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Management of ovarian cancer associated with BRCA and other genetic mutations

Management of ovarian cancer associated with BRCA and other genetic mutations
Authors:
Kathleen M Moore, MD
Merry Jennifer Markham, MD, FACP, FASCO
Section Editors:
Barbara Goff, MD
Don S Dizon, MD, FACP
Deputy Editor:
Sadhna R Vora, MD
Literature review current through: Jun 2022. | This topic last updated: Jun 21, 2022.

INTRODUCTION — In the United States, ovarian cancer is the second most common gynecologic cancer, but it is the deadliest of the gynecologic cancers [1]. A female's lifetime risk of developing ovarian cancer is 1.3 percent [2]. While the majority of diagnosed cases of epithelial ovarian cancer (EOC) are not associated with genetic mutations, an estimated 18 percent of cases are associated with germline mutations, most of which are attributable to breast cancer susceptibility gene 1 (BRCA1) or breast cancer susceptibility gene 2 (BRCA2) mutations [3-5]. High-grade serous is the most common histology associated with germline BRCA1/2 mutations, but germline mutations have been identified in all epithelial histologies, except for mucinous, supporting genetic testing of all patients with EOC [6]. Patients with Lynch syndrome, characterized by a mutation in a DNA mismatch-repair gene (eg, mutL homolog 1 [MLH1], mutS homolog 2 [MSH2], mutS homolog 6 [MSH6], or postmeiotic segregation increased 2 [PMS2]), however, are more likely to have nonserous EOC [7].

Management of BRCA-associated ovarian cancers is discussed here. Other issues, including management of ovarian cancer that is not associated with genetic mutations, as well as cancer risks among patients with BRCA mutations, are discussed elsewhere.

(See "Overview of epithelial carcinoma of the ovary, fallopian tube, and peritoneum".)

(See "First-line chemotherapy for advanced (stage III or IV) epithelial ovarian, fallopian tube, and peritoneal cancer".)

(See "Medical treatment for relapsed epithelial ovarian, fallopian tube, or peritoneal cancer: Platinum-sensitive disease".)

(See "Medical treatment for relapsed epithelial ovarian, fallopian tube, or peritoneal cancer: Platinum-resistant disease".)

(See "Cancer of the ovary, fallopian tube, and peritoneum: Surgical options for recurrent cancer".)

(See "Cancer risks and management of BRCA1/2 carriers without cancer".)

GERMLINE AND SOMATIC TESTING FOR GENETIC ALTERATIONS — All patients with a diagnosis of ovarian, fallopian tube, or peritoneal cancer should have a genetic risk evaluation, irrespective of their family history, as the results may impact treatment decisions. (See "Overview of epithelial carcinoma of the ovary, fallopian tube, and peritoneum", section on 'Testing for hereditary cancer syndromes'.)

If germline testing is negative, we proceed with somatic BRCA testing to determine who may most benefit from a poly(ADP-ribose) polymerase (PARP) inhibitor. (See 'Those with somatic BRCA mutations' below.)

Multiple commercial and academic tumor genotyping assays exist for detection of somatic genetic alterations [8,9]. Guidelines favor testing patients for both germline and somatic mutations in order to optimize identification of germline mutations (which would open access to cascade testing of family members). Additionally, this strategy would expand identification of patients who may benefit from PARP inhibitors. Relying only on somatic testing to identify patients for "reflex" genetic testing may miss up to 5 percent of germline mutations due to differences in test coverage, variant classification, and the inability to detect large rearrangements by available commercial next-generation sequencing [10]. Relying only on germline testing will miss approximately 7 percent of patients who have somatic mutations only [11]. Improvement of testing sequencing and strategy remains an urgent area of investigation.

For patients with recurrent ovarian cancer, genomic testing for DNA mismatch repair-deficient or microsatellite-instable ovarian cancer should also be performed, given the option of immunotherapy as later-line treatment. (See 'Mismatch repair deficiency/high microsatellite instability' below.)

EPIDEMIOLOGY OF BRCA-ASSOCIATED OVARIAN CANCERS — Approximately 13 to 15 percent of ovarian cancers are attributable to heritable mutations in BRCA1 and 2, although somatic BRCA mutations have also been identified in ovarian cancer specimens.

The Cancer Genome Atlas Research Network evaluated 316 stage II through IV high-grade serous epithelial ovarian cancer specimens and found that 3 percent of the cases showed somatic BRCA1/2 mutations, compared with germline BRCA1 mutations in 9 percent and germline BRCA2 mutations in 8 percent [12].

In another study, 367 individuals with 390 ovarian carcinomas were analyzed; 88 germline mutations were identified among these cases [11]. Of the 88 germline mutations, 49 (56 percent) were in BRCA1, 17 (19 percent) were in BRCA2, and 22 (25 percent) were in other homologous-recombination genes (BRCA1-associated RING domain 1 [BARD1], BRCA-interacting protein 1 [BRIP1], checkpoint kinase 1 [CHEK1], checkpoint kinase 2 [CHEK2], family with sequence similarity 175, member A [FAM175A], nibrin [NBN], partner and localizer of BRCA2 [PALB2], RAD51 paralog C [RAD51C], RAD51 paralog D [RAD51D]). Thirty-two of the 367 patients had 35 somatic mutations, including 19 (54 percent) in BRCA1 and 6 (17 percent) in BRCA2, for a total somatic BRCA1/2 mutation rate of 7 percent out of 367.

Patients with BRCA gene mutations have a greatly increased risk of ovarian and breast cancer (table 1). Further details of BRCA mutations as a risk factor for ovarian cancer are found elsewhere. (See "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Incidence and risk factors", section on 'BRCA variants'.)

The lifetime risks for other cancers found in BRCA mutation carriers are also discussed elsewhere. (See "Cancer risks and management of BRCA1/2 carriers without cancer", section on 'Cancer risks in BRCA1/2 carriers'.)

NEWLY DIAGNOSED BRCA-ASSOCIATED OVARIAN CANCERS — In general, the approach to newly diagnosed ovarian cancer among BRCA mutation carriers mirrors that for patients without a BRCA mutation. (See "Overview of epithelial carcinoma of the ovary, fallopian tube, and peritoneum".)

