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PER® International Symposium on Ovarian Cancer and Other Gynecologic Malignancies

Transformative clinical trials of PARP inhibitors have revolutionized the frontline setting in advanced ovarian cancer, Kathleen Moore MD, explained in a virtual presentation during the 11th Annual International Symposium on Ovarian Cancer and Other Gynecologic Malignancies™.

In her discussion, Moore highlighted 4 groundbreaking trials of PARP inhibitors in the frontline setting: the SOLO-1 olaparib (Lynparza) trial,

 the PAOLA-1 olaparib plus bevacizumab (Avastin) trial,

 and the VELIA veliparib combination trial.

The FDA approved olaparib (Lynparza) in December 2018 as a maintenance treatment for patients with deleterious or suspected deleterious germline or somatic 

-mutated advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response (PR) to frontline platinum-based chemotherapy.

The approval was based on findings from the phase 3 SOLO-1 trial, in which olaparib reduced the risk of disease progression or death by 70% in patients with 

-mutant advanced ovarian cancer who were in complete or PR to platinum-based chemotherapy (HR, 0.30; 95% CI, 0.23-0.41; 

 <.0001) compared with placebo following platinum-based chemotherapy. 

The SOLO-1 trial evaluated maintenance olaparib following platinum-based chemotherapy in newly diagnosed patients with advanced ovarian cancer with a 

 mutation. Patients with newly diagnosed, FIGO stage III-IV, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube cancer with germline or somatic 

 mutations were enrolled. These patients must have also received cytoreductive surgery, and be in clinical complete response (CR) or PR after platinum-based chemotherapy.

The study treatment in SOLO-1 continued until disease progression, and treatment was ceased for patients with no evidence of disease at 2 years. However, patients with a partial response at 2 years could continue treatment. Secondary end points of the trial were PFS2, which is defined as time from randomization to second progression event, overall survival (OS), and quality of life.

Results showed that, at a median follow-up of 41 months, the median progression-free survival (PFS) by independent central review was not reached in the olaparib arm (n = 260), versus 14.1 months in the placebo arm (n = 131). The investigator-assessed PFS in the olaparib arm was not reached, compared with 13.8 months in the placebo arm (HR, 0.30; 95% CI, 0.23-0.41; 

 <.0001). The median PFS for olaparib has not yet been reached.

Additionally, patients who received olaparib maintenance showed a statically significant improvement in PFS2, with a median PFS2 not reached, compared with 41.9 months in the placebo group (HR, 0.50; 95% CI, 0.35-0.72; 

 =.0002). Overall survival data are not yet mature. Regarding quality of life, there were no clinically relevant changes. The discontinuation rate in the olaparib arm was 12%.

Adverse events (AEs) observed were low-grade, with the most common grade ≥3 AEs in the olaparib arm being anemia (22%) and neutropenia (8%). Baseline characteristics, including health-related quality-of-life scores, were balanced between the 2 arms.

Moore noted that a key byproduct of the unprecedented success of SOLO-1 was that it showed that genetic testing had to be done in newly diagnosed patients.

“You [now] had to know if your patient had a 

mutation,” explained Moore. “We’re still not at 100% [with upfront genetic testing], we’re still at about 60%, so we still have a way to go, but we’re better than we were because it’s really unacceptable to not know whether or not your patient has a 

mutation at the time of diagnosis…Everyone should be offered testing.”

Shortly before the PER meeting, on April 29, 2020, the FDA approved niraparib (Zejula) for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to first-line platinum-based chemotherapy, regardless of biomarker status.

The all-comer approval means that niraparib can be used across the entire population of patients with advanced epithelial ovarian cancer, regardless of histosubtype, explained Moore.  

The approval was based on findings from the phase 3 PRIMA study (ENGOT-OV26/GOG-3012), in which frontline maintenance therapy with niraparib improved median PFS by 5.6 months compared with placebo for patients with newly diagnosed, advanced ovarian cancer who responded to platinum-based chemotherapy.

In the overall population of the PRIMA study, the median PFS in the niraparib arm was 13.8 months compared with 8.2 months in the placebo group, representing a 38% reduction in the risk of progression or death with the addition of the PARP inhibitor (HR, 0.62; 95% CI, 0.50-0.76; 

 <.0001). In patients with tumors that tested positive for homologous recombination deficiency (HRD), the median PFS was 21.9 months with niraparib compared with 10.4 months for placebo (HR, 0.43; 95% CI, 0.31-0.59; 

The PRIMA study randomized 733 patients in a 2:1 ratio to receive niraparib (n = 487) or placebo (n = 246). Patients were randomized within 12 weeks of finishing the last cycle of chemotherapy. At the initiation of the study, niraparib was given at a fixed dose of 300 mg, which was adjusted to include a lower dose of 200 mg for those weighing less than 77 kg and for those with platelet counts below 150K/μL. The median relative dose intensity in the study was 63%. Gonzalez-Martin noted that future presentations would focus on the potential impact of this dose change.

Patient characteristics were similar across groups. The ECOG performance status was 1 for approximately 70% of patients, two-thirds had a FIGO stage of III, and a third had stage IV disease. The primary tumor locations were the ovary, fallopian tube, and peritoneum. The majority of patients had serous histology (~95%). Most patients had achieved a complete response to prior chemotherapy (70%). Two-thirds of patients received neoadjuvant chemotherapy, and none received bevacizumab, as the study was designed prior to approval of the VEGF inhibitor in the frontline setting.

