CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: September 09, 2020
Expiration: September 08, 2021
Bradley J. Monk, MD, FACS, FACOG:
Recent advances with single‑agent poly(ADP‑ribose) polymerase (PARP) inhibitors have been practice-changing in ovarian cancer. The evolution of PARP inhibition has been remarkable since the first FDA approval of olaparib in 2014. To date, 3 PARP inhibitors are approved by the FDA for ovarian cancer treatment in the United States: olaparib, niraparib, and rucaparib.22-24
Olaparib is approved as frontline maintenance therapy for patients with BRCA-mutated advanced disease who have achieved CR or PR to platinum-based chemotherapy; in combination with bevacizumab as frontline maintenance therapy for patients with homologous recombination deficiency (HRD)–positive disease (defined as either BRCA mutated or with genomic instability) who have achieved CR or PR to platinum-based chemotherapy; as maintenance therapy for recurrent disease who have achieved CR or PR to platinum-based chemotherapy regardless of BRCA mutation status; and as fourth-line and later-line treatment for patients with advanced disease with germline BRCA mutations.
Rucaparib is approved as maintenance therapy for recurrent disease who have achieved CR or PR to platinum-based chemotherapy regardless of BRCA mutation status and as third-line and later-line therapy for patients with advanced disease with either germline or somatic BRCA mutations.
Niraparib is approved as frontline maintenance therapy for patients with advanced disease who have achieved CR or PR to platinum-based chemotherapy and as maintenance therapy for recurrent disease who have achieved CR or PR to platinum-based chemotherapy regardless of BRCA mutation status. In addition, niraparib is also approved to treat patients with HRD-positive status who have received ≥ 3 lines of chemotherapy. HRD positivity includes either a deleterious or suspected deleterious BRCA mutation or genomic instability in patients with disease progression ≥ 6 months after a confirmed response to the last platinum-based chemotherapy.
At ASCO 2020, Poveda and colleagues25 presented mature data from the phase III SOLO2 trial of maintenance olaparib in recurrent, platinum-sensitive ovarian cancer with a BRCA mutation (Capsule Summary). We have previously seen the improvements in PFS that led to the approval of olaparib; now we can see the final OS analysis.26
Bradley J. Monk, MD, FACS, FACOG:
Patients with platinum-sensitive relapsed ovarian cancer (≥ 2 previous lines of platinum-based therapy) and a germline BRCA1/2 mutation who were in CR or PR on most recent therapy were randomized 2:1 to receive olaparib 300 mg twice daily or placebo (N = 295). The final OS analysis was adjusted for subsequent PARP inhibitor use and included post hoc sensitivity analysis based on electronic case reporting and prespecified OS sensitivity analysis of the germline BRCA mutation subgroup.
Bradley J. Monk, MD, FACS, FACOG:
The treatment arms were well balanced. The majority of patients had serous histology. Approximately two thirds had germline mutation in BRCA1 and one third had germline BRCA2 mutation.
Bradley J. Monk, MD, FACS, FACOG:
The final OS analysis showed that olaparib maintenance for a patient with platinum-sensitive recurrent ovarian cancer with a BRCA mutation can extend survival for 12.9 months vs placebo: median OS of 51.7 months vs 38.8 months, respectively (HR: 0.75; 95% CI: 0.54-1.00; P = .0537). Although the difference did not quite reach statistical significance, a 12.9 month OS improvement is still clinically meaningful—we can help our patients live longer.
Not only that, we have already seen in this trial that the improvement in OS is not associated with a decrement in quality of life. These results are very exciting. There also appears to be a tail on the OS curve, which suggests there might be some patients who benefit long-term from this treatment approach, although we need longer follow-up to confirm this. In an exploratory analysis of OS data adjusted for subsequent PARP inhibitor use, there remains an OS benefit for patients receiving olaparib maintenance.
Bradley J. Monk, MD, FACS, FACOG:
We know the time to subsequent relapse shortens with each therapy in recurrent ovarian cancer, so a goal of treatment is to delay that progression and the need for subsequent treatment. Olaparib prolonged the time to subsequent therapy by 20 months, with a median of 27.4 months vs 7.2 months with placebo (HR: 0.37; 95% CI: 0.28-0.48; P < .0001).
Bradley J. Monk, MD, FACS, FACOG:
However, the efficacy of PARP inhibition comes with an increased risk of myeloid leukemia or myeloid dysplastic syndrome. PARP inhibitors work by inhibiting single‑stranded DNA repair, causing double‑stranded breaks that mutated BRCA is unable to repair, leading to apoptosis in patients with BRCA mutation. But they also damage noncancerous DNA and can cause acute myeloid leukemia and myelodysplastic syndromes.
The study’s primary analysis reported 2% to 4% incidence of acute myeloid leukemia and myelodysplastic syndromes. In this final analysis, acute myeloid leukemia/myelodysplastic syndromes incidence has increased to 8% in the olaparib arm and 4% in the placebo arm. I commend the investigators for reporting mature adverse reaction data so that we can understand the potential risks.