However, special considerations are present specific to this population; this is discussed in the sections below.

Components of therapy

Surgery — The surgical management of BRCA mutation carriers with ovarian cancer is the same as of those without BRCA mutations and is discussed elsewhere. (See "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Surgical staging".)

Surgical considerations, including risk-reducing salpingo-oophorectomy as well as the option of opportunistic salpingectomy, for BRCA mutation carriers without ovarian cancer are discussed elsewhere. (See "Cancer risks and management of BRCA1/2 carriers without cancer" and "Opportunistic salpingectomy for ovarian, fallopian tube, and peritoneal carcinoma risk reduction".)

Adjuvant chemotherapy — The indications and approach to adjuvant chemotherapy for those with newly diagnosed ovarian cancer, irrespective of BRCA mutation status, are discussed elsewhere. (See "Adjuvant therapy of early-stage (stage I and II) epithelial ovarian, fallopian tube, or peritoneal cancer", section on 'Selection of patients' and "First-line chemotherapy for advanced (stage III or IV) epithelial ovarian, fallopian tube, and peritoneal cancer".)

Retrospective data suggest that BRCA carriers with ovarian cancer may experience greater benefits with intraperitoneal (IP) chemotherapy compared with noncarriers, and, in particular, with platinum agents (which lead to DNA crosslinking, leading to cell death in BRCA-mutated tumors due to deficient cellular DNA repair mechanisms). It is unclear, however, if the benefit for intravenous (IV)/IP treatment persists if poly(ADP-ribose) polymerase (PARP) inhibitors are used as maintenance, given the absence of data addressing this question. Therefore IV therapy without IP treatment is also acceptable.

In order to be actionable, the BRCA status of patients must be ascertained at initial diagnosis.

In the randomized, phase III clinical trial, GOG 172, which tested intraperitoneal chemotherapy versus intravenous (IV) chemotherapy in stage IIIC epithelial ovarian cancer (EOC) or primary peritoneal carcinoma, aberrant BRCA1 expression was an independent predictor for improved survival in patients randomized to the intraperitoneal arm (hazard ratio [HR] 0.67, 95% CI 0.47-0.97) [13]. Of 393 patients with archival tissue available, 189 (48 percent) had aberrant BRCA1 (evaluated by immunohistochemistry staining), and 204 (52 percent) had normal expression.

One-hundred patients with high-grade ovarian cancer who were treated with adjuvant intraperitoneal chemotherapy at a single institution between 2005 and 2016 were identified and had median follow-up of 47 months [14]. Seventy-seven of the 100 patients underwent BRCA testing and 25 (32 percent) were BRCA positive, including 23 with germline mutations and two with somatic mutations. The median progression-free survival (PFS) was longer in the BRCA mutation arm: median PFS not reached compared with 17.3 months in BRCA-negative group (HR 0.38, 95% CI 0.11-0.73).

PARP inhibitor maintenance therapy — Poly(ADP-ribose) polymerase (PARP) inhibitors block the repair of DNA single-strand breaks, and, for tumors associated with BRCA mutations, they result in cell death due to inefficiencies in DNA cell repair mechanisms. Our approach is generally consistent with guidelines from the American Society of Clinical Oncology [15].

All patients with newly diagnosed ovarian cancer require genetic counseling and genetic and somatic testing for BRCA mutations. We suggest maintenance PARP inhibition for patients with advanced ovarian cancer and a germline or somatic mutation in BRCA1 or BRCA2 and a response to front-line, platinum-based therapy. Some, but not all, UpToDate contributors also offer maintenance PARP inhibitors to such patients with earlier-stage disease, although they have not been evaluated in this setting.

In addition, for patients with a BRCA1 or BRCA2 mutation deemed to be at a high risk of recurrence (eg, ascites, pleural effusion) in whom bevacizumab will be administered with a conventionally dosed IV chemotherapy regimen, we suggest the addition of olaparib during maintenance bevacizumab.

The following PARP inhibitors have been evaluated:

Olaparib, with or without bevacizumab, has regulatory approval in the United States by the US Food and Drug Administration (FDA) for the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA-mutated advanced EOC who are in complete or partial response to first-line platinum-based chemotherapy [16].

Approval for olaparib monotherapy was based on the phase III SOLO1 trial, in which 391 patients with advanced, high-grade, BRCA-associated serous or endometrioid ovarian cancer who had a complete or partial response to front-line, platinum-based chemotherapy were randomly assigned to maintenance with olaparib or placebo [10]. Most (388) had a germline BRCA mutation, and no patients received bevacizumab. At a median follow-up of 41 months, olaparib resulted in a lower three-year rate of disease progression or death compared with placebo (60 versus 27 percent; HR for disease progression or death 0.30, 95% CI 0.23-0.41) [10], with no detriment in health-related quality of life [17]. At a median follow-up of five years, median PFS was 56 versus 14 months, in the olaparib versus placebo group [18]. In an interim analysis of overall survival (OS; data maturity, 21 percent), three-year rate of freedom from death for olaparib versus placebo was 84 versus 80 percent (HR for death 0.95, 95% CI 0.60-1.53) [10]. Grade 3 or 4 toxicities were frequent with olaparib (39 versus 18 percent), with anemia and neutropenia being the most common severe adverse events. Acute myeloid leukemia occurred in 3 of 260 patients (1 percent) in the olaparib group and in none of the 130 patients receiving placebo. Analysis of long-term toxicity data will further inform use of front-line maintenance PARP inhibition.

The approval for olaparib plus bevacizumab was supported by results of the PAOLA-1 trial. In this trial, patients with advanced, high-grade, serous, or endometrioid cancers who had responded to chemotherapy plus bevacizumab were randomly assigned to maintenance bevacizumab with or without olaparib. Among the subgroup with BRCA-positive ovarian cancer, the combination of olaparib plus bevacizumab improved PFS over bevacizumab alone (37 versus 22 months; HR 0.31, 95% CI 0.20-0.47) [19]. However, it is unclear whether bevacizumab improved efficacy relative to olaparib alone, a question this trial was not designed to answer.

