Treatment Considerations for PARP Inhibitors in First-Line Maintenance Therapy in Patients With Advanced Ovarian Cancer

KEY TAKEAWAYS:

• Despite available treatments, 85% of patients with advanced ovarian cancer will experience recurrence at some point
  after chemotherapy.
• For patients with advanced ovarian cancer, emerging evidence shows that poly (ADP-ribose) polymerase (PARP) inhibitors are effective for first-line maintenance after chemotherapy.
• The choice of first-line maintenance therapy in patients with advanced ovarian cancer should be individualized based on molecular status and initial therapy.

Ovarian cancer is the fifth most common cause of cancer deaths in women and the leading cause of death among cancers of the female reproductive system in the United States. More than 21,400 women in the United States are expected to be diagnosed with the disease in 2021, and 13,770 will die from it.¹ Up to 90% of ovarian cancer cases are epithelial in origin, and 7 of every 10 epithelial ovarian cancers are high-grade serous tumors.²

First-line treatment for ovarian cancer typically involves surgical staging, followed by debulking surgery and, in most patients, platinum- and taxane-based chemotherapy with or without bevacizumab, a monoclonal antibody.³ Some patients require neoadjuvant chemotherapy to shrink the tumor before surgery. Usually, 3 cycles of chemotherapy are given before surgery, with at least 3 cycles after surgery.⁴ Adjuvant therapy with hormonal agents may also be an option for patients with tumors of specific histologic subtypes.³ Despite these treatments, 85% of patients with advanced ovarian cancer will experience recurrence at some point after chemotherapy.⁵

First-line therapy is often followed by maintenance therapy. According to Rebecca Previs, MD, a gynecologic oncologist at Duke Cancer Center in Durham, North Carolina, all patients should be offered first-line maintenance therapy. “The concept of maintenance,” Previs explains, “is to enable patients to have a higher rate of cure and to prevent the cancer from coming back, because we know once a cancer comes back, it’s even more difficult to treat.”

Whether or not a patient elects to start maintenance therapy depends on her preferences, her goals of care, and her understanding of the data. Previs counsels patients about Food and Drug Administration (FDA) approvals of all frontline maintenance options, including potential adverse effects (AEs). “Those patients who require multiple blood transfusions and multiple dose reductions are the patients who may opt not to continue maintenance therapy. It is a very personal [choice in] each patient’s cancer journey,” she said.

The concept of maintenance is to enable patients to have a higher rate of cure and to prevent the cancer from coming back, because we know once a cancer comes back, it’s even more difficult to treat.”

Choosing a Maintenance Therapy

A number of options are available for patients who elect to undergo maintenance therapy. The choice of maintenance therapy must be individualized based on the patient’s clinical features and preferences, with consideration of the National Comprehensive Cancer Network (NCCN) guideline recommendations and FDA-approved indications. For patients with stage IV disease or recurrent ascites, Previs typically recommends bevacizumab as maintenance therapy. “I have a very honest conversation with patients at the time of diagnosis and treatment to really discuss that the addition of bevacizumab, while it has shown an improvement in progression-free survival, [it has not] translated in follow-up with overall survival,” she explained. “It’s really important to break these clinical trials down to a patient level and explain, ‘What does progression-free survival mean?’ ‘How does this translate into overall survival?’ ‘What are the costs associated with additional maintenance therapy?’ By cost, I mean financial as well as the time burden to patients.”

For patients with advanced ovarian cancer, emerging evidence shows that PARP inhibitors are effective for first-line maintenance after chemotherapy.³ Two PARP inhibitors, olaparib and niraparib, were approved by the FDA in 2020 for use in this setting. Olaparib was approved for maintenance treatment of BRCA-mutated advanced epithelial ovarian, fallopian tube, or primary perineal cancer in complete or partial response to first-line platinum-based chemotherapy.⁶ Niraparib was approved for maintenance treatment in patients with advanced epithelial ovarian, fallopian tube, or primary perineal cancer who have had surgery and are in complete or partial response to first-line platinum-based chemotherapy, regardless of biomarker status.⁷ NCCN recommends PARP inhibitors in the first-line maintenance setting as well, but further specifies that olaparib alone or in combination with bevacizumab be used for maintenance in patients who received a bevacizumab-containing regimen as initial therapy.³

The question of whether to offer a PARP inhibitor as a maintenance therapy, and which one to offer, depends on a number of factors, Previs said. “What is the patient’s tumor stage, what is the grade of that tumor, and what is the specific histologic subtype?” Previs asks after primary treatment. “When [the patient] had her primary debulking, what was the volume of residual disease? What other medical problems does she have?” She also considers a patient’s age, nutritional status, transportation options, and, importantly, what the patient herself desires from treatment before making her recommendation.

“In my patient practice, I recommend that all patients with epithelial ovarian cancer undergo genetic counseling and testing,” Previs said. “At a minimum, this should be for BRCA1 and BRCA2 germline and somatic mutations. I also order testing on tumors to evaluate for homologous recombination deficiency. Together, these 2 tests inform my counseling of patients with ovarian cancer, because they really help me predict the benefit from a PARP inhibitor in the maintenance setting.”