At the interim analysis, median OS was not yet reached, at just 10.8% data maturity. At this early time point, however, the 24-month OS rate in the full population was 84% in the niraparib group and 77% in the placebo arm (HR, 0.70; 95% CI, 0.44-1.11). In the HRD-positive cohort, the 24-month OS rate was 91% with niraparib and 85% for placebo (HR, 0.61; 95% CI, 0.27-1.39).

Analysis of the HRD group was further broken down by 

 mutation, the median PFS was 22.1 months with niraparib compared with 10.9 months for placebo (HR, 0.40; 95% CI, 0.27-0.62). In those with HRD-positive tumors who were negative for a 

 mutations, the median PFS was 19.6 versus 8.2 months, for niraparib and placebo, respectively (HR, 0.50; 95% CI, 0.31-0.83).

Niraparib outperformed placebo across several patient subgroups for PFS, including those with HRD-negative tumors. In this group, the median PFS was 8.1 months with niraparib and 5.4 months for placebo (HR, 0.68; 95% CI, 0.49-0.94). Interim OS data for HRD-negative patients showed an 81% 24-month OS rate for niraparib compared with 59% for placebo (HR, 0.51; 95% CI, 0.27-0.97).

More patients experienced treatment-related AE of any grade in the niraparib arm compared with placebo (96.3% vs 68.9%). Grade ≥3 treatment-related AEs were experienced by 65.3% of patients in the niraparib arm compared with 6.6% of those in the placebo group. The most common AEs of grade ≥3 severity in the niraparib and placebo groups, respectively, were anemia (31.0% vs 1.6%), thrombocytopenia (28.7% vs 0.4%), platelet count decrease (13.0% vs 0%), and neutropenia (12.8% vs 1.2%).

Overall, 70.9% of patients required a dose reduction in the niraparib arm, and 12% of patients discontinued therapy due to AEs. The main AEs relating to discontinuation were myelosuppressive in nature, with 4.3% from thrombocytopenia.

The FDA  granted a priority review designation to a supplemental new drug application (sNDA) for the combination of olaparib (Lynparza) and bevacizumab (Avastin) for the maintenance treatment of patients with advanced ovarian cancer who are in complete or PR to first-line platinum-based chemotherapy with bevacizumab. Under the Prescription Drug User Fee Act, the FDA is expected to make a decision on the sNDA in the second quarter of 2020.

The designation is based on results from the pivotal phase 3 PAOLA-1 trial, in which the combination led to an investigator-assessed 41% reduction in the risk of disease progression or death compared with bevacizumab alone in this patient population (HR, 0.59; 95% CI, 0.49-0.72; 

<.001). Additionally, after a median follow-up of 22.9 months, the median PFS was 22.1 months and 16.6 months with the combination and bevacizumab alone, respectively.

In the double-blind, placebo-controlled, phase 3 PAOLA-1 trial, patients with newly diagnosed, advanced, FIGO stage III to IV, high-grade, serous or endometrioid ovarian, fallopian tube, or peritoneal cancer who had a CR or PR to frontline platinum-based chemotherapy and bevacizumab, regardless of genetic biomarker status or their outcome to prior surgery, were randomized 2:1 to receive olaparib in combination with bevacizumab (n = 537) or bevacizumab with placebo (n = 269) as a first-line maintenance treatment. Bevacizumab was administered at 15 mg/kg every 3 weeks on day 1; in the experimental arm, olaparib was given at 300 mg twice daily.

Patients were enrolled regardless of the type or extent of surgery (upfront or interval). The median age was 60.5 years, and all patients had an ECOG performance status of 0 or 1. A total of 95.5% patients had serous histology. The primary end point was investigator-assessed PFS; secondary end points included PFS2, overall survival, time until first subsequent therapy or death, and global health status—quality of life dimension of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire.

Results also showed that the benefit with olaparib was most pronounced in patients with tumors positive for HRD, including tumors that had 

 mutations (HR, 0.33; 95% CI, 0.25-0.45). In this subgroup, the median PFS was 37.2 months and 17.7 months with the olaparib combination and bevacizumab alone, respectively.

In those who had HRD-positive tumors without 

mutations, the median PFS was 28.1 months with olaparib/bevacizumab and 16.6 months with bevacizumab alone, respectively (HR, 0.43; 95% CI, 0.28-0.66).

Regarding safety, the most common AEs occurring in ≥20% of patients in the combination arm versus the bevacizumab-alone arm were fatigue (53% vs 32%, respectively), nausea (53% vs 22%), hypertension (46% vs 60%), anemia (41% vs 10%), lymphopenia (24% vs 9%), vomiting (22% vs 11%), and arthralgia (22% vs 24%).

Grade ≥3 AEs were reported in 57% of patients who received the addition of olaparib to bevacizumab and occurred in 51% of patients on bevacizumab alone. These AEs included hypertension (19% with olaparib/bevacizumab vs 30% with bevacizumab alone), anemia (17% vs <1%, respectively), lymphopenia (7% vs 1%), fatigue (5% vs 1%), neutropenia (6% vs 3%), nausea (2% vs 1%), diarrhea (both 2%), leukopenia (2% vs 1%), vomiting (1% vs 2%), and abdominal pain (1% vs 2%).

AEs that led to dose interruption occurred in 54% of patients on olaparib plus bevacizumab compared with 24% of patients on single-agent bevacizumab. Dose reductions occurred in 41% and 7% of patients on olaparib/bevacizumab and bevacizumab alone, respectively. Treatment discontinuations occurred in 20% of patients on the combination compared with 6% of those on bevacizumab alone.