Bradley J. Monk, MD, FACS, FACOG:
Other adverse events are consistent with the primary safety analysis, with mostly low-grade events. The exceptions are 21% incidence of grade ≥ 3 anemia and 7% grade ≥ 3 neutropenia in the olaparib arm.
Bradley J. Monk, MD, FACS, FACOG:
Overall, this final survival analysis shows that maintenance olaparib prolongs OS and time to subsequent treatment. The increased risk of acute myeloid leukemia/myelodysplastic syndromes is a concern that warrants further study, but otherwise, prolonged olaparib treatment appears to be well tolerated.
These data confirm current clinical practice for the use of olaparib as maintenance therapy for patients with recurrent ovarian cancer who are in CR or PR after platinum-based chemotherapy.
Bradley J. Monk, MD, FACS, FACOG:
The phase II AVANOVA2 trial evaluated another combination, the PARP inhibitor niraparib with or without the VEGF inhibitor bevacizumab (Capsule Summary).27,28 Two anti‑VEGF molecules have been studied in combination with PARP inhibitors in phase II trials, one is oral (cediranib) and one is intravenous (bevacizumab). The combination of bevacizumab and the PARP inhibitor olaparib was FDA approved in 2020 as frontline maintenance for advanced ovarian cancer, based on data from the PAOLA-1 trial. In this study, the addition of olaparib to bevacizumab extended median PFS to 37.2 months compared with 17.7 months with bevacizumab alone (HR: 0.33; 95% CI: 0.25-0.45) in patients with HRD-positive tumors.29
At ASCO, Mirza and colleagues28 presented an extended follow-up of AVANOVA2. This was a small, hypothesis-generating study that was not placebo controlled, comparing niraparib/bevacizumab vs niraparib in platinum‑sensitive recurrent cancer. A previous analysis reported longer PFS with the combination compared with niraparib alone.27
Bradley J. Monk, MD, FACS, FACOG:
Patients were randomized to receive either niraparib 300 mg daily and bevacizumab 15 mg/kg every 3 weeks (n = 48) or niraparib alone (n = 40). It is important to note that this was a 2-arm study, with no bevacizumab-only arm. That makes it difficult to evaluate whether any activity of the combination may be due to the bevacizumab.
This extended analysis presented updated survival data, as well as additional safety and efficacy endpoints.
Bradley J. Monk, MD, FACS, FACOG:
The updated survival analysis reports that median PFS with the combination was 12.5 months, more than twice as long as the 5.5 months with niraparib alone (HR: 0.34; 95% CI: 0.21-0.54; P < .0001). There was no significant difference in OS or improvement in other endpoints, including time to subsequent therapy and PFS2. The OS event maturity was 52%.
Bradley J. Monk, MD, FACS, FACOG:
As with any anti‑VEGF agent, we would expect to see some hypertension, and an oral agent can cause some GI side effects as well as proteinuria, wound healing, and even GI perforation. In this trial, the most common adverse events in both treatment arms included nausea, anemia, fatigue, constipation, and thrombocytopenia. Hypertension and proteinuria, along with vomiting and peripheral sensory neuropathy, were more common with niraparib plus bevacizumab vs niraparib alone.
However, VEGF and PARP inhibitors are tolerated well together and this is reflected in the EORTC QLQ-C30 global health status of quality-of-life scores, which were similar between the treatment arms. We have seen similar trends with the FDA-approved regimen olaparib/bevacizumab, with olaparib/cediranib in the GY004 study,30 and now this combination, niraparib and bevacizumab, in the AVANOVA2 trial.
Bradley J. Monk, MD, FACS, FACOG:
In conclusion, the extended follow-up of AVANOVA2 showed that niraparib plus bevacizumab did significantly improve clinical outcomes over niraparib alone in platinum‑sensitive recurrent ovarian cancer, with the caveat that there was no bevacizumab arm, as I mentioned. The combination was generally well tolerated, and these results support a phase III trial of this combination.
Bradley J. Monk, MD, FACS, FACOG:
The next emerging concept in ovarian cancer is immunotherapy. We have multiple immune checkpoint inhibitors that are approved by the FDA, including pembrolizumab monotherapy and/or combinations in endometrial cancer and cervical cancer, but none yet in ovarian cancer. Here, Matulonis and colleagues31 presented the final results of the largest single-agent checkpoint inhibitor trial in recurrent ovarian cancer, called KEYNOTE‑100 (Capsule Summary).