The discussions above are largely driven by data in patients with germline BRCA mutations (eg, SOLO1 almost exclusively enrolled patients with germline BRCA mutations, with only 2 of 391 patients having a somatic mutation in BRCA only). Further rationale for expanding use of front-line olaparib maintenance to include those with somatic BRCA mutations is extrapolation from the recurrent setting, discussed above. (See 'Germline and somatic testing for genetic alterations' above.)

NiraparibNiraparib has FDA approval as maintenance therapy in the first-line setting, irrespective of tumor BRCA status [20]. In the PRIMA trial, patients with advanced ovarian cancer who had responded to first-line, platinum-based chemotherapy were randomly assigned to niraparib or placebo for 36 months. For the subgroup with BRCA-associated cancers, niraparib prolonged PFS compared with placebo (22.1 versus 10.9 months; HR 0.40, 95% CI 0.27-0.62) [21].

Veliparib – Results for maintenance veliparib have also been reported, but veliparib does not have regulatory approval in the United States. In the VELIA trial, patients with stage III or IV, high-grade, serous ovarian cancer were randomly assigned to treatment in one of three arms: chemotherapy plus placebo followed by maintenance placebo (control), chemotherapy plus veliparib followed by maintenance placebo (chemotherapy only), or chemotherapy plus veliparib followed by maintenance veliparib (veliparib throughout) [22]. Compared with placebo, administration of veliparib throughout was associated with improvement in PFS among patients with BRCA-mutated cancers (35 versus 22 months; HR 0.44, 95% CI 0.28-0.68).

RucaparibRucaparib does not have regulatory approval in any country for use as front-line maintenance. The ATHENA mono trial was presented at the American Society of Clinical Oncology Annual meeting in 2022, but has not yet been published [23]. The randomized phase III trial evaluated monotherapy rucaparib compared with placebo in patients undergoing surgical cytoreduction and responding to platinum doublet chemotherapy. The homologous recombination deficiency population experienced a PFS benefit with rucaparib versus placebo (29 versus 11 months; HR 0.47, 95% CI 0.31-0.72), as did the overall population (20 versus 9.2 months; HR 0.52, 95% CI 0.40-0.68). ATHENA has a second component of the study which compares rucaparib with rucaparib nivolumab. That portion of the study has not yet reported.

Further details of these trials, which also included patients whose cancers were not associated with BRCA mutations, are found elsewhere. Subset analysis for those with homologous recombination-deficient tumors is found further below in this topic. (See "First-line chemotherapy for advanced (stage III or IV) epithelial ovarian, fallopian tube, and peritoneal cancer", section on 'BRCA-wildtype cancers that are homologous recombination proficient' and 'Other homologous recombination deficiencies' below.)

Adverse effects of PARP inhibitors — Adverse effects of poly(ADP-ribose) polymerase (PARP) inhibitors are discussed elsewhere. (See "First-line chemotherapy for advanced (stage III or IV) epithelial ovarian, fallopian tube, and peritoneal cancer", section on 'Adverse effects'.)

RECURRENT BRCA-ASSOCIATED OVARIAN CANCERS

Definition of platinum-sensitive versus platinum-resistant recurrence — Patients with a platinum-free interval (PFI) of six months or longer are considered to have "platinum-sensitive" disease, while those with a PFI of less than six months are considered to have "platinum-resistant" disease. Many aspects of the management of recurrent BRCA-associated ovarian cancers, including initial chemotherapy selection, are similar to the management of non-BRCA-associated recurrent disease. These issues are discussed elsewhere. (See "Medical treatment for relapsed epithelial ovarian, fallopian tube, or peritoneal cancer: Platinum-sensitive disease" and "Medical treatment for relapsed epithelial ovarian, fallopian tube, or peritoneal cancer: Platinum-resistant disease".)

The sections below focus on specific differences between management of BRCA-associated recurrent ovarian cancer and such cancers without associated BRCA mutations. Importantly, much of the data below come from clinical trials of people with BRCA-associated ovarian cancer that had recurred and who were not treated with maintenance poly(ADP-ribose) polymerase (PARP) inhibitors in the adjuvant (or first-line) setting.

Overview of PARP inhibitors for recurrent BRCA-associated ovarian cancers — Multiple poly(ADP-ribose) polymerase (PARP) inhibitors have achieved approval for use in patients with recurrent ovarian cancer associated with a BRCA mutation, in different settings:

Maintenance after retreatment with chemotherapy – In regards to maintenance, single-agent niraparib, rucaparib, and olaparib are approved for use in patients with recurrent ovarian cancer who are PARP inhibitor naïve and whose disease has responded to platinum-based retreatment (regardless of BRCA mutation status). (See 'Maintenance' below.)

Subsequent-line treatment – In regards to subsequent-line treatment (see 'Retreatment with platinum-based chemotherapy' below):

OlaparibOlaparib has US Food and Drug Administration (FDA) approval for use in patients with PARP-inhibitor-naïve recurrent ovarian cancer associated with a germline BRCA mutation as single-agent therapy after three or more prior lines of treatment. Relapse may be either platinum sensitive or platinum resistant. (See 'Platinum-sensitive disease' below and 'Olaparib' below.)

RucaparibRucaparib is indicated for use in patients with PARP-inhibitor-naïve recurrent ovarian cancer and a known BRCA mutation (either germline or somatic) after at least two prior lines of treatment. Relapse may be either platinum sensitive or platinum resistant. (See 'Rucaparib not used in this setting' below.)

NiraparibNiraparib is FDA approved for treatment of PARP-inhibitor-naïve advanced ovarian cancer that has been treated with three or more prior chemotherapy regimens and is associated with homologous recombination deficiency-positive status, defined by either 1) a deleterious or suspected deleterious BRCA mutation, or 2) genomic instability, with progression more than six months after response to the last platinum-based chemotherapy. Genomic instability is identified by the FDA-approved companion diagnostic test for niraparib based on the presence of three biomarkers: loss of heterozygosity, telomeric allelic imbalance, and large-scale state transitions. (See 'Other homologous recombination deficiencies' below.)