The frontline combination of veliparib, carboplatin, and paclitaxel followed by maintenance veliparib monotherapy led to a 32% reduction in the risk of progression or death when compared with placebo plus chemotherapy with placebo maintenance for patients with high-grade serous ovarian cancer, according to results of the phase 3 VELIA study 

Across all patient subgroups, the median PFS for the induction and maintenance phases combined in the veliparib arm was 23.5 months compared with 17.3 months in the placebo arm (HR, 0.68; 95% CI, 0.56-0.83; 

 <.001). The benefit was more pronounced for those with 

 mutations. In this group, the median PFS was 34.7 months compared with 22.0 months for veliparib and placebo, respectively (HR, 0.44; 95% CI, 0.28-0.68; 

Another arm explored frontline veliparib plus chemotherapy followed by placebo maintenance; however, a benefit for veliparib was not demonstrated in this arm of the trial compared with chemotherapy plus placebo with placebo maintenance.

The VELIA study randomized patients evenly between 3 arms: the first arm (control) consisted of carboplatin and paclitaxel with placebo followed by placebo as maintenance (n = 375). The second arm of the study examined the addition of veliparib at 150 mg twice daily to carboplatin and paclitaxel as induction therapy followed by placebo maintenance (n = 383). In the third arm, veliparib was added at 150 mg twice daily to carboplatin and paclitaxel followed by veliparib alone at 400 mg twice daily as maintenance (n = 382).

Patient characteristics were well balanced across arms. The median age of patients was 62 years, and approximately 60% had an ECOG performance status of 0. Two-thirds of patients had stage III disease, and most had received primary surgery, with the remaining having interval surgery. Nearly half of patients in both groups had no residual disease, and approximately 30% had residual disease.

In those testing positive for HRD, the median PFS was 31.9 months in those receiving veliparib throughout the trial compared with 20.5 months in the control arm (HR, 0.57; 95% CI, 0.43-0.76; 

 <.001). Data were not yet sufficiently mature to conduct overall survival analyses across the groups.

In those receiving veliparib with induction chemotherapy followed by placebo maintenance, the median PFS across the full study was 15.2 months compared with 17.3 months in the control arm (HR, 1.07; 95% CI, 0.90-1.29). In the 

 group, the median PFS was 21.1 months with this regimen compared with 22.0 months for the control (HR, 1.22; 95% CI, 0.82-1.80). In the HRD-positive group, the median PFS was 18.1 months with the combination compared with 20.5 months for the control (HR, 1.10; 95% CI, 0.86-1.41).

An objective response rate (ORR) was available for patients with measurable disease at study entry (25% of study). Those receiving veliparib throughout the full study had an ORR of 84% compared with 79% and 74% in the veliparib upfront alone and control arms, respectively.

An assessment of PFS prior to beginning maintenance therapy revealed some data on the efficacy of adding veliparib to the frontline therapy. In this analysis, PFS was not improved with the combination of veliparib and chemotherapy versus the control group (HR, 1.07; 95% CI, 0.90-1.29). These findings were consistent across subgroups.

At least one treatment-emergent AE was experienced by all patients across the 3 arms. Grade 3/4 AEs were experienced by 88% of those receiving veliparib throughout and for 88% of those receiving veliparib only in the induction combination. In the control arm, grade 3/4 AEs were experienced by 77% of patients.

The most commonly observed grade 3/4 AEs in the veliparib throughout group compared with control, respectively, were neutropenia (58% vs 49%), anemia (38% vs 26%), thrombocytopenia (28% vs 8%), and leukopenia (18% vs 9%). In the veliparib induction/placebo maintenance group, the most common grade 3/4 AEs were neutropenia (62%), anemia (41%), thrombocytopenia (31%), and leukopenia (12%).

Going forward, Moore said the key will be to analyze the data from the various subgroups across the 4 trials to identify differences to “start to make sense of how we are going to take care of women in this era of increased options.”

Moore, K. Advances in frontline treatment options for patients with ovarian cancer. Presented at: 11th Annual International Symposium on Ovarian Cancer and Other Gynecologic Malignancies™; May 2, 2020.

Moore K, Colombo N, Scambia G, et al. Olaparib maintenance therapy following first-line platinum-based chemotherapy in patients with FIGO stage III—IV ovarian cancer (OC) with a BRCA1/2 mutation (BRCAm): Phase III SOLO1 trial. In: Proceedings from the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA7_PR.

Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer [published online ahead of print on October 21, 2018]. 

FDA approves niraparib for first-line maintenance of advanced ovarian cancer. Published April 29, 2020. https://bit.ly/3aO6uKP. Accessed April 29, 2020.

Ray-Coquard I, Pautier P, Pignata S, et al. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. 

. 2019;381(25):2416-2428. doi: 10.1056/NEJMoa1911361.

Coleman RL, Fleming GF, Brady MF, et al. VELIA/GOG-3005: Integration of veliparib (V) with front-line chemotherapy and maintenance in women with high-grade serous carcinoma of ovarian, fallopian tube, or primary peritoneal origin (HGSC). Presented at: ESMO Congress 2019, Barcelona, Spain, September 27 to October 1, 2019. LBA3.

Coleman RL, Fleming GF, Brady MF, et al. Veliparib with First-Line Chemotherapy and as Maintenance Therapy in Ovarian Cancer [published online September 28, 2019]. 

View More from the 2020 International Symposium on Ovarian Cancer and Other Gynecologic Malignancies 

Transformative clinical trials of PARP inhibitors have revolutionized the frontline treatment paradigm in advanced ovarian cancer. 