“Those tumors that have inherent mismatch repair or DNA damage repair mechanisms—and that can be with homologous recombination [or] nonhomologous end joining—we know are also susceptible to PARP inhibitors,” she continued. “So that is why I’m offering PARP inhibitor maintenance to those patients with homologous recombination deficiency.”

Latest Data on PARP Inhibitors

Olaparib, the first PARP inhibitor approved by the FDA, is recommended by the NCCN guidelines as a maintenance drug therapy for ovarian cancer patients who have germline or somatic BRCA mutations.³ American Society of Clinical Oncology (ASCO) also recommends olaparib for maintenance in women who have, or likely have, germline or somatic BRCA mutations.²

The FDA’s approval of olaparib for frontline maintenance therapy was based on the results of the phase 3 SOLO-1 clinical trial, which compared olaparib with placebo in 391 patients with newly advanced ovarian cancer. Study results indicated that after the median follow-up of 41 months, patients with suspected or confirmed BRCA1/2 mutation who were taking olaparib had a 70% lower risk of disease progression or death than those taking placebo (Kaplan–Meier estimate of the rate of freedom from disease progression and from death at 3 years, 60% vs 27%; HR for disease progression or death, 0.30; 95% CI, 0.23-0.41; P < .001).⁸

The results of the PAOLA-1 trial similarly confirmed the benefits of olaparib when combined with bevacizumab in patients with newly diagnosed, advanced, high-grade ovarian cancer. A total of 806 patient were randomized 2:1 to receive either olaparib + bevacizumab (n = 537) or placebo + bevacizumab (n = 269). Results indicated that after a median follow-up of 22.9 months, patients in the olaparib group experienced a median progression-free survival (PFS) of 22.1 months (vs 16.6 months in the placebo group [HR for disease progression or death, 0.59; 95% CI, 0.49-0.72; P < .001]). The largest benefits were shown in patients with BRCA mutations and those with positive homologous recombination deficiency (HRD) status.⁹

NCCN guidelines include niraparib as maintenance therapy for patients with BRCA1/2 mutations. For patients who have BRCA1/2 wild-type, or whose BRCA status is unknown, NCCN guidelines include niraparib as a maintenance therapy in patients achieving partial or complete remission after platinum-based chemotherapy without bevacizumab. If the patient does not have a BRCA mutation or if her BRCA status is unknown, HRD status can help physicians determine the likely benefit to be derived from niraparib.³

Niraparib is not recommended as maintenance therapy for patients with BRCA wild-type or unknown BRCA status who have received chemotherapy with bevacizumab. In these patients, the PARP inhibitor olaparib is recommended in combination with bevacizumab. Niraparib or olaparib may be considered for patients with germline or somatic BRCA mutations who received chemotherapy with bevacizumab and achieved a partial or complete response, although data on maintenance therapy with single-agent PARP inhibitors are limited.³

ASCO guidelines include a strong recommendation that niraparib or olaparib be offered as maintenance therapy to patients with newly diagnosed stage III-IV endothelial ovarian cancer who have completely or partially responded to platinum-based first-line chemotherapy and have never received a PARP inhibitor.²

The approval of niraparib as a first-line maintenance therapy comes in the wake of results of clinical trials such as PRIMA, in which 733 patients with newly diagnosed advanced ovarian cancer were randomized to receive either niraparib or placebo after response to platinum-based chemotherapy. Median PFS with niraparib was 13.8 months vs 8.2 months with placebo (HR, 0.62; 95% CI, 0.50-0.76; P < .001).⁵

In patients with HRD tumors, median PFS was 21.9 months with niraparib compared with 10.4 months with placebo (HR for disease progression or death, 0.43; 95% CI, 0.31-0.59; P < .001). The study’s authors concluded that niraparib provided a benefit to patients with advanced ovarian cancer regardless of HRD status.⁵

“I do offer patients with HRD in their tumor niraparib maintenance,” said Previs. “In my mind, when reviewing the trials, the statistically significant benefit of progression-free survival was substantial. So, for these patients, I am strongly recommending niraparib maintenance.”

In the ENGOT-OV16/NOVA trial, 533 patients with platinum-sensitive, recurrent ovarian cancer were categorized by presence or absence of a germline BRCA mutation and randomized to receive niraparib (300 mg) or placebo once a day. In both the BRCA-mutated and wild-type groups, patients randomized to niraparib experienced significantly longer PFS than those randomized to placebo (P < .001). Median PFS was 21.0 months in the BRCA-mutated group compared with 5.5 months in the placebo group (HR, 0.27; 95% CI, 0.17-0.41; P < .001). In women who received niraparib in the overall non-gBRCA cohort, median PFS was 9.3 months vs 3.9 months (HR, 0.45; 95% CI, 0.34-0.61; 95% CI; P < .001). Those in the non-BRCA niraparib cohort who had HRD tumors had a median PFS of 12.9 months vs 3.8 months (HR, 0.38; 95% CI, 0.24-0.59; P < .001).¹⁰

“What’s different about niraparib is that this approval comes irrespective of BRCA mutational status or homologous recombination deficiency,” Previs said. “What we saw is that, regardless of those different statuses, there was an improvement in progression-free survival in all of the different groups. The biggest progression-free survival benefit, however, was in the BRCA-mutated patients, followed by the patients with homologous recombination deficiency, and then patients with homologous recombination–proficient (HRP) tumors.” For patients with HRD tumors, Previs recommends niraparib for first-line maintenance therapy.