We were very excited about this trial. Most patients with ovarian cancer relapse, and there are few treatment options for recurrent disease. Pembrolizumab has shown response rates of approximately 8% to 11% in patients with PD-L1–positive recurrent ovarian cancer in KEYNOTE-028 and in the interim analysis of KEYNOTE-100.32,33
Bradley J. Monk, MD, FACS, FACOG:
KEYNOTE-100 enrolled 376 patients with advanced recurrent ovarian cancer to receive pembrolizumab monotherapy.31 Patients were divided into 2 cohorts based on prior treatment. Cohort A included 285 patients who had received 1-3 previous lines of therapy, with the most recent within the last 3-12 months. Cohort B had 91 patients who had 4-6 previous lines of therapy, with the most recent at least 3 months earlier.
Patients received pembrolizumab 200 mg IV every 3 weeks for up to 2 years or until progression, death, or unacceptable toxicity. The primary endpoint was ORR and secondary endpoints included duration of response, disease control rate, survival, and safety.
Bradley J. Monk, MD, FACS, FACOG:
Approximately one third of the enrolled patients were younger than 65 years, and two thirds had an ECOG performance status of 0.
Bradley J. Monk, MD, FACS, FACOG:
This trial was strategically designed to evaluate whether heavily pretreated patients have poorer outcomes. In general, checkpoint inhibition is not especially effective for patients with recurrent advanced ovarian cancer, but the good news is that the number of lines of prior therapy do not appear to make a big difference. Heavily pretreated patients do not have T-cell exhaustion, and pembrolizumab shows some activity. Unfortunately, the response rates are not impressive in either cohort.
The patients in cohort A with 1-3 previous lines of therapy had an ORR of 8.1% and a disease control rate of 22.1%. In the more heavily pretreated cohort B with 4-6 previous lines of therapy, the ORR was 9.9% with a disease control rate of 22%. Those rates are generally consistent with other reports of the activity of checkpoint inhibitors in recurrent ovarian cancer—usually approximately 10%.
Bradley J. Monk, MD, FACS, FACOG:
A subgroup analysis looked at ORR by PD-L1 expression, histologic subtype, platinum sensitivity, and more, but unlike in other tumors, there were no subgroups or biomarkers that make this agent exciting in ovarian cancer.
Bradley J. Monk, MD, FACS, FACOG:
A small subset of patients did respond to pembrolizumab. Between the 2 cohorts, 31.6% of patients had a decrease in target lesion, but this did not translate into an impressive response rate.
Bradley J. Monk, MD, FACS, FACOG:
When we look at responses broken down by PD-L1 expression level, ORR may be slightly numerically higher among patients with CPS ≥ 10 (ORR: 8.0% in CPS ≥ 1 vs 13.8% in CPS ≥ 10). However, there is no meaningful difference in ORR or disease control rate based on PD-L1 expression.
Bradley J. Monk, MD, FACS, FACOG:
Looking at the PFS curve reminds us that approximately one half of the patients have progressed by the first assessment. The median PFS was 2.1 months in both cohorts and the estimated 12-month PFS rate was 10.1% in cohort A and 13.1% in cohort B.
These data highlight the malignant potential of recurrent ovarian cancer: These patients have a large tumor burden and progress very quickly. Some hypothesize that these patients may not be able to remain on therapy long enough for the medication to make a difference.
Similarly, the OS data also show absolutely no difference, with a median OS of approximately 18 months for both cohorts and an estimated 12-month OS rate of 66% for both cohorts.
Bradley J. Monk, MD, FACS, FACOG:
PD-L1 CPS ≥ 10 may slightly prolong OS, particularly in the heavily pretreated cohort.
Bradley J. Monk, MD, FACS, FACOG:
The safety profile of pembrolizumab in recurrent ovarian cancer is consistent with what we might expect to see. Approximately 20% of patients experienced grade ≥ 3 treatment-emergent adverse events, and 5.1% discontinued study drug due to adverse events. There were 2 deaths attributed to treatment: one case of Stevens-Johnson syndrome and one of hypoaldosteronism.
Bradley J. Monk, MD, FACS, FACOG:
Immune-mediated adverse events were also as expected, with primarily low-grade cases of hypothyroidism and hyperthyroidism.
Bradley J. Monk, MD, FACS, FACOG:
Overall, the outcomes of this trial were not what we might have hoped to see, with only moderate efficacy of pembrolizumab monotherapy in both patient cohorts. I think that treatment with immune checkpoint inhibitors is still evolving, and the investigators say they are continuing to analyze potential predictive biomarkers. The bottom line is that immune checkpoint inhibitors used as single agents are not active in this patient population. They also seem to not have much effect when added to chemotherapy, as in the JAVELIN 100 and JAVELIN 200 studies.34,35
More exciting for ovarian cancer, in my view, is using multiple targeted therapies together in combinations. There are multiple randomized trials in the frontline setting and some single‑arm trials in the recurrent setting evaluating the addition of PARP inhibitors to checkpoint inhibitors. The IMagyn50 study (NCT03038100), combining the anti‑VEGF inhibitor bevacizumab to the checkpoint inhibitor atezolizumab, will be the first of those trials to mature, later this year.36
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