PARP Inhibitor Trials Revolutionize Frontline Ovarian Cancer

Strategies with PARP inhibitors in ovarian cancer should revolve around combining this class of agents with chemotherapy, checkpoint inhibitors, and DNA damage&shy;&shy;—repair targets to more effectively treat a heterogeneous patient population in the up-front and recurrent settings, explained Susana M. Campos, MD, MPH, in a virtual presentation during the 

 International Symposium on Ovarian Cancer and Other Gynecologic Malignancies™.

“Even though we have trials with different stratifications, eligibility, and designs, we certainly have a heterogenous patient population,” said Campos, an institute physician of Dana-Farber Cancer Institute and assistant professor of medicine of Harvard Medical School. “We are starting to see more and more patients with recurrent ovarian cancer, we’re treating them much more aggressively in the up-front setting, and we have to face PARP [inhibitor] resistance in the future. Some of these trials, not only [with] antiangiogenic agents, but immunotherapy, or some of these DNA damage—repair targets, are going to be incredibly important going forward. At the end of the day, what we have to quite remember is that we craft care to each and every one patient.”

In the up-front settings, the use of PARP inhibitors is designed to improve progression-free survival (PFS), objective response rates (ORRs), and overall survival (OS). In the recurrent space, the goal of using this type of therapy is to improve efficacy, overcome resistance, improve immunogenic response, target multiple oncogenic pathways, and provide options for all patients with ovarian cancer, regardless of their homologous recombination deficiency (HRD) status, Campos explained.

Nevertheless, the next steps of combining PARP inhibitors with a multitude of other agents, in an effort to improve on these goals, are garnering excitement in the landscape.

The combination of the PARP inhibitor olaparib (Lynparza) and the angiogenesis inhibitor bevacizumab (Avastin) has been explored in the frontline maintenance setting for patients with advanced ovarian cancer who are in complete or partial response (PR) to first-line platinum-based chemotherapy with bevacizumab.

In the double-blind, placebo-controlled, phase 3 PAOLA-1 trial, patients with newly diagnosed, advanced, FIGO stage III to IV, high-grade, serous or endometroid ovarian, fallopian tube, or peritoneal cancer who had a CR or PR to frontline platinum-based chemotherapy and bevacizumab, regardless of genetic biomarker status or their outcome to prior surgery, were randomized 2:1 to receive olaparib in combination with bevacizumab (n = 537) or bevacizumab with placebo (n = 269) as a first-line maintenance treatment.

Findings showed that the combination led to a 41% reduction in the risk of disease progression or death compared with bevacizumab alone in this patient population, based on an investigator assessment (HR, 0.59; 95% CI, 0.49-0.72; 

 Additionally, after a median follow-up of 22.9 months, the median PFS was 22.1 months and 16.6 months with the combination and bevacizumab alone, respectively. When stratified by somatic 

 status, the PFS favored the combination who were 

-mutant (HR, 0.31; 95% CI, 0.20-0.47) versus those who were not 

Results also showed that the benefit with olaparib was most pronounced in patients with tumors positive for HRD, which included tumors with 

 mutations, the median PFS was 28.1 months with olaparib/bevacizumab and 16.6 months with bevacizumab alone, respectively (HR, 0.43; 95% CI, 0.28-0.66). However, with those who had an HRD-negative/unknown status, the median PFS was 16.9 months and 16.0 months with olaparib/bevacizumab and bevacizumab alone, respectively (HR, 0.92; 95% CI, 0.72-1.17).

Based on the PAOLA-1 data, the FDA granted a priority review designation to a supplemental new drug application for the combination of olaparib and bevacizumab for the maintenance treatment of patients with advanced ovarian cancer who are in CR or PR to first-line platinum-based chemotherapy with bevacizumab.

The FDA is expected to make a decision on the application in the second quarter of 2020.

“Understanding the data that was put forth by the SOLO-1 trial, what is the contribution of bevacizumab to olaparib in this particular study?” Campos asked of the PAOLA-1 findings. “The PAOLA-1 study did not have an olaparib-only arm. This draws us into the equation, and question, of: What patient population is this combination most appropriate for? I bring myself back to, ‘Who would I have put bevacizumab on? What are the data that surround GOG-218 or ICON7?’” 

The addition of a PARP inhibitor to chemotherapy in patients with high-grade serous ovarian cancer was evaluated in the phase 3 VELIA trial, which comprised the investigational agent veliparib. VELIA randomized patients evenly between 3 arms: the first arm (control) consisted of carboplatin and paclitaxel with placebo followed by placebo as maintenance (n = 375). The second arm examined the addition of veliparib to carboplatin/paclitaxel as induction therapy, followed by placebo maintenance (n = 383). In the third arm, veliparib was added at 150 mg twice daily to carboplatin/paclitaxel followed by veliparib alone at 400 mg twice daily as maintenance (n = 382).

Results showed that the arm of veliparib plus carboplatin/paclitaxel followed by maintenance veliparib led to a 32% reduction in the risk of progression or death versus placebo/chemotherapy with placebo maintenance in the intent-to-treat (ITT) population.

