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Key Advances in Gynecologic Cancers: Expert Insight for Incorporating New Clinical Evidence
  • CME
  • CE

Eva Y. Pan, PharmD, BCOP
Ritu Salani, MD, MBA
Released: May 13, 2022

Ovarian Cancer

Genetic Testing in Ovarian Cancer: Who Should Be Tested?

Ritu Salani, MD, MBA:
It is important to recognize that the leading oncology societies—including the National Comprehensive Cancer Network (NCCN), the Society of Gynecologic Oncology (SGO), the American Society of Clinical Oncology, and the European Society for Medical Oncology (ESMO)—have recommended that all women with epithelial ovarian cancer undergo genetic testing.4-7 The recommended testing is predominantly for BRCA1/2 mutations, but also there are additional genetic abnormalities that can predispose women to epithelial ovarian cancer that may be identified.

Single-Gene vs Multigene (Panel) Germline Testing

Ritu Salani, MD, MBA:
If the patient has a known family history of breast cancer, single-gene testing may be appropriate. However, most patients do not have a known family history; panel testing is more comprehensive and may identify genetic mutations beyond BRCA. Of importance, panel testing also is useful when a patient tests negative for BRCA but may have evidence of inherited risk.

Tumor (Somatic) Tests: Phenotype of HRD Can Be Detected With Cause and Effect Assays

Ritu Salani, MD, MBA:
Somatic tumor testing can help guide treatment and thereby influence outcomes of patients with ovarian cancer.1,8,9 This is known as HRD testing, and it can identify mutations in BRCA or other specific genes associated with the homologous recombination pathway. It also can reveal genomic instability, which may increase a patient’s tumor sensitivity to available therapeutic agents, particularly PARP inhibitors. More recently, BRCA mutation status and genomic instability scores have been combined to more accurately assess a patient’s HRD status.

Approximately 50% of High-Grade Serous Ovarian Cancers Have Alterations in HRR Genes

Eva Y. Pan, PharmD, BCOP:
About 50% of ovarian cancers have alterations in the homologous recombination repair (HRR) genes, which are involved in repair of double-strand DNA breaks.9 For example, these genes can have mutations, deletions, amplifications, or promoter methylation. This pie chart shows the major pathogenic mutations in HRR genes, most prominently the germline and somatic BRCA mutations that can render cells sensitive to PARP inhibition. Cancer cells in patients with HRD are more susceptible to PARP inhibition as well.

Mechanism of Action of PARP Inhibitors

Eva Y. Pan, PharmD, BCOP:
In normal cells, the PARP enzymes work by binding to single-strand break sites on DNA and repairing them in a process called base excision repair.10 PARP inhibitors work by trapping the PARP enzymes at the single-strand breaks, preventing DNA repair leading to double strand breaks, crisis, and cell death. Cells that are proficient in homologous recombination (eg, are able to repair the double-strand breaks) can survive, whereas HRD cannot adequately repair double-strand breaks and undergo cell death (apoptosis). Therefore, this is why PARP inhibitors are most effective in cells that have HRD, whether that’s due to mutations in BRCA or other genes.

Advent of Maintenance Therapy in Advanced Ovarian Cancer

Ritu Salani, MD, MBA:
In addition to the influence of both germline testing and tumor testing on tumor characterization and prognostication of outcomes, the evolving role of maintenance therapy in advanced ovarian cancer also has meaningfully improved management of this disease. This timeline shows how maintenance therapy in ovarian cancer has changed over time. In 2003, paclitaxel maintenance was explored but did not change practice for most oncologists given its association with the development of peripheral neuropathy after prolonged use. Then, in 2011, GOG 218 and ICON7 demonstrated the benefit of bevacizumab as first-line maintenance therapy.11,12 Bevacizumab was slowly incorporated into treatment regimens and continues to be part of the standard of care today.

