Strategies with PARP inhibitors in ovarian cancer should focus on combination strategies to more effectively treat a heterogeneous patient population.
Susana M. Campos, MD
Strategies with PARP inhibitors in ovarian cancer should revolve around combining this class of agents with chemotherapy, checkpoint inhibitors, and DNA damage­­—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 11th Annual International Symposium on Ovarian Cancer and Other Gynecologic Malignancies™.1
“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; P <.0001).2 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 BRCA status, the PFS favored the combination who were BRCA-mutant (HR, 0.31; 95% CI, 0.20-0.47) versus those who were not BRCA-mutant (HR, 0.71; 95% CI, 0.58-0.88).
Results also showed that the benefit with olaparib was most pronounced in patients with tumors positive for HRD, which included tumors with BRCA 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 BRCA 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.3 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; P <.001).
The benefit was more pronounced in those with BRCA 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; P <.001). In a subset of patients with both BRCA 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; P <.001).
In BRCA 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 BRCA wild-type/HRD-positivity (HR, 0.74; 95% 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.”
Regimens for Recurrent Settings
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 BRCA1/2 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; P = .007).4 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; P = .11).
When stratified by somatic BRCA 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 BRCA mutations (HR, 0.32; 95% CI, 0.16-0.66; P = .002). However, this improvement was not mirrored in the somatic BRCA-mutant carrier subgroup (median PFS 16.4 months and 16.5 months, respectively; HR, 0.75; 95% CI, 0.38-1.49; P = .42).
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; P <.0001).5 The combination improved PFS regardless of HRD-positivity (HR, 0.38; 95% CI, 0.20-0.72; P = .0019) or negativity (HR, 0.40; 95% CI, 0.19-0.85; P = .0129).
"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.6
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).
PARP Plus Immunotherapy
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 BRCA-mutant, platinum-sensitive population (n = 35).7 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.8 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.9
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.”