 The median PFS was 23.5 months compared with 17.3 months in the placebo arm (HR, 0.68; 95% CI, 0.56-0.83; 

The benefit was more pronounced in those with 

 <.001). In a subset of patients with both 

 mutations and HRD-positivity, the median PFS was 31.9 months with the addition of veliparib and 20.5 months for the control arm (HR, 0.57; 95% CI, 0.43-0.76; 

 wild-type patients, the addition of the PARP inhibitor did not demonstrate a PFS benefit versus the control arm, at 18.2 months and 15.1 months, respectively (HR, 0.80; 95% CI, 0.64-0.997). There was a similar effect in patients with 

CI, 0.52-1.06) and HRD-negativity (HR, 0.81; 95% CI, 0.60-1.09).

“How do we interpret the VELIA data? It did show a clinically significant improvement of chemotherapy plus the PARP inhibitor followed by the PARP inhibitor,” said Campos. “It draws some questions in terms of the second arm. If you combine chemotherapy with a PARP inhibitor, do you actually just add toxicity, and can you, at that point in time, abbreviate the backbone of that therapy, which is carboplatin/paclitaxel? We have many different patients; [the combinations in PAOLA-1 and VELIA] may have utility in a particular patient group.”

Combination strategies utilizing PARP inhibition are also being evaluated in the recurrent setting of both patients with platinum-sensitive and platinum-resistant disease. While Campos explained there can be challenges to combining PARP with other agents, such as dose-limiting toxicities, she added there are also opportunities to overcome PARP inhibitor—resistance mechanisms and enhance tumor mutational load and immunogenicity.

Some of these studies, which include PARP inhibitors plus antiangiogenic agents, immunotherapy, or chemotherapy, have already reported data showcasing their efficacy, while others are expected to read out in the near future.

For example, olaparib plus the investigational antiangiogenic agent cediranib was explored in a small phase 2 trial (NCT01116648) of 90 patients with platinum-sensitive, relapsed, high-grade serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer, as well as other histologies with deleterious germline 

 mutations. Updated findings showed that, in the ITT population, the median PFS was 16.5 months and 8.2 months with the combination and olaparib alone, respectively (HR, 0.50; 95% CI, 0.30-0.83; 

 The median OS was also improved with the combination, at 44.2 months versus 33.3 months with olaparib alone (HR, 0.64; 95% CI, 0.36-1.11; 

 mutation status, the median PFS was 23.7 months with olaparib/cediranib and 5.7 months with olaparib alone in those who did not harbor somatic 

 mutations (HR, 0.32; 95% CI, 0.16-0.66; 

 = .002). However, this improvement was not mirrored in the somatic 

-mutant carrier subgroup (median PFS 16.4 months and 16.5 months, respectively; HR, 0.75; 95% CI, 0.38-1.49; 

Similarly, the AVANOVA study investigated the PARP inhibitor niraparib (Zejula) in combination with bevacizumab versus niraparib. alone. The regimen was tested in patients with high-grade serous, endometrioid, platinum-sensitive recurrent ovarian cancer who could have received any number of prior therapies. Data showed that the median PFS was 11.9 months with niraparib/bevacizumab and 5.5 months with single-agent niraparib (adjusted HR, 0.35; 95% CI, 0.21-0.57; 

 The combination improved PFS regardless of HRD-positivity (HR, 0.38; 95% CI, 0.20-0.72; 

 = .0019) or negativity (HR, 0.40; 95% CI, 0.19-0.85; 

"Both of these studies [olaparib/cediranib and AVANOVA] really have paved the way for looking at the combination of antiangiogenic therapies and a PARP inhibitor," said Campos.

Ongoing trials continue to explore these 2 types of agents, such as the phase 3 ICON9 study (NCT03278717), which is testing maintenance olaparib and cediranib compared with olaparib alone in patients with relapsed, platinum-sensitive ovarian, fallopian tube, or peritoneal cancer.

Additionally, the phase 3 NRG-GY004 (NCT02446600) is looking at olaparib alone or in combination with cediranib versus platinum-based chemotherapy in patients with platinum-sensitive relapsed ovarian cancer. However, in March 2020, a press released noted that the combination of cediranib plus olaparib did not lead to a statistically significant improvement in PFS versus platinum-based chemotherapy in these patients.

Furthermore, similar combination strategies are being tested in platinum-resistant settings: NRG-GY005 (COCOS; NCT02502266), OCTOVA (NCT03117933), CONCERTO (NCT02889900), and a proof-of-concept study of olaparib/cediranib (NCT02681237).

While, historically, response rates and PFS with single-agent immunotherapy in ovarian cancer has been “less than exciting,” said Campos, intriguing research has demonstrated synergy when PD-1/PD-L1 inhibitors are partnered with PARP inhibitors.

Smaller studies have shown preliminary efficacy with these types of regimens in different ovarian cancer populations. In the phase 2 MEDIOLA trial, for example, durvalumab (Imfinzi) plus olaparib led to a 71.9% objective response rate in a germline 

-mutant, platinum-sensitive population (n = 35).

 Yet the phase 1/2 TOPACIO trial (n = 60) of pembrolizumab (Keytruda) and niraparib had a more modest ORR at 25%, with a median duration of response of 9.3 months.

Another small trial of durvalumab plus olaparib (n = 35) showed that the combination had a modest ORR in a mostly platinum-resistant recurrent ovarian cancer population.

Campos explained that these smaller studies in the recurrent setting put researchers on the path to explore immunotherapy combinations with PARP inhibitors for those with newly diagnosed ovarian cancer, including: DUO-O (AGO-OVAR23/ENGOT OV46; NCT03737643) with durvalumab/olaparib; FIRST (ENGOT OV44; NCT03602859)

with dostarlimab, niraparib, and potentially bevacizumab; KEYLYNK-001 (ENGOT OV43; (NCT03740165) with olaparib, pembrolizumab, and potentially bevacizumab; and ATHENA (GOG3020/ENGOT OV45; NCT03522246) of rucaparib (Rubraca) and nivolumab (Opdivo).

