Advances in Ovarian Cancer: Using Genomics and Optimizing Maintenance Therapy

Ovarian cancer remains one of the most challenging malignancies to manage, with high morbidity and mortality rates due to the frequency of late-stage diagnoses.¹ Because deeper understanding of tumor genomics has opened the door to targeted therapies and improved outcomes for subsets of patients, integration of these evidence-based genomic advancements into clinical decision-making is essential to maximize outcomes while minimizing unnecessary treatment.

Genomic Testing

Amy VanGalder, PharmD, BCOP | Image provided by Evolent Health

Recent advances in the understanding of advanced ovarian cancer (aOC) genomics have begun to challenge the treatment paradigm for this difficult disease. Although several genomic aberrations have been identified in aOC, the most important pathway is the homologous recombination (HR) pathway, with HR deficiency (HRD) present in approximately 50% of high-grade serous OC (HGSOC).² Within the HR pathway, there can also be mutations in the BRCA1/2 genes, which occur in approximately 20% of HGSOC.² National Comprehensive Cancer Network (NCCN) Guidelines for OC recommend, at a minimum, testing for BRCA1/2, loss of heterozygosity, and HRD, even in the absence of a germline BRCA mutation, because these mutations can and should steer treatment options in the primary maintenance setting.³ If patients enter the recurrent setting, the focus may be expanded to a broader set of molecular alterations to inform treatment interventions and potentially improve outcomes. These include HER2 status (by immunohistochemistry), microsatellite instability, mismatch repair status, tumor mutational burden, and mutations in BRAF, FOLR1, RET, and NTRK.³

Primary Maintenance Therapy
It has been standard of care for decades that patients with newly diagnosed aOC receive a combination of debulking surgery and platinum-based chemotherapy. Despite high response rates to this approach, 70% of women will relapse within 3 years of completing treatment.⁴

With a need for better treatment options to reduce the rate of relapse in aOC, poly ADP-ribose polymerase (PARP) inhibitors entered the scene and quickly became a new standard of care for primary maintenance therapy. Initially, trials focused on patients with BRCA mutations, but in 2017, niraparib (Zejula; GSK) became the first PARP inhibitor to be approved for maintenance of recurrent OC, regardless of mutation status, in women who had a response to platinum-based chemotherapy.⁵ The opportunity to forgo mutation testing and still be able to offer patients maintenance therapy is certainly tempting—but is outside of NCCN recommendations. In addition, PARP inhibitors are known to cause adverse events such as anemia, fatigue, nausea, hypertension, and thrombocytopenia.⁴

Exposing patients to years of maintenance therapy without a meaningful clinical benefit in progression free survival (PFS) and overall survival (OS) can be detrimental to a patient’s cancer journey. Therefore, patient selection becomes a crucial component of optimizing maintenance therapy with PARP inhibitors, and utilizing genomics to select patients is supported by the consistency of data from randomized phase 3 trials, including SOLO-1⁶ (NCT01844986), PAOLA-1⁷ (NCT02477644), PRIMA⁸ (NCT02655016), and ATHENA-MONO⁹ (NCT03522246).

Patient Selection for Primary Maintenance Therapy

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Optimizing patient selection for primary maintenance therapy relies on mutational testing for BRCA and HRD status. The PARP inhibitor olaparib (Lynparza; AstraZeneca) was first studied in the SOLO-1 trial in patients with BRCA-mutated aOC and demonstrated statistically significant benefits vs placebo through increased median PFS and OS¹⁰ (TABLE ^6-12). The PAOLA-1 trial extended beyond BRCA mutations by also taking a glimpse into how patients with HRD performed on PARP inhibitors. This trial combined olaparib with bevacizumab (Avastin) in the investigational arm and compared it with placebo plus bevacizumab in the control arm.⁸ The addition of bevacizumab to maintenance therapy can be considered if patients received bevacizumab as part of their primary platinum-based therapy.³ Like the SOLO-1 trial, PAOLA-1 demonstrated improvements in PFS and OS for patients with BRCA mutations, but it also identified benefits for HRD-positive patients, including those without a BRCA mutation.¹¹ Patients in the trial without mutations (BRCA wild type and/or HRD negative) did not have any significant PFS benefit from the addition of olaparib, and they also had shorter OS than the placebo group.¹¹

The PRIMA trial outlined additional agents in this space. Originally, there was excitement for activity of niraparib in an unselected patient population (those without BRCA and HRD mutations), but with longer follow-up and a closer look, it became clear that the benefits for the overall population were primarily driven by BRCA-mutated and HRD-positive patients. The median PFS for the overall population was approximately 5.5 months longer for niraparib vs placebo, whereas the median PFS for BRCA-mutated and/or HRD-positive patients was more than double for niraparib (24.5 months) vs placebo (11.2 months).¹² For patients without BRCA mutations or HRD, the median PFS was much lower, showing approximately a 3-month difference between niraparib and placebo.¹² Although this was considered statistically significant, the 3-year PFS rates for patients without BRCA mutations or HRD were 11% for niraparib and 10% for placebo, which altogether suggests there was no clinically meaningful benefit in PFS for patients without mutations in the PRIMA trial.¹² In addition, OS benefit was not significant for any groups in the PRIMA trial, although a high proportion of patients (48.4%) in the placebo arm with BRCA mutations and/or HRD received subsequent PARP inhibitor therapy.¹²