The most substantial change in the maintenance setting came about with the advent of PARP inhibitors: olaparib, niraparib, and rucaparib.1-3

Multiple studies have demonstrated strong benefit from PARP inhibition both in patients with recurrent platinum-sensitive relapse as well as in the frontline setting. Olaparib was the first PARP inhibitor to receive FDA approval in 2018, and this class of drugs has made a very meaningful difference in our day-to-day treatment of patients with ovarian cancer. Of note, the combination of olaparib and bevacizumab is approved as first-line maintenance therapy after a response to CT.2

First-Line Maintenance Studies in Ovarian Cancer: PFS

Ritu Salani, MD, MBA:
The graphic on the right provides an overview of 3 key first-line phase III maintenance studies comparing approved PARP inhibitors vs placebo in ovarian cancer: SOLO-1 (olaparib), PAOLA-1 (olaparib/bevacizumab), and PRIMA (niraparib).13-15 It is important to note that this is not a head-to-head comparison, as these studies evaluated the various PARP inhibitors in different patient populations. But the take home message is that all 3 studies showed that the introduction of a PARP inhibitor, either as a single agent or in combination with bevacizumab, improved PFS compared with placebo. In particular, BRCA mutation carriers had much longer PFS with a PARP inhibitor, but substantial benefit also was seen in those patients with HRD-positive tumors. Moreover, as seen in the PRIMA trial results for the intention-to-treat (ITT) population, even HR-proficient patients with wild-type BRCA obtained a benefit with niraparib.

First-Line Olaparib in Ovarian Cancer (SOLO-1), 5-Year Follow-up: Safety

Ritu Salani, MD, MBA:
A 5-year follow-up with a safety analysis from SOLO-1 was presented in late 2021.13,16 This phase III study compared olaparib vs placebo as maintenance therapy in patients with advanced ovarian cancer and a BRCA mutation. Updated results showed no new safety signals compared with the original analysis in 2018, and the safety profile is not significantly different from other PARP inhibitors. In addition, no new cases of myelodysplastic syndromes or acute myeloid leukemia were seen in patients who were treated with olaparib. Olaparib is a well-tolerated drug, with AEs leading to treatment discontinuation in approximately 12% of patients.

Niraparib in Newly Diagnosed Ovarian Cancer (PRIMA): Hematologic Toxicity and Hypertension by Dose Group

Ritu Salani, MD, MBA:
The phase III PRIMA study compared the PARP inhibitor niraparib vs placebo as maintenance therapy in patients with newly diagnosed advanced ovarian cancer and a response to first-line platinum CT.15 The safety data from this study showed a higher rate of hematologic toxicities and hypertension, but these were manageable with dose reductions.

Olaparib + Bev vs Placebo + Bev in Advanced Ovarian Cancer (PAOLA-1): Adverse Events

Ritu Salani, MD, MBA:
PAOLA-1 was a phase III trial that showed a significant median PFS benefit for olaparib plus bevacizumab vs placebo plus bevacizumab as maintenance therapy in patients with newly diagnosed, advanced, high-grade ovarian cancer and a BRCA mutation.14 Safety results showed no significant new safety signals with the combination, although the rate of discontinuation due to AEs was somewhat higher in the combination arm vs the placebo/bevacizumab arm (20% vs 6%). The most common any grade and grade ≥3 AEs in the olaparib-containing arm were fatigue/asthenia (53% vs 5%), nausea (53% vs 2%), hypertension (46% vs 19%), and anemia (41% vs 17%). Overall, olaparib plus bevacizumab is a well-tolerated regimen, and no new malignancies or treatment-related myeloid neoplasms were reported.

PARP Inhibitors: Management of Hematologic AEs

Ritu Salani, MD, MBA:
This table provides an overview for the management of hematologic AEs associated with the use of PARP inhibitors.17 Monitoring of hematologic toxicities is important, as the safety profiles vary between agents.