In addition, the FDA approvals are accompanied by a companion diagnostic test (BRACAnalysis CDX) to identify patients with advanced ovarian cancer who are candidates for these treatments.

Platinum-sensitive disease

Retreatment with platinum-based chemotherapy — Patients who relapse six months or longer after receiving initial therapy with a platinum-based treatment are more likely than others to respond to retreatment with a chemotherapy regimen that contains a platinum agent (eg, carboplatin, cisplatin). This is regardless of whether they have BRCA-associated disease or not. Further details are discussed elsewhere. (See "Medical treatment for relapsed epithelial ovarian, fallopian tube, or peritoneal cancer: Platinum-sensitive disease" and "Medical treatment for relapsed epithelial ovarian, fallopian tube, or peritoneal cancer: Platinum-resistant disease".)

For BRCA carriers with platinum-sensitive disease who did not undergo maintenance PARP inhibitor therapy in the first-line (or adjuvant) setting and who are not deemed to be candidates for or prefer to avoid further treatment with platinum, an appropriate alternative is to administer a PARP inhibitor, which has shown a progression-free survival (PFS) benefit over nonplatinum chemotherapy in a randomized trial.

In the phase III SOLO3 trial, among 266 patients who were BRCA carriers; never treated with a PARP inhibitor previously; and had platinum-sensitive, recurrent ovarian cancer, olaparib improved both objective response rate (ORR; 72 versus 51 percent) and PFS (13 versus 9 months; hazard ratio [HR] 0.62, 95% CI 0.43-0.91) relative to nonplatinum chemotherapy (of the treating clinician's choice) [24]. The most common adverse events with olaparib were nausea (65 versus 34 percent) and anemia (50 versus 25 percent), and with chemotherapy were palmar-plantar erythrodysesthesia (36 versus 1 percent) and nausea. Most common grade ≥3 adverse events in either arm were anemia (21 versus 0 percent), palmar-plantar erythrodysesthesia (0 versus 12 percent), and neutropenia (6 versus 11 percent) for olaparib and chemotherapy, respectively.

The PARP inhibitor rucaparib has also demonstrated PFS improvements over chemotherapy in a randomized trial in PARP-inhibitor-naïve patients whose cancer had progressed on ≥2 prior chemotherapy regimens (7.4 versus 5.7 months; HR 0.67, 95% CI 0.52-0.86) [25]. Patients assigned to the chemotherapy arm of this trial received platinum-based chemotherapy if they had platinum-sensitive disease, or weekly paclitaxel if they had partially platinum-sensitive disease or platinum-resistant disease.

Among the 74 patients with platinum-sensitive disease (progression ≥12 months), PFS was 12.9 versus 9.6 months, respectively (HR 0.69, 95% CI 0.37-1.29). Those with partially platinum-sensitive disease (progression within ≥6 months to <12 months) experienced a PFS of 8.0 versus 5.5 months (HR 0.40, 95% CI 0.24-0.65).

Among the 23 patients with reversion mutations (which restore function to BRCA1 and BRCA2), there was no benefit with PARP inhibitors over chemotherapy (HR 2.8 favoring chemotherapy, 95% CI 0.99-7.8).

In the overall study, rucaparib resulted in serious adverse events in 27 percent, versus 12 percent in the chemotherapy group.

It is not indicated to treat those with platinum-resistant disease as a later line therapy. These are discussed below. (See 'Rucaparib not used in this setting' below.)

Further data regarding olaparib, rucaparib, and niraparib, which come from trials enrolling patients with both platinum-sensitive and platinum-resistant relapse, are discussed below. (See 'Other homologous recombination deficiencies' below and 'PARP inhibitors' below.)

Maintenance — Several trials suggest that patients with platinum-sensitive disease achieve better response rates and PFS using maintenance after response to chemotherapy.

Data regarding available agents are discussed below, as is choosing between them. (See 'PARP inhibition' below and 'Angiogenesis inhibition' below and 'Choosing between a PARP inhibitor and an angiogenesis inhibitor' below.)

PARP inhibition — For patients with platinum-sensitive relapsed ovarian cancer with a partial or complete response to platinum-based chemotherapy and who are previously untreated with a poly(ADP-ribose) polymerase (PARP) inhibitor, niraparib, olaparib, and rucaparib are approved by the FDA for maintenance therapy [16,20,26].

While PFS outcomes are improved with these agents regardless of BRCA mutation status, the effect may be more pronounced among BRCA carriers.

Niraparib – In the phase III NOVA study, 553 patients with platinum-sensitive, previously PARP-inhibitor-untreated, recurrent ovarian cancer were randomly assigned after completion of platinum-based chemotherapy in a 2:1 ratio to niraparib maintenance or placebo [27]. Compared with placebo, niraparib increased PFS in all cohorts, with improvements in the group with genomic BRCA mutations as follows: 21.0 versus 5.5 months (HR 0.27, 95% CI 0.17-0.41). In a subsequent letter to providers, these advantages did not translate to overall survival (OS) benefits (44 versus 42 months with placebo in the genomic BRCA group) [28]. OS results were likely influenced by treatment crossover, however, as patients in the control group likely received a subsequent PARP inhibitor after progression.

The most common severe toxicities associated with niraparib were hematologic, but myelodysplastic syndrome occurred in a small percentage of patients. Overall results of this study are discussed elsewhere. (See "Medical treatment for relapsed epithelial ovarian, fallopian tube, or peritoneal cancer: Platinum-sensitive disease", section on 'Niraparib'.)

Olaparib – Positive results were observed in the phase III SOLO2/ENGOT-Ov21 trial, in which 295 patients with relapsed, platinum-sensitive, germline BRCA-associated, high-grade serous ovarian cancer or high-grade endometrioid cancer who had received at least two lines of previous chemotherapy and were previously PARP-inhibitor-untreated were randomly assigned in a 2:1 ratio to olaparib maintenance or placebo [29]. Those receiving olaparib experienced improved PFS (19.1 versus 5.5 months; HR 0.30, 95% CI 0.22-0.41). In subsequent reporting, median OS was 52 months with olaparib versus 39 months with placebo (HR 0.74, 95% CI 0.54-1.00) [30].

