PARP Inhibitor Trials Revolutionize Frontline Ovarian Cancer

May 4, 2020
Jason M. Broderick

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

Kathleen N. Moore, MD

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™.1

In her discussion, Moore highlighted 4 groundbreaking trials of PARP inhibitors in the frontline setting: the SOLO-1 olaparib (Lynparza) trial,2,3 the PRIMA niraparib (Zejula) trial,4 the PAOLA-1 olaparib plus bevacizumab (Avastin) trial,5 and the VELIA veliparib combination trial.6,7

SOLO-1

The FDA approved olaparib (Lynparza) in December 2018 as a maintenance treatment for patients with deleterious or suspected deleterious germline or somatic BRCA-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 BRCA-mutant advanced ovarian cancer who were in complete or PR to platinum-based chemotherapy (HR, 0.30; 95% CI, 0.23-0.41; P <.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 BRCA1/2 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 BRCA 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; P <.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; P =.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 BRCA 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 BRCA mutation at the time of diagnosis…Everyone should be offered testing.”

PRIMA

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; P <.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; P <.0001).

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 BRCA status. For those with a BRCA 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 BRCA 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.

PAOLA-1

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; P <.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 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).

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.

VELIA

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; P <.001). The benefit was more pronounced for 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).

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; P <.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 BRCA 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.”

References

  1. 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.
  2. 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.
  3. 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]. N Eng J Med. doi: 10.1056/NEJMoa1810858.
  4. FDA approves niraparib for first-line maintenance of advanced ovarian cancer. Published April 29, 2020. https://bit.ly/3aO6uKP. Accessed April 29, 2020.
  5. Ray-Coquard I, Pautier P, Pignata S, et al. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. N Eng J Med. 2019;381(25):2416-2428. doi: 10.1056/NEJMoa1911361.
  6. 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.
  7. 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]. N Engl J Med. doi: 10.1056/NEJMoa1909707

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