The ATHENA-MONO trial demonstrated very similar outcomes for rucaparib (Rubraca; pharmaand GmbH) to the PRIMA trial with niraparib. ATHENA-MONO showed a statistically significant and clinically meaningful PFS benefit in the intention-to-treat patient population, but this can be attributed to the BRCA-mutated/HRD-positive patients.⁹ The patients without BRCA/HRD aberrations had a marginal 3-month difference in PFS, and overall survival
data are still maturing.⁹

Duration of Primary Maintenance Therapy
Once patient selection has been optimized for those with BRCA mutations and/or HRD, it is then important to think about the ideal length of time for maintenance therapy. Within the SOLO-1, PAOLA-1, and ATHENA-MONO trials, olaparib and rucaparib were administered for up to 24 months.^6,7,9 For the PRIMA trial, the planned duration of study treatment was 3 years, but patients could receive niraparib beyond that if they were benefiting (range of treatment exposure, 0-80 months; median, 11.3 months).⁸

With increased time on treatment, however, there is the potential for more adverse events and long-term toxicities, including acute myeloid leukemia and myelodysplastic syndromes.^8,12 And no current evidence suggests that lengthening primary maintenance therapy duration beyond 2 years (olaparib and rucaparib) or 3 years (niraparib) will reduce the risk of aOC recurrence.¹³ Researchers in the NRG-GY036 trial (NCT06580314) are investigating the efficacy of decreasing maintenance therapy to 1 year vs 2 years for olaparib, but these data will not be available for quite some time.¹⁴

With the current data pointing to a fixed treatment duration, it is important to also think about how the patient will interpret a recommendation to stop therapy. Although some may welcome the idea due to their experience with adverse events or financial concerns, others may feel anxious about disease recurrence.¹⁵ Shared decision-making between patients and their oncologist—considering the risks and possibility of unproven benefits—is critical for deciding whether to stop treatment after 2 years (olaparib and rucaparib) or 3 years (niraparib).

Recurrence Maintenance Therapy
Despite primary maintenance therapy, some patients will, unfortunately, experience disease recurrence. If this recurrence occurs at least 6 months after completing prior platinum-based therapy, then the patient is considered platinum sensitive and should receive another course of platinum-based chemotherapy and be considered for secondary cytoreductive surgery and maintenance therapy.³ In the maintenance setting for platinum-sensitive, recurrent aOC, the SOLO-2 (NCT01874353), NOVA (NCT01847274), and ARIEL3 (NCT01968213) trials demonstrated similar benefits to those seen in the aOC primary maintenance setting.^16-18 The clinically meaningful benefit from adding olaparib, niraparib, or rucaparib was restricted to the BRCA-mutated and/or HRD-positive patient population and to those that did not progress during prior PARP inhibitor treatment.^16-18 Unlike in the primary maintenance therapy setting, using genomics for patient selection in the recurrence maintenance setting is reflected in FDA labels for all the products and in NCCN Guidelines.^3,19-21 The optimal duration of aOC recurrence maintenance therapy is unclear because patients were allowed to continue until disease progression or unacceptable toxicity in the trials. In the SOLO-2 trial, 32% of patients received olaparib for 2 years or more, and 20% of patients in the NOVA trial received niraparib for at least 2 years.^22,23 Unfortunately, with recurrence being a more challenging scenario, there is not adequate evidence to suggest a benefit to limiting the time on maintenance PARP inhibitor treatment for these patients.

Immunotherapy
It is estimated that 56% of all patients with cancer will be eligible for an immune checkpoint inhibitor (ICI) during their cancer journey.²⁴ The opportunity to utilize these agents in the maintenance setting to extend responses in OC is attractive and has generated a lot of interest. Unfortunately, efforts to utilize ICIs as single therapy or in combination with chemotherapy have largely failed to improve patients’ outcomes in aOC.²⁵ In addition, combining ICI with the antiangiogenic agent bevacizumab in the phase 3 ATALANTE trial (NCT02891824) yielded no difference in PFS, including no difference in patients with PD-L1 expression.²⁶ Attempts to use ICI with PARP inhibitors have also yielded dismal results. The ATHENA-COMBO study (NCT03522246) was designed to evaluate treatment with nivolumab plus rucaparib vs just rucaparib in the primary maintenance aOC setting, but unfortunately it failed to show any PFS benefit for any groups, including subgroups of patients selected for HRD and PD-L1 expression.²⁷

Summary
Incorporating genomics into maintenance therapy for aOC has significantly advanced the optimization of patient selection. BRCA-mutation and HDR status have demonstrated particular importance in maximizing outcomes for PARP inhibitors, whereas ICIs continue to show dismal results in the maintenance setting, even for patients with higher levels of PD-L1
expression. Limiting patients’ duration on PARP inhibitor treatment based on currently available data is equally important to minimize the risk of adverse events. As our understanding of tumor genomics and long-term effects of maintenance treatment progresses, we look forward to additional opportunities to maximize outcomes while minimizing unnecessary treatment.

Author Information
Amy VanGalder, PharmD, BCOP, is a board-certified oncology pharmacist at Evolent Health with extensive experience in the field of oncology pharmacy practice. At Evolent, a primary and specialty care enablement company, VanGalder is focused on engaging with fellow pharmacists and providers at oncology practices to facilitate scientific data exchange, enhance value-based initiatives, and support evidence-based decision-making.

References
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