Grade 3 or higher adverse events occurred in 18 percent of those receiving olaparib versus 8 percent of those receiving placebo. Olaparib maintenance therapy did not have a detrimental effect on health-related quality of life outcomes compared with placebo [31].

Similarly, a subanalysis of Study 19, which enrolled those with platinum-sensitive, high-grade, recurrent epithelial ovarian cancer, evaluated the outcomes of maintenance therapy of olaparib specifically in patients with a known BRCA mutation (either germline or somatic) and suggested that the clinical benefit was greatest among these patients [32]. Patients with a BRCA mutation had a benefit in PFS with olaparib compared with placebo (median, 11 versus 4 months; HR 0.18, 95% CI 0.10-0.31), with a trend toward improved OS (HR 0.73, 95% CI 0.45-1.17), which became more pronounced at longer follow-up (>5 years) [33,34]. By contrast, patients without a BRCA mutation had a smaller PFS benefit (median, 7 versus 5.5 months; HR 0.54, 95% CI 0.34-0.85), but no benefit in OS (HR 0.99, 95% CI 0.63-1.55). A post-hoc analysis of patients with BRCA mutations that excluded those from sites where any crossover occurred demonstrated an improved OS with olaparib (HR 0.52, 95% CI 0.28-0.970). This implies that later treatment with olaparib may have confounded the OS endpoint from the primary trial [35]. Full results of Study 19 are discussed elsewhere. (See "Medical treatment for relapsed epithelial ovarian, fallopian tube, or peritoneal cancer: Platinum-sensitive disease", section on 'Olaparib'.)

Rucaparib – In the phase III ARIEL3 trial, 564 patients with relapsed, high-grade, serous or endometrioid ovarian carcinoma, all of whom had received ≥2 previous platinum-based therapies and achieved a complete or partial response to their most recent platinum-based treatment and were previously PARP-inhibitor-untreated, were randomly assigned in a 2:1 ratio to maintenance therapy with rucaparib or to placebo [36]. In contrast to other studies of PARP inhibitors, patients were permitted to enroll in this study even if they had residual bulky disease (≥2 cm). Rucaparib improved PFS among those with a known genomic or somatic BRCA mutation (16.6 versus 5.4 months; HR 0.23, 95% CI 0.16-0.34) [37]. Full details of this trial are discussed elsewhere. (See "Medical treatment for relapsed epithelial ovarian, fallopian tube, or peritoneal cancer: Platinum-sensitive disease", section on 'Rucaparib'.)

Angiogenesis inhibition — Results of trials of the angiogenesis inhibitor bevacizumab with and following chemotherapy were not stratified according to BRCA mutation status. Results in the general population of patients with platinum-sensitive relapse are discussed elsewhere. (See "Medical treatment for relapsed epithelial ovarian, fallopian tube, or peritoneal cancer: Platinum-sensitive disease", section on 'Angiogenesis inhibitors'.)

Choosing between a PARP inhibitor and an angiogenesis inhibitor — Choice between a poly(ADP-ribose) polymerase (PARP) inhibitor and an angiogenesis inhibitor as maintenance therapy depends on prior treatment history.

For those with prior exposure to a PARP inhibitor – There are no data to inform use of PARP maintenance after platinum-sensitive relapse among patients who received a PARP inhibitor as maintenance treatment following first-line treatment. In the absence of prospective data, UpToDate contributors are divided in their approach:

Some UpToDate contributors opt for bevacizumab if the recurrence recurred on, or within 12 months of, the last dose of maintenance PARP inhibitor, and retreatment with a PARP inhibitor if the recurrence occurred more than 12 months from the last dose of maintenance PARP inhibitor.

However, other UpToDate contributors consider either bevacizumab or a PARP inhibitor to be an appropriate maintenance option for PARP-exposed patients with a platinum-sensitive recurrence, irrespective of interval since last dose of PARP inhibitor.

For those without prior exposure to a PARP inhibitor – For those with platinum-sensitive relapse of BRCA-associated cancers, without prior exposure to a poly(ADP-ribose) polymerase (PARP) inhibitor, we suggest a PARP inhibitor rather than bevacizumab as maintenance therapy (bevacizumab being the preferred option for those without BRCA mutations). Considerations in patients who have not received prior PARP inhibitors are as follows.

There have been no trials directly comparing an antiangiogenesis inhibitor (bevacizumab) with and following platinum-based chemotherapy versus a PARP inhibitor following response to platinum-based chemotherapy.

With some caveats, which will be discussed, some observations based on cross-trial comparisons may be made. Among patients with BRCA-associated cancers, the PFS HRs favoring use of a PARP inhibitor as maintenance are overwhelmingly positive, and statistically significant, at 0.27, 0.23, and 0.30 for NOVA, ARIEL3, and SOLO2, respectively [27,29,36]. The median PFS for these three trials ranges from 16.6 to 21 months with use of a PARP inhibitor as compared with only 5.5 months for placebo.

Among patients unselected for BRCA mutation status, the HRs for PFS in favor of use of bevacizumab were 0.48 and 0.63 in OCEANS and GOG 213, respectively, and statistically significant. Importantly, GOG 213 also demonstrated a statistically significant improvement in OS with an HR of 0.823. Subsequently, preliminary results of AGO-OVAR 2.21 support carboplatin and pegylated liposomal doxorubicin plus bevacizumab as another standard-of-care option (although this trial did not compare treatments with versus without bevacizumab). When one looks at the median PFS for platinum doublets plus bevacizumab, they range from 11.7 to 13.8 months (from the start of chemotherapy, as discussed above).

Acknowledging the lack of data for BRCA-associated cancers that responded to induction chemotherapy and then received bevacizumab, the degree of benefit for use of PARP inhibitors makes this the preferred choice in a PARP inhibitor-naïve patient with a BRCA-associated cancer and response to induction chemotherapy.

However, comparisons of the trials that have reported on these two strategies must be interpreted with caution, given discrepant study designs and inclusion criteria. Notable differences between the trials were as follows:

The three randomized phase III trials of maintenance PARP inhibitors (NOVA, ARIEL3, and SOLO2) only enrolled patients who had responded to induction chemotherapy. By contrast, the studies evaluating bevacizumab concurrently and following chemotherapy for platinum-sensitive relapse (OCEANS trial and GOG 213) included patients who responded, as well as those who did not respond, to platinum-based therapy.