But beyond doublet regimens, researchers are also beginning to evaluate triplet therapies with all 3 classes of agents, as seen in the phase 2 OPAL study (NCT03574779) with niraparib, TSR-042, and bevacizumab in patients with recurrent, platinum-resistant, ovarian, fallopian tube, or peritoneal cancer.

There has been a “tremendous amount of interest” in looking at other emerging combinations in terms of DNA damage repair targets and other agents, Campos explained, citing Wee-1, PI3K/Akt/mTOR, ATR, Chk1, and MEK as all targets being explored in a number of clinical trials.

For example, the Wee-1 inhibitor adavosertib

(AZD 1775) is being explored with and without olaparib in the phase 2 EFFORT trial (NCT03579316) of patients with recurrent ovarian, primary peritoneal, or fallopian tube Cancer. Activated Wee-1, phosphorylates CDK1, Campos said, and therefore results in G2-M arrest.

Additionally, the MEK inhibitor selumetinib (Koselugo) is also being combined with olaparib in a phase 1 trial (NCT03162627) of patients with recurrent solid tumors, including ovarian cancer. The addition of MEK inhibitors to PARP could decrease homologous recombination repair gene expression, she said.

“In a very short period of time, there is a tremendous amount of work,” Campos concluded. “The landscape is expanding; it’s a moving target.”

Campos S. Incorporating combination therapy in an evolving treatment landscape. Presented at: 11th Annual International Symposium on Ovarian Cancer and Other Gynecologic Malignancies™; May 2, 2020.

. 2019;381(25):2416-2428. doi: 10.1056/NEJMoa1911361

Coleman RL, Fleming GF, Brady MF, et al. Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer. 

. 2019;381(25):2403-2415. doi: 10.1056/NEJMoa1909707

Liu JF, Barry WT, Birrer MJ, et al. Overall survival and updated progression-free survival results from a randomized phase 2 trial comparing the combination of olaparib and cediranib against olaparib alone in recurrent platinum-sensitive ovarian cancer. 

. 2017;35(suppl_15; abstr 5535). doi: 10.1200/JCO.2017.35.15_suppl.5535

Mirza MR, Åvall Lundqvist E, Birrer MJ, et al. Niraparib plus bevacizumab versus niraparib alone for platinum-sensitive recurrent ovarian cancer (NSGO-AVANOVA2/ENGOT-ov24): a randomised, phase 2, superiority trial. 

. 2019;20(10):1409-1419. doi: 10.1016/S1470-2045(19)30515-7

Update on phase 3 GY004 for cediranib and Lynparza (olaparib) in platinum-sensitive relapsed ovarian cancer [news release]: Merck. Published March 12, 2020. https://bit.ly/2VYlwcJ. Accessed March 12, 2020.

Drew Y, Kaufman B, Banerjee S, et al. Phase II study of olaparib + durvalumab (MEDIOLA): Updated results in germline BRCA-mutated platinum-sensitive relapsed (PSR) ovarian cancer (OC). 

. 2019;30(suppl_5):v485-v486. doi: 10.1093/annonc/mdz253.016

Konstantinopoulos PA, Waggoner SE, Vidal GA, et al. TOPACIO/Keynote-162 (NCT02657889): A phase 1/2 study of niraparib + pembrolizumab in patients (pts) with advanced triple-negative breast cancer or recurrent ovarian cancer (ROC)—results from ROC cohort. 

. 2018;36(suppl; abstr 106). doi: 10.1200/JCO.2018.36.15_suppl.106

Lee J-M, Annunziata CM, Houston N, et al. A phase 2 study of durvalumab, a PD-L1 inhibitor and olaparib in recurrent ovarian cancer (ovca). 

. 2018;29(suppl_8):viii332-viii358. doi: 10.1093/annonc/mdy285

Strategies with PARP inhibitors in ovarian cancer should focus on combination strategies to more effectively treat a heterogeneous patient population.

Innovative Combo Regimens Are Necessary in Heterogeneous Ovarian Cancer Population

The surge of treatment options for patients with ovarian cancer poses a daunting challenge as answers for optimal sequencing continue to elude clinicians. Bevacizumab (Avastin) continues to hold the most utility in this disease setting, but the addition of PARP inhibitors, and immunotherapy raises the question of how to best deliver efficient regimens to patients. The future looks to be defined by essential clinical trials.

“The problem relates to chaos in ovarian cancer management,” said Maurie Markman, MD during the virtual live webcast of the 11th Annual International Symposium on Ovarian Cancer and Other Gynecologic Malignancies™ hosted by Physicians’ Education Resource®, LLC (PER®). “The questions that confront the clinicians the individuals designing clinical trials are profound and overwhelming.”

Markman, who is the president of Medicine & Science at Cancer Treatment Centers of America and clinical professor of medicine, Drexel University College of Medicine in Philadelphia, PA, discussed the how currently available treatments may hold untapped potential and how the design of clinical trials can help unlock the best outcomes for patients.

