is why one must always remain vigilant. Once initial side effects are controlled, we see patients every 4 weeks.

6. HRD and BRCA are important biomarkers for treatment with niraparib. What is the most useful HRD and BRCA testing regimen for you?

Dr. Mirza: At Rigshospitalet, we want to make sure we don’t miss anything, so we have established that all patients are tested for somatic BRCA mutations. We then ask the patient if she agrees to another test to detect a germline mutation. BRCAwt patients are also tested for other HRDs.

Prof. Heubner: At the Cantonal Hospital in Baden, we test all patients for germline mutations. However, we do not test for somatic mutations as standard. We screen BRCAwt patients for somatic BRCA mutations and other HRD.

7. can you give an outlook on which questions will be relevant for the use of PARPi in the future?

Prof. Heubner: A rechallenge with PARPi following first-line therapy certainly needs to be carefully considered. An initial study showed that some patients may benefit [13]. However, back mutations and other mechanisms can sometimes cause PARPi resistance. It is possible to test this and we need to decide whether appropriate algorithms should be adopted in our daily routine.

Dr. Mirza: There continues to be an unmet need for better treatment options for HR-proficient patients. That is why it is important to plan clinical trials targeting the HR-proficient population. In addition, further studies are needed to investigate the efficacy of PARPi in combination with other agents such as ATR inhibitors or even other PARPi.

Prof. Heubner: Combinations could be the future. We hope that numerous female patients will benefit from these emerging opportunities.

Dr. Mirza: Our current progress suggests a good outlook for these patients. It is a privilege for us to be a part of this because we have made a tremendous difference in the treatment of ovarian cancer.