The time-to-event calculations for PFS in the PARP inhibitor trials start from the end of platinum-based chemotherapy. In the bevacizumab trials, they start from the beginning of chemotherapy.

The PARP inhibitor trials included subset analyses of BRCA versus non-BRCA-associated cancers, while these analyses are not available for the bevacizumab trials.

The PARP inhibitor trials enrolled patients who had high-grade serous or high-grade endometrioid disease only. All histologies (including clear cell and mucinous) were allowed on the bevacizumab trials.

While recognizing the limitations in the data, we continue to prefer PARP inhibitors as maintenance therapy for patients with platinum-sensitive relapse and response to platinum-based chemotherapy, provided that they were not previously exposed to a PARP inhibitor.

Selection between the two regimens in BRCA-wildtype tumors is discussed elsewhere. (See "Medical treatment for relapsed epithelial ovarian, fallopian tube, or peritoneal cancer: Platinum-sensitive disease", section on 'Choice of therapy'.)

Platinum-resistant disease

Approach to treatment selection — Most patients with platinum-resistant relapse will have had prior exposure to PARP inhibitors as maintenance treatment in an earlier line of treatment. For these patients, either single-agent chemotherapy or a PARP inhibitor are appropriate options, although we acknowledge that the trials below examined use of PARP inhibitors in those without prior exposure to these agents. Nonetheless, particularly in multiply relapsed platinum-resistant disease, there are likely diminishing returns with further lines of chemotherapy and known toxicities, and as such, we consider a PARP inhibitor a reasonable option.

For patients who have not been exposed to a PARP inhibitor and present with platinum-resistant relapse, we suggest a PARP inhibitor, given evidence of improved PFS over chemotherapy in randomized trials in patients with multiply relapsed disease, as discussed below. We acknowledge that data are lacking among patients with first relapse, but we consider PARP inhibitors to be an appropriate option in these patients as well if they have no prior exposure to these agents, extrapolating from data in other settings. Chemotherapy is an appropriate alternative, however. (See 'PARP inhibitors' below.)

Chemotherapy — Decisions regarding chemotherapy versus use of PARP inhibitors are discussed above. (See 'Approach to treatment selection' above.)

Selection of chemotherapy agents is discussed elsewhere. (See "Medical treatment for relapsed epithelial ovarian, fallopian tube, or peritoneal cancer: Platinum-resistant disease", section on 'Overview of the treatment approach'.)

PARP inhibitors — Data regarding poly(ADP-ribose) polymerase (PARP) inhibitors in multiply relapsed disease (naïve to prior PARP inhibition) are presented below.

Olaparib — Studies have shown that patients with advanced cancer and a germline BRCA mutation may respond to olaparib if they have experienced progression on multiple previous lines of chemotherapy [38,39]. For example, in a meta-analysis of phase I and II trials including 273 patients with advanced, BRCA-associated ovarian cancer who were naïve to prior PARP inhibition, in the cohort of 205 patients who had received ≥3 lines of chemotherapy [39]:

The tumor response rate was 31 percent (95% CI 25-38).

The median duration of response was 7.8 months (95% CI 5.6-9.5).

The rate of serious (grade 3/4) toxicities was 54 percent, with the most frequent toxicities being anemia and fatigue. Of note, in one of the studies included in this meta-analysis, two patients were diagnosed with leukemia and one was diagnosed with myelodysplastic syndrome during follow-up. The exact incidence of these hematologic disorders requires further clarification.

These data support the use of olaparib as monotherapy for patients with recurrent ovarian cancer associated with a BRCA mutation, many of whom will also be platinum resistant. Of note, the European Medicines Agency has also recommended approval of olaparib in Europe, although the indication is in patients with platinum-sensitive ovarian cancer. This indication and the data in support of it are discussed separately. (See "Medical treatment for relapsed epithelial ovarian, fallopian tube, or peritoneal cancer: Platinum-sensitive disease".)

Hypersensitivity reactions have been observed rarely with olaparib, and, in general, the drug should be discontinued in this setting. Desensitization approaches have been attempted, however [40]. Although we would not typically use such a desensitization approach for olaparib, it may be appropriate to consider on a case-by-case basis, in consultation with an allergist, where available. However, we recognize that more information is needed regarding the incidence of hypersensitivity and whether this is a class effect or a drug-specific effect.

Niraparib, in select patients — Niraparib is FDA approved for treatment of advanced ovarian cancer that has been treated with three or more prior chemotherapy regimens and is associated with homologous recombination deficiency-positive status, which includes patients whose tumors harbor a deleterious or suspected deleterious BRCA mutation. Supporting data are discussed below. (See 'Other homologous recombination deficiencies' below.)

Rucaparib not used in this setting — Rucaparib previously had regulatory approval in the United States for advanced ovarian cancer patients who had received ≥2 chemotherapies and had a deleterious germline or somatic BRCA mutation, based on previously reported PFS benefits over chemotherapy [25]. However, the manufacturer has withdrawn the agent from use in this setting based on longer term data demonstrating worsened overall survival results with rucaparib (19.6 versus 27.1 months, with chemotherapy) [41]. We no longer use this rucaparib as treatment for multiply relapsed BRCA-associated advanced ovarian cancer, but it remains an appropriate option as maintenance therapy in patients with recurrent ovarian cancer who are in complete or partial response to platinum-based chemotherapy. (See "Medical treatment for relapsed epithelial ovarian, fallopian tube, or peritoneal cancer: Platinum-sensitive disease", section on 'Rucaparib'.)

PROGNOSIS — BRCA mutation carriers, particularly BRCA2 carriers, appear to have a better prognosis than noncarriers. An analysis of 1213 epithelial ovarian cancer cases with germline mutations in BRCA1 or BRCA2 and 2666 noncarriers revealed a five-year overall survival rate of 36 percent (95% CI 34-38 percent) for noncarriers, 44 percent (95% CI 40-48 percent) for BRCA1 carriers, and 52 percent (95% CI 46-58 percent) for BRCA2 carriers [42].