Navigating the Ovarian Cancer Treatment Landscape

Bevacizumab’s approval in 2014 kicked off the wave of new agents and indications in a stagnant treatment landscape. The initial approval was based on results from the phase 3 AURELIA study (NCT00976911) in 361 women with epithelial ovarian, primary peritoneal, or fallopian tube cancer in which bevacizumab plus chemotherapy decreased the risk of progression or death by 62% compared with chemotherapy alone. The median progression-free survival (PFS) was 6.8 months with bevacizumab versus 3.4 months with chemotherapy alone (HR, 0.38; 

“There had never been a phase 3 randomized trial in 50 years since cisplatin was developed showing an impact on an end point like PFS in platinum-resistant disease, the AURELIA trial was the first and remains the only positive trial with bevacizumab,” Markman said.

Next, bevacizumab was approved for platinum-resistant disease based on results of the AURELIA study and for recurrent platinum-sensitive disease based on results of the OCEANS (NCT00434642), and GOG-0213 (NCT00262847) studies, where it was combined with carboplatin/gemcitabine and carboplatin/paclitaxel, respectively.

In the OCEANS study, bevacizumab in combination with platinum-based chemotherapy increased the median PFS to 12.4 months versus 8.4 months with chemotherapy alone (HR, 0.46; 95% CI; 0.37-0.58; 

 <.0001) in patients with recurrent, platinum-sensitive disease.

In June 2018, bevacizumab was approved in combination with carboplatin and paclitaxel, followed by bevacizumab as a single agent, for patients with stage III or IV disease following initial surgical resection. Efficacy was determined in the GOG-0218 study in which the use of initial and maintenance bevacizumab demonstrated a median PFS of 18.2 months compared with 12.0 months for chemotherapy alone (HR, 0.62; 95% CI, 0.52-0.75; 

 <.0001). In a third arm of the study, patients who received bevacizumab plus carboplatin and paclitaxel without the maintenance phase reached a median PFS of 12.8 months compared with 12.0 months chemotherapy alone, a difference that was not statistically significant.

In final analysis none of the 3 treatment arms resulted in a statistically significant gain in OS after a median follow-up of 102.9 months. However, in patients who started with stage IV disease, the use of concurrent-plus-maintenance bevacizumab with chemotherapy was associated with a longer median OS of 42.8 months versus 32.6 months with chemotherapy alone (HR, 0.75; 95% CI, 0.59-0.95).

“Data that demonstrates not only in ovarian cancer but other cancer types, the ability to give bevacizumab after bevacizumab continues to improve outcomes if you have a different backbone,” he added.

Three FDA-approved PARP inhibitors include olaparib (Lynparza), niraparib (Zejula), and rucaparib (Rubraca), which currently have 7 indications in ovarian cancer.

Most recently on April 29, 2020, niraparib gained another indication with the approval of the agent for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response (PR) to first-line platinum-based chemotherapy, regardless of biomarker status.

While these approvals all mark progress, Markman noted that one of the controversies surrounding these 3 agents are their utility across real-world patient populations. “Is there a superior anti-PARP agent and does this differ based on specific clinical settings?” asked Markman.

Combinations for PARP inhibitors also extends beyond their utility and sequencing of one another, it also should be thought of for treatments such as bevacizumab, said Markman. “What is the role of adding an anti-PARP agent to bevacizumab in primary or second-line therapy, in specific molecular subtypes, like BRCA mutations or patients who are HRD positive, and is there greater clinical benefit associated with either combination versus sequential therapy?”

PARP inhibitors in combination with bevacizumab are in fact on the horizon as the FDA considers olaparib plus bevacizumab as frontline maintenance therapy for the treatment of patients with advanced ovarian cancer who are in complete or partial response to first-line platinum-based chemotherapy with bevacizumab. Of note, none of the other FDA-approved PARP inhibitors have received regulatory approval as frontline maintenance.

Data from the phase 3 PAOLA-1 trial (NCT02477644) showed a benefit with maintenance PARP inhibition in this setting. Patients were randomly assigned maintenance therapy with olaparib plus bevacizumab (n = 537) or placebo plus bevacizumab (n = 269). Olaparib or placebo were administered for up to 24 months and bevacizumab was administered for up to 15 months.

The trial met its primary end point, showing that for the overall population, patients who received olaparib plus bevacizumab as maintenance therapy had a 5.5 longer median PFS and a 41% lower likelihood of relapse or death compared with patients who received placebo plus bevacizumab (22.1 vs 16.6 months; HR, 0.59; 95% CI, 0.49-0.72; 

Further, patients harboring a BRCA1/2 mutation had an even greater PFS benefit of 37.2 months versus 21.7 months (HR, 0.31; 95% CI, 0.20-0.47), and patients who were HRD-positive also had a greater PFS benefit of 37.2 months versus 17.7 months (HR, 0.33; 95% CI, 0.25-0.45).

Markman also posed whether there is untapped potential of these agents that would come with optimal sequencing. “Is there a clinical utility associated with employing a PARP after PARP strategy and if there is, what difference does that specific combination or sequence make?” asked Markman.

In addition to testing for BRCA and HRD in patients, Markman transitioned to discussing the presence of mismatch repair deficiency (MMR) or microsatellite instability (MSI).

In a recent study, 582 patients with ovarian cancer were screened for MMR deficiency by immunohistochemistry. MMR deficiency/MSI was predominantly seen in endmetrioid cancers (8 of 35, 23%) signaling a higher prevalence of patients in this tumor subtype who may benefit from tailored treatments.

“The question is should it be standard of care in that setting to do such testing and what line of therapy [should be used?” asked Markman.

The future of ovarian cancer management is in clinical trials. However, he stressed the need for pragmatic clinical trials designed to address simply address questions that are relevant to patients and their oncologists. “By quickly addressing multiple current clinical issues and controversies we can help oncologists optimally plan treatment for future patients,” he said.