The key hematologic AEs associated with PARP inhibitors are anemia, neutropenia, and thrombocytopenia. If patients develop these hematologic events, the healthcare professional should hold the therapy, then consider resuming at a lower dose when the symptoms or laboratory abnormalities have resolved.2 Subsequently, these patients need close monitoring to ensure that they can tolerate the lower dose. Patients receiving niraparib or rucaparib should be monitored weekly for the first month until it is clear that they can tolerate that dose and then monitored monthly.1,3 An individualized starting dose for niraparib has been developed to help prevent or mitigate the potential for hematologic AEs: The recommended starting dose is 200 mg/day in patients who weigh <77 kg (<170 lb) or if their baseline platelet count is lower than 150,000/μL.1 Patients receiving olaparib can be monitored monthly.2

PARP Inhibitors: Management of Nonhematologic AEs

Ritu Salani, MD, MBA:
In addition to hematologic toxicities, there are general symptoms that are class effects of PARP inhibitors.17 Most commonly, fatigue and gastrointestinal symptoms such as nausea and diarrhea. It is interesting to note that the highest frequency of these AEs occurs at treatment initiation and improves over time. Therefore, we should educate patients that these symptoms are unlikely to persist in the long term and instead are most likely to be just an initial hurdle to overcome.

For fatigue, exercise and behavioral cognitive therapy are the most widely used management approaches in our clinic. Pharmacologic options such as methylphenidate also are available; however, most patients will benefit from nonpharmacologic interventions.

Nausea typically can be managed with basic symptom management and some behavioral changes. For instance, for once-daily dosing of niraparib, patients can take this medication at nighttime so they can sleep through the nausea, and when they are awake, they can have a late meal or snack before they take their dose. Antinausea medications also can help manage these symptoms.

Diarrhea, fortunately, is not as common. However, if patients do experience it, they are advised to notify their physician as severe diarrhea can potentially lead to dehydration. Physicians also may prescribe antidiarrheal medication (loperamide) to help support the patient.

If a patient is experiencing an AE that is more common with a specific PARP inhibitor, it may be reasonable to switch to another PARP inhibitor. For example, a patient receiving niraparib who develops hematologic toxicity could be switched to olaparib, and a patient receiving olaparib twice daily who is experiencing significant nausea can be switched to once-daily niraparib and take it before bed.

When patients have concerns or symptoms preventing them from adhering to their prescribed medication, dose adjustments usually can help, including holding the therapy to let their bodies reset. That said, setting patient expectations is key with regard to nausea and fatigue.

Choosing PARP Inhibitors When Indications Overlap

Eva Y. Pan, PharmD, BCOP:
It can be challenging to determine which PARP inhibitor to use because most of the indications overlap, meaning that for any given indication 1, 2, or all 3 PARP inhibitors approved by the FDA may be options. To date, Niraparib is the only PARP inhibitor approved as frontline maintenance for epithelial ovarian cancer regardless of a biomarker (BRCA or HRD).1 If BRCA mutated, patients have the option to use olaparib, niraparib, or olaparib plus bevacizumab as first-line maintenance therapy. For patients with platinum-sensitive relapse or recurrent disease, niraparib, olaparib, or rucaparib can be used. So, how does a healthcare professional decide which PARP inhibitor to use? In addition to clinical efficacy, key factors include:

  • Copay/cost: Which PARP inhibitor is covered by a patient’s insurance varies by insurance provider, and it can be more cost effective for a patient to receive a particular PARP inhibitor over another.
  • Dosing frequency: As mentioned, niraparib is dosed once daily and may be a better option for patients who are historically noncompliant as opposed to olaparib and rucaparib which must be taken twice a day.
  • Drug metabolism and drug interactions: When patients are starting a new agent, clinical pharmacists perform a check for drug interactions against their medication history. In addition, the specialty pharmacist does another check for drug interactions before processing and filling the prescription. A patient taking strong CYP3A inducers or inhibitors should not be prescribed olaparib or rucaparib. In those patients, niraparib would be a better option. If a conflicting medication cannot be substituted, we may reduce the dosage of the PARP inhibitor or CYP3A agent and may reach out to the oncologist to work together on the best solution for the patient.
  • Safety: Niraparib can have higher rates of myelosuppression compared with olaparib or rucaparib. However, working with an individualized starting dose based on patients’ platelet count and weight, as previously discussed, should help counter the higher rates of myelosuppression observed with niraparib.