This improved survival appears to be due to a higher sensitivity of platinum-based treatment of these tumors relative to sporadic cases, which is maintained across repeated courses of chemotherapy [43-45]. (See "First-line chemotherapy for advanced (stage III or IV) epithelial ovarian, fallopian tube, and peritoneal cancer".)

Some data suggest that the improved prognosis for BRCA mutation carriers is only in the short term. The median follow-up in the analysis above was three years. By contrast, a registry study that compared 281 patients with BRCA mutations with other patients with ovarian cancer reported a higher survival rate in the BRCA group at three years (approximately 75 versus 65 percent), but no significant difference at five or more years [46].

SPECIAL CONSIDERATIONS

Those with somatic BRCA mutations — Rationale for poly(ADP-ribose) polymerase (PARP) inhibition in those with somatic BRCA alterations comes from Study 19 and NOVA, both in the setting of relapsed, platinum-sensitive disease. In these studies, the hazard ratio (HR) favoring maintenance PARP inhibition after response to platinum-based induction therapy for platinum-sensitive recurrence was almost identical between those with somatic and germline BRCA-associated tumors. In Study 19, the HR for somatic BRCA was 0.23 (95% CI 0.04-1.12) as compared with 0.17 (95% CI 0.09-0.34) for those with germline mutations [47]. In NOVA, the HR in favor of niraparib was 0.27 (95% CI 0.08-0.90) for somatic BRCA mutations as compared with 0.27 (95% CI 0.17-0.41) for germline [27].

Similarly, in the retreatment setting, as opposed to maintenance, the PARP inhibitor rucaparib has shown similar overall response rates in somatic and germline BRCA-associated tumors at 63 and 74 percent, respectively [48].

Other homologous recombination deficiencies — Homologous recombination deficiency (HRD) is being evaluated as a biomarker for selection of patients for PARP inhibitor maintenance after initial therapy, as well as for later-line treatment among those with platinum-sensitive relapse.

Treatment-naïve disease – Trials evaluating PARP inhibitor maintenance therapy have found greater benefits for those with HRD tumors relative to nongenetically altered ovarian cancers, and similar to those with BRCA-associated tumors. Olaparib plus bevacizumab has regulatory approval in the United States by the US Food and Drug Administration (FDA) for the maintenance treatment of adult patients with advanced epithelial ovarian cancer who are in complete or partial response to first-line platinum-based chemotherapy, and whose cancer is associated with HRD-positive status defined by either: a deleterious or suspected deleterious BRCA mutation and/or genomic instability [16].

In the PAOLA trial, among patients with stage III to IV, high-grade serous or endometrioid ovarian cancer with a response to initial chemotherapy and bevacizumab, maintenance therapy with olaparib and bevacizumab improved progression-free survival (PFS) relative to bevacizumab alone in the overall trial population, and particularly in those with HRD (37.2 versus 17.7 months; HR 0.33, 95% CI 0.25-0.45) [19].

In a randomized trial enrolling patients with treatment-naïve, stage III or IV, high-grade, serous ovarian cancer (VELIA), the PARP inhibitor veliparib, administered with platinum-based chemotherapy and continuing as maintenance, improved PFS relative to placebo in the overall trial population, with greater benefits among those with HRD [22]. In this subset, the median PFS was 31.9 months with veliparib versus 20.5 months with placebo (HR 0.57, 95% CI 0.43-0.76).

In a separate phase III trial in patients with newly diagnosed advanced ovarian cancer who had a response to platinum-based chemotherapy (PRIMA), maintenance with the PARP inhibitor niraparib also demonstrated PFS benefits over placebo in the overall trial population, with greater benefits among those with HRD [21]. In the subset of patients with HRD and no BRCA mutation, median PFS with niraparib versus placebo was 19.6 and 8.2 months, respectively (HR 0.50, 95% CI 0.31-0.83).

Overall results of these trials are discussed elsewhere, along with further details regarding toxicities. Data among those with BRCA-mutated cancers are discussed above. (See "First-line chemotherapy for advanced (stage III or IV) epithelial ovarian, fallopian tube, and peritoneal cancer", section on 'BRCA-wildtype cancers that are homologous recombination proficient' and 'PARP inhibitor maintenance therapy' above.)

Recurrent diseaseNiraparib is FDA approved for treatment of advanced ovarian cancer that has been treated with three or more prior chemotherapy regimens and is associated with HRD-positive status, defined by either 1) a deleterious or suspected deleterious BRCA mutation, or 2) genomic instability with progression more than six months after response to the last platinum-based chemotherapy. Genomic instability is identified by the FDA-approved companion diagnostic test for niraparib based on the presence of three biomarkers: loss of heterozygosity, telomeric allelic imbalance, and large-scale state transitions [20].

Maintenance – In the phase III NOVA study discussed above, among the subset of patients with non-BRCA-associated, platinum-sensitive, recurrent ovarian cancer with HRD, maintenance niraparib improved PFS relative to placebo (12.9 versus 3.8 months; HR 0.38, 95% CI 0.24-0.59) [27]. Data for those in the germline BRCA (gBRCA) cohort and overall non-gBRCA cohort are discussed elsewhere. (See 'PARP inhibitor maintenance therapy' above and "Medical treatment for relapsed epithelial ovarian, fallopian tube, or peritoneal cancer: Platinum-sensitive disease", section on 'Niraparib'.)

Later-line treatment – In a single-arm trial, niraparib (300 mg orally daily) was administered to patients with a median of four previous lines of therapy, of whom over two-thirds had disease that had become resistant or refractory to the last administered platinum therapy [49]. Among 47 patients with HRD-positive tumors sensitive to their last platinum therapy who had received three or four previous anticancer therapy regimens (primary efficacy population), the response rate was 28 percent, with 68 percent having achieved clinical benefit. In the overall trial population, efficacy was lower. These results are discussed elsewhere. (See "Medical treatment for relapsed epithelial ovarian, fallopian tube, or peritoneal cancer: Platinum-resistant disease", section on 'PARP inhibitors in BRCA-wildtype tumors'.)