Included in suggestions for how to best assess these patient populations were selecting end points that are meaningful to patients including efficacy, toxicity, and quality of life. Markman also added that trial design should strive to reflect real world populations by avoiding objectively unnecessary inclusion and exclusion criteria. Additionally, designs should address multiple current clinical issues and optimally plan treatments for future patients, while also allowing for and encouraging crossover.

“Hopefully these trials can be strongly supported by the FDA and receive the appropriate funding from agencies, payers, academic centers, patient advocacy groups, and pharmaceutical or biotech companies,” Markman concluded.

Markman M. Future directions: where are we headed. Presented at: 11th Annual International Symposium on Ovarian Cancer and Other Gynecologic Malignancies™ hosted by Physicians’ Education Resource®, LLC (PER®). May 2, 2020.

Bevacizumab solution in combination with paclitaxel. FDA website. Accessed May 2, 2020. bit.ly/33ZCsS9

Tewari KS, Burger RA, Enserro D, et al. Final overall survival of a randomized trial of bevacizumab for primary treatment of ovarian cancer. 

 2019;37(26):2317-2328. doi:10.1200/JCO.19.01009

Lynparza. Prescribing information. AstraZeneca Pharmaceuticals LP; 2018. Accessed May 2, 2020. www.accessdata.fda.gov/drugsatfda_docs/label/2018/208558s006lbl.pdf

Zejula. Prescribing information. Tesaro, Inc; 2017. Accessed May 2, 2020. www.accessdata.fda.gov/drugsatfda_docs/label/2017/208447lbl.pdf

Rubraca. Prescribing information. Clovis Oncology, Inc; 2018. Accessed May 2, 2020. www.accessdata.fda.gov/drugsatfda_docs/label/2018/209115s003lbl.pdf

Lynparza (olaparib) regulatory submission granted priority review in US for 1st-line maintenance treatment with bevacizumab in advanced ovarian cancer. News release. Kenilworth, NJ. AstraZeneca and Merck & Co, Inc. Published January 13, 2020. bit.ly/2Tl5GYS

Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. 

 2019;381(25):2416-2428. doi:10.1056/NEJMoa1911361

Fraune C, Rosebrock J, Simon R, et al. High homogeneity of MMR deficiency in ovarian cancer. 

. 2020;156(3):669-675. doi:10.1016/j.ygyno.2019.12.031

The surge of treatment options for patients with ovarian cancer poses a daunting challenge as answers for optimal sequencing continue to elude clinicians.

Optimal Sequencing Remains a Hurdle in Ovarian Cancer Treatment

Robert L. Coleman, MD, FACOG, FACS, chief scientific officer, The US Oncology Network, discusses recent advancements made in the cervical cancer space.

In the recurrent space, or locally advanced cervical cancer that is not amenable to curative surgery, radiation, or the combination, investigators are channeling their efforts into drug development, says Coleman. One of the most prevalent first advances observed in cervical cancer is that investigators were able to augment the effect of chemotherapy by using antiangiogenesis-based therapies; this research led to an FDA approval. That approach increased not only progression-free survival, but overall survival as well in this patient population; that was a major advance, says Coleman.

Most recently, in 2018, the space saw the FDA approval of pembrolizumab (Keytruda) FDA for use in patients with PD-L1—positive, recurrent cervical cancer. The decision was based on data from the phase 2 KEYNOTE-158 trial, which evaluated pembrolizumab in patients with multiple types of advanced solid tumors who progressed on standard-of-care therapy. At a median follow-up of 10.2 months, the median objective response rate (ORR) was 12.2% (95% CI, 6.5%-20.4%), with 3 complete and 9 partial responses. All 12 responses were in patients with PD-L1–positive tumors, for an ORR of 14.6% (95% CI, 7.8%-24.2%). The median duration of response (DOR) was not reached (range, ≥ 3.7-≥ 18.6 months).

Although the response rates are quite low, the DOR observed in that patient subgroup was actually quite long, notes Coleman. That was a really important advancement in the field. By continuing to examine novel combinations and other modalities, investigators are trying to leverage the immune system even more effectively, concludes Coleman.

Robert L. Coleman, MD, FACOG, FACS, discusses recent advancements made in the cervical cancer space.

Dr. Coleman on Recent Advancements Made in Cervical Cancer Treatment

Brian M. Slomovitz, MD, gynecologic oncology, Broward Health, professor of obstetrics and gynecology, Herbert Wertheim College of Medicine, Florida International University, discusses sequencing strategies in endometrial cancer.

Historically, patients with advanced and recurrent endometrial cancer have received chemotherapy and radiation, says Slomovitz. However, findings from the phase 3 GOG-258 trial showed that chemotherapy plus radiation did not prolong relapse-free survival compared with chemotherapy alone in patients with stage 3 or 4A endometrial carcinoma. As such, waiting to give radiation therapy until a patient requires salvage treatment is an alternate strategy, explains Slomovitz.

Brian M. Slomovitz, MD, discusses sequencing strategies in endometrial cancer.

PER® International Symposium on Ovarian Cancer and Other Gynecologic Malignancies | Conference

PARP Inhibitor Trials Revolutionize Frontline Ovarian Cancer

Innovative Combo Regimens Are Necessary in Heterogeneous Ovarian Cancer Population

Optimal Sequencing Remains a Hurdle in Ovarian Cancer Treatment

Dr. Coleman on Recent Advancements Made in Cervical Cancer Treatment

Dr. Slomovitz on Sequencing Strategies in Endometrial Cancer