Adverse Events and Dosing

In the ENGOT-OV16/NOVA trial, thrombocytopenia and neutropenia were reported at 3 months in 33% and 18%, respectively, of patients who received niraparib. Dose reduction due to treatment-emergent adverse events (TEAEs) occurred in 68.9% of patients overall, and the discontinuation rate due to TEAEs was 14.7%, including 3.3% due to thrombocytopenia. Further analysis revealed that lower baseline platelet counts (<180,000/µL) were associated with thrombocytopenia grade 1 or higher in 71.1% of participants and with thrombocytopenia grade 3 or higher in 42.2% of participants.¹¹

Baseline body weight was also correlated with AEs leading to dose reduction, with these events occurring more frequently in patients weighing less than approximately 58 kg (51%) compared with patients weighing at least 77 kg (33%).¹¹

Because low baseline body weight and low platelet counts were predictive of AEs in patients who received 300 mg of niraparib daily, the starting dose was reduced to 200 mg in patients who weighed less than 77 kg or who had platelet counts of less than 150,000/µL in ongoing clinical trials.¹¹

Starting doses were also individualized in the NORA study, which randomized 265 patients with platinum-sensitive recurrent ovarian cancer to receive either niraparib or placebo. Patients weighing less than 77 kg and with a platelet count of less than 150,000/µL received 200 mg of niraparib daily, and patients weighing at least 77 kg and with a platelet count of at least 150,000/µL received 300 mg of niraparib daily.¹²

Previs explained that she introduces niraparib at a dose of 200 mg daily for patients weighing less than 77 kg and whose starting platelet count is less than 150,000/µL. For patients beginning at a dose of 300 mg of niraparib daily, Previs ensures they understand that fatigue, anemia, and thrombocytopenia are commonly experienced.

“What is really exciting about niraparib is that it comes in capsules that are easily administered,” she said. “They’re in 100-mg increments. So based on follow-up data, we know that if we do have to reduce a patient’s dose to 200 mg based on their hematologic blood counts, then I can tell my patient that it is as effective.”

An Emerging PARP Inhibitor

Another PARP inhibitor, veliparib, is currently being tested in ovarian cancer. The VELIA trial studied veliparib added to first-line induction chemotherapy and continued as maintenance monotherapy in 1140 patients with previously untreated stage III or IV high-grade serous ovarian carcinoma. Overall, patients who received veliparib achieved a median PFS duration of 23.5 months in the induction and maintenance groups compared with 17.3 months for placebo (HR for disease progression or death, 0.68; 95% CI, 0.56-0.83; P < .001).¹³

For patients with a BRCA mutation, median PFS was 34.7 months in patients taking veliparib throughout the study, compared with 22.0 months in the control group (HR, 0.44; 95% CI, 0.28-0.68; P < .001). For patients with positive HRD status, median PFS was 31.9 months compared with 20.5 months in the control group (HR, 0.57; 95% CI, 0.43-0.76; P < .001).¹³

Looking Forward

The past few years of ovarian cancer research have yielded new maintenance therapies but, according to Previs, more research is needed for women who do not have a BRCA germline or somatic mutation and who do not have HRD tumors.

“We know that the addition of niraparib offers a small improvement in progression-free survival in the frontline setting, but these patients aren’t deriving the same degree of benefit as patients who have an actual mutation or have HRD in their tumor,” she said. “So, I would love for future clinical trials to really focus on this patient population and think about ways that we can make these tumors more susceptible to the great maintenance therapies that we have available for a lot of our patients.”n

REFERENCES

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8. Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018;379(26):2495-2505. doi:10.1056/NEJMoa1810858

9. Ray-Coquard I, Pautier P, Pignata S, et al. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. N Engl J Med. 2019;381(25):2416-2428. doi:10.1056/NEJMoa1911361

10. Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375(22):2154-2164.doi:10.1056/NEJMoa1611310

11. Berek JS, Matulonis UA, Peen U, et al. Safety and dose modification for patients receiving niraparib. Ann Oncol. 2018;29(8):1784-1792. doi:10.1093/annonc/mdy181

12. Wu XH, Zhu JQ, Yin RT, et al. Niraparib maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer using an individualized starting dose (NORA): a randomized, double-blind, placebo-controlled phase III trial. Ann Oncol. 2021;32(4):512-521. doi:10.1016/j.annonc.2020.12.018

13. Coleman RL, Fleming GF, Brady MF, et al. Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer. N Engl J Med. 2019;381(25):2403-2415. doi:10.1056/NEJMoa1909707

Editor’s Note: Interview quotes slightly modified for readability.

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