While other mutations have been associated with an increased risk of ovarian cancer (eg, BRCA-interacting protein 1 [BRIP1], RAD51 paralog C [RAD51C], RAD51 paralog D [RAD51D], partner and localizer of BRCA2 [PALB2], and BRCA1-associated RING domain 1 [BARD1]), strategies targeting these mutations have not been elaborated. Cancer risks for carriers of partner and localizer of BRCA2 (PALB2), RAD51, and other genes associated with hereditary ovarian cancer, and screening for such cancer susceptibility syndromes, are discussed elsewhere. (See "Overview of hereditary breast and ovarian cancer syndromes associated with genes other than BRCA1/2" and "Genetic testing and management of individuals at risk of hereditary breast and ovarian cancer syndromes".)

Mismatch repair deficiency/high microsatellite instability — For patients with recurrent ovarian cancer, genomic testing for DNA mismatch repair-deficient (dMMR) or microsatellite-instable (MSI) ovarian cancer should be performed. The immune checkpoint inhibitor pembrolizumab is approved by the US Food and Drug Administration for the treatment of dMMR or MSI cancers, including ovarian cancer, that have progressed following prior treatment, and for which there are no satisfactory alternative treatment options [50].

In KEYNOTE-158, enrolling 233 patients with 27 tumor types with confirmed dMMR/MSI tumors refractory to prior therapy, the objective response rate (ORR) to pembrolizumab was 34 percent [51]. Among 15 patients with ovarian cancer, the ORR was similar (33 percent), including three complete responses. Further details of this study are found elsewhere. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors".)

Special considerations during the COVID-19 pandemic — The COVID-19 pandemic has increased the complexity of cancer care. Important issues in areas where viral transmission rates are high include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. These and other recommendations for cancer care during active phases of the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Ovarian, fallopian tube, and peritoneal cancer" and "Society guideline links: Hereditary breast and ovarian cancer".)

SUMMARY AND RECOMMENDATIONS

Overview – Approximately one-fifth of cases of epithelial ovarian cancer (EOC) are associated with germline mutations, with most of these attributable to breast cancer susceptibility gene 1 (BRCA1) or breast cancer susceptibility gene 2 (BRCA2) mutations. (See 'Introduction' above.)

Surgical management – The surgical management of BRCA mutation carriers with ovarian cancer is the same as of those without BRCA mutations. (See "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Surgical staging".)

Systemic treatment for newly diagnosed disease – For most patients with optimally cytoreduced, BRCA-associated EOC, we suggest intravenous (IV)/intraperitoneal (IP) chemotherapy rather than IV chemotherapy only (Grade 2C), although IV therapy alone is also acceptable. It is unclear if the benefit for IV/IP treatment persists if poly(ADP-ribose) polymerase (PARP) inhibitors are used as maintenance, as there are no available data addressing this question. (See 'Adjuvant chemotherapy' above.)

Initial chemotherapy – The indications and choice of adjuvant chemotherapy for those with newly diagnosed ovarian cancer, irrespective of BRCA mutation status, are discussed elsewhere. (See "Adjuvant therapy of early-stage (stage I and II) epithelial ovarian, fallopian tube, or peritoneal cancer", section on 'Selection of patients' and "First-line chemotherapy for advanced (stage III or IV) epithelial ovarian, fallopian tube, and peritoneal cancer".)

Maintenance therapy

-For patients with advanced BRCA1/2-associated EOC, or with homologous recombination-deficient (HRD) tumors, who experienced a response to front-line, platinum-based therapy, we suggest maintenance with a PARP inhibitor rather than observation (Grade 2B). Some UpToDate contributors also offer maintenance PARP inhibitors to those with earlier-stage, BRCA-associated EOC that has responded to platinum-based therapy, particularly stage II disease, extrapolating from data in advanced cancer. (See 'PARP inhibitor maintenance therapy' above.)

-In addition, for patients with a BRCA1 or BRCA2 mutation deemed to be at a high risk of recurrence (eg, ascites, pleural effusion) in whom bevacizumab is being administered with a conventionally dosed IV chemotherapy regimen, we suggest the addition of olaparib during maintenance bevacizumab (Grade 2C).

Systemic treatment for relapsed disease

Platinum-sensitive relapse

-For patients with BRCA1/2-associated, platinum-sensitive, relapsed EOC, we suggest retreatment with platinum-based chemotherapy rather than a non-platinum-based chemotherapy (Grade 2C). For such patients who experience a complete or partial response to platinum-based therapy, and who did not receive PARP inhibitor maintenance in the front-line setting, we suggest maintenance with a PARP inhibitor rather than bevacizumab (Grade 2C). There are no data to inform use of PARP inhibitors (either as treatment or as maintenance) after platinum-sensitive relapse among patients with previous PARP exposure.

For BRCA carriers with platinum-sensitive disease who did not undergo maintenance PARP inhibitor therapy in the first-line (or adjuvant) setting, a PARP inhibitor is an appropriate alternative to chemotherapy. (See 'Maintenance' above and 'Overview of PARP inhibitors for recurrent BRCA-associated ovarian cancers' above.)

Platinum-resistant relapse – For patients with BRCA-associated ovarian cancer that is platinum resistant, prior treatment history affects choice of therapy.

-For patients with platinum-resistant relapse and no prior PARP inhibitor exposure, we suggest olaparib rather than chemotherapy (Grade 2C), although chemotherapy is an appropriate alternative, particularly for those presenting with first relapse (given the lack of data for PARP inhibitors in that setting). Niraparib may be an acceptable alternative in patients with HRD-positive disease and ≥3 prior treatments.

-For patients with platinum-resistant relapse and prior PARP inhibitor exposure, either chemotherapy or PARP inhibitors are acceptable options. However, data regarding retreatment with PARP inhibitors for patients with previous exposure to PARP-inhibitors are limited. (See 'Retreatment with platinum-based chemotherapy' above.)

PrognosisBRCA mutation carriers with ovarian cancer, particularly BRCA2 carriers, have a better prognosis than noncarriers. (See 'Prognosis' above.)

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