PARP Inhibitor Comparison: Target, Dose, AEs

Eva Y. Pan, PharmD, BCOP:
Olaparib and rucaparib target PARP-1, PARP-2, and PARP-3. Niraparib targets PARP-1 and PARP-2. As previously mentioned, olaparib and rucaparib are dosed twice daily, whereas niraparib is taken once daily. The starting dose for olaparib is 300 mg twice daily, niraparib is dosed at 300 mg once daily, and rucaparib is dosed at 600 mg twice daily.1-3

As a class, PARP inhibitors can cause significant gastrointestinal toxicities, and the nausea, vomiting, diarrhea can be quite severe. These agents also cause profound fatigue and potentially severe bone marrow suppression.1-3

A rare but also likely serious AE with these agents includes secondary malignancy in the form of myelodysplastic syndrome or acute myeloid leukemia.1-3

Unique AEs seen with niraparib include insomnia and hypertension.1

AEs more likely with olaparib and rucaparib include elevated serum creatinine. Olaparib also has been shown to cause hypomagnesemia and pneumonitis, and rucaparib has been shown to cause transaminitis, acid reflux, dysgeusia, and rash. 2,3

Dosing, Schedule, and Drug Interactions for PARP Inhibitors

Eva Y. Pan, PharmD, BCOP:
The dosing schedules for olaparib and niraparib can be reduced up to 2 times for toxicities and then must be discontinued.1,2 For rucaparib, there are 3 recommended dose reductions before discontinuation.3

Olaparib and rucaparib are metabolized primarily via the cytochrome P450 enzyme, which means that pharmacists need to be mindful of different drug interactions (eg, with warfarin). There are specific recommendations for dose reduction of olaparib in the presence of strong or moderate CYP3A4 inhibitors. Niraparib, because it’s metabolized by carboxylesterases, is less concerning with regard to drug interactions compared with olaparib or rucaparib.

Managing Costs for PARP Inhibitors

Eva Y. Pan, PharmD, BCOP:
One big challenge for all cancer patients is managing costs of treatment, and PARP inhibitor therapy is no exception. Most patients pay thousands of dollars in monthly copays, which can be a significant burden, especially as patients continue taking their medication for many years. Several methods can help lessen these costs:

  • Private foundations can provide medication assistance programs for ovarian cancer patients.
  • Manufacturers for all 3 PARP inhibitors approved by the FDA sponsor patient assistance programs.
  • Some specialty pharmacies, particularly those with vast resources at their disposal, also may have their own patient assistance programs in the form of grants.
  • Specialty pharmacy technicians can help obtain preauthorization and can reach out to obtain assistance funds.
  • If none of aforementioned resources is able to reduce the costs of a particular therapy, consider enrolling the patient on a clinical trial where the standard of care may be an option for the patient.

Data for Other Agents in Recurrent/Advanced Ovarian Cancer

Ritu Salani, MD, MBA:
As discussed earlier, clinically meaningful improvements in ovarian cancer have been occurring in the maintenance setting with data continuing to mature for various novel agents of interest. Beyond PARP inhibitor maintenance treatment, there are several exciting ongoing studies that have begun to yield data, as highlighted in this table.

The phase III single-arm SORAYA study is evaluating mirvetuximab soravtansine, an antibody–drug conjugate (ADC) that binds the folate receptor α and delivers a toxic maytansinoid drug, DM4.18 SORAYA enrolled 110 patients with platinum-resistant ovarian cancer and high expression levels of folate receptor α (by immunohistochemistry), which is one of the most challenging groups of patients to treat. Results presented at the SGO 2022 annual meeting showed an ORR of 32.4%, which is higher than historically seen with CT.19 Studies of mirvetuximab in ovarian cancer are ongoing in both the platinum-resistant and platinum-sensitive settings.

There also is growing excitement in ovarian cancer treatment about continuing PARP inhibition combined with a new agent after developing resistance to previous PARP inhibitor therapy. EFFORT is a randomized phase II study of adavosertib, a WEE1-targeted tyrosine kinase inhibitor, plus the PARP inhibitor olaparib vs olaparib in 104 women with ovarian cancer who experienced disease progression while on a PARP inhibitor.20 Early results show a trend toward higher ORR in patients with wild-type BRCA disease: 39% with the combination vs 31% with olaparib alone.

Similarly, the ongoing phase III OReO/ENGOT Ov-38 study is evaluating olaparib maintenance retreatment vs placebo in a planned 220 patients with ovarian cancer who relapsed following maintenance therapy with a PARP inhibitor (including with olaparib).21 Results presented at the 2021 European Society of Medical Oncology suggested a longer median PFS (4.3 vs 2.8 months; HR: 0.57; P = .022) with olaparib rechallenge vs placebo in BRCA-mutant patients and in those with wild-type BRCA disease (5.3 vs 2.8; HR: 0.43; P = .0023). With the caveat that the data from both EFFORT and OReO are very preliminary, these are promising data that may help overcome PARP inhibitor resistance in later lines of treatment.

Upifitamab rilsodotin is an ADC targeted to cells expressing the sodium-dependent phosphate transport protein 2B (NaPi2b) and delivers the cytotoxic drug auristatin F-HPA. The ongoing phase I/II UPGRADE study is evaluating upifitamab auristatin in 48 patients with platinum-sensitive ovarian cancer and NaPi2b expression (NCT04907968). The preliminary data presented at the 2022 SGO scientific plenary session suggested this agent is well tolerated with promising antitumor activity in patients with NaPi2b-high ovarian cancer (all doses ORR: 34%; 36 mg/m2 dose ORR: 44%; 43 mg/m2 dose ORR: 27%).22

Select Ongoing Trials in First-Line Maintenance Ovarian Cancer

Ritu Salani, MD, MBA:
Several ongoing phase III trials continue to explore maintenance strategies with PARP inhibitors in ovarian cancer after first-line treatment.

The FIRST trial is comparing latinum-based CT plus bevacizumab vs standard of care (SoC) followed by maintenance bevacizumab vs SoC followed by maintenance with bevacizumab plus niraparib vs SoC plus dostarlimab followed by maintenance with bevacizumab, niraparib, and dostarlimab (NCT03602859). The planned enrollment for this study is 1405 patients, and the primary endpoint is PFS.

The ATHENA study is comparing rucaparib plus nivolumab vs rucaparib or nivolumab alone in platinum-sensitive ovarian cancer. The planned enrollment for that study is 1000 patients (NCT03522246). A press release report of early data showed that the rucaparib-alone arm met the primary endpoint of improved PFS. We await presentation of these data, which may have implications for rucaparib as perhaps the third PARP inhibitor to be approved as first-line maintenance therapy in ovarian cancer.

The DUO-O trial is also a 3-arm trial evaluating platinum-based CT plus bevacizumab (SoC) followed by maintenance bevacizumab vs SoC plus durvalumab followed by maintenance bevacizumab and durvalumab vs SoC plus durvalumab followed by maintenance bevacizumab and durvalumab and olaparib. There is also an experimental cohort with tumor BRCA mutations which will receive the same regimen as arm 3. The planned enrollment is 1374 patients, and primary endpoint is PFS.

The main takeaway from these 3 ongoing studies is that first-line maintenance therapy should be discussed with all patients with advanced epithelial ovarian cancer because it can yield a tangible benefit for the majority of patients.

It remains unclear whether PARP inhibitors are effective in early (stage I/II) ovarian cancer. We as healthcare professionals need to become more comfortable using PARP inhibitors in advanced disease while managing the associated toxicities. As discussed, some patients may benefit from switching to a different PARP inhibitor with different toxicities than their original regimen, even if the efficacy remains similar. Setting expectations with regard to toxicity concerns is critical to help patients stay adherent to these therapies, particularly in the beginning.

It is important to reiterate that patients with HRD and wild-type BRCA benefited from the PARP inhibitor niraparib vs placebo, with a median PFS of 19.6 months vs 8.2 months (HR: 0.50). Patients who were homologous recombination proficient (HRP) had moderate benefit with a median PFS of 8.1 vs 5.4 months with niraparib compared with placebo. This finding is important because this is a very high-risk population. Patients with ovarian cancer and HRP often don’t respond well to PARP inhibitors, whereas those with HRD have significant responses. I think that response to platinum CT is a good marker of who will benefit from PARP inhibitors. I explain to patients with HRP that there is a “window” of time between response to CT and becoming platinum-resistant that may be their sole opportunity to gain benefit from a PARP inhibitor.

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