CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: January 23, 2023
Expiration: January 22, 2024
Domenica Lorusso, MD, PhD:
The phase III SOLO‑1 was the first randomized trial to evaluate the approved PARP inhibitor maintenance with olaparib vs placebo in newly diagnosed, International Federation of Gynecology and Obstetrics (FIGO) stage III/IV, high-grade serous or endometrioid advanced ovarian cancer. Initial results of this trial presented in 2018 showed a 3-year increase in median PFS with olaparib.16
Domenica Lorusso, MD, PhD:
At the 2022 ESMO Congress, DiSilvestro and colleagues presented OS results after 7 years of follow-up for SOLO-1.17
In that report, 67% of patients receiving olaparib were still alive compared with 46.5% of patients receiving placebo (HR: 0.55; P <.0004). Moreover, this was despite nearly 45% of patients who initially received placebo crossing over to a PARP inhibitor upon disease progression.
Domenica Lorusso, MD, PhD:
Analysis of time to first subsequent treatment showed that 45.3% of patients receiving olaparib remained alive with no subsequent treatment at 7 years compared with 20.6% of patients receiving placebo. This is remarkable considering that these patients probably had not recurred. Likewise at 7 years, 56.9% of patients in the olaparib arm had not yet received a second subsequent therapy vs 32.5% of patients in the placebo arm.
Domenica Lorusso, MD, PhD:
The toxicity profile was reassuringly similar to the initial presentation of data from SOLO-1.16 In particular, the risk of developing MDS or leukemia did not increase. At 7 years, fewer than 2% of patients receiving olaparib presented with MDS or leukemia.
Alexandra Leary, MD, PhD:
We have long hoped for a new class of drugs able to cure more patients with ovarian cancer. Although additional follow-up will be conducted, I too am impressed with these data. Remember, the PARP inhibitor was stopped after 2 years, so patients are no longer receiving active treatment.
Domenica Lorusso, MD, PhD:
At the 2022 ESMO Congress, Ray-Coquard and colleagues presented final OS results of the PAOLA‑1 trial.18 PAOLA‑1 was a randomized phase III trial comparing olaparib plus bevacizumab with bevacizumab alone as maintenance therapy for newly diagnosed, high‑grade, stage III/IV ovarian cancer, regardless of BRCA mutation or HRD status. The primary endpoint was investigator-assessed PFS per Response Evaluation Criteria in Solid Tumors v1.1. Initial results from PAOLA-1 showed the trial met its primary endpoint with a significant median PFS benefit (21.1 vs 16.6 months; HR: 0.59; P <.001) for the combination of olaparib and bevacizumab vs bevacizumab monotherapy in the overall population and in patients with HRD-positive ovarian cancer (37.2 vs 17.7 months; HR: 0.33; P <.001).19 In this trial, the Myriad myChoice next-generation sequencing assay was used to evaluate HRD status.
Domenica Lorusso, MD, PhD:
In the results from the 2022 ESMO Congress, as with PFS, there was a significant OS benefit for olaparib plus bevacizumab in patients with HRD‑positive cancer, but not in patients with HRD-negative cancer (HR: 0.62). The 5-year OS rate in the HRD‑positive group was 65.5% in those who received olaparib plus bevacizumab vs 48.4% in those who received placebo plus bevacizumab.
Domenica Lorusso, MD, PhD:
The initial results showing a PFS benefit also were confirmed, with 5-year PFS rates of 46.1% for olaparib plus bevacizumab vs 19.2% for bevacizumab plus placebo (HR: 0.41).
By contrast, in the HRD-negative population, there was no significant OS benefit from olaparib plus bevacizumab, with an HR of 1.19 in favor of bevacizumab plus placebo.
Alexandra Leary, MD, PhD:
These data show that PARP inhibition can produce an OS benefit in HRD‑positive disease, even if BRCA wild-type. In the HRD-negative group, olaparib did not provide an OS benefit, and these patients should be treated with single-agent bevacizumab maintenance to avoid increased toxicity. In general, this group has worse PFS and OS than those with HRD-positive disease.
Domenica Lorusso, MD, PhD:
Absolutely—I agree. This HRD-negative population has the worst prognosis.
Domenica Lorusso, MD, PhD:
I want to also point out that the 5-year safety data from PAOLA‑1 were reassuring, with no significant increase in MDS and leukemias. In total, fewer than 2% of patients receiving olaparib presented with MDS, leukemia, or anaplastic anemia in either arm. The percentage of patients with new primary malignancies also remained low, and they were comparable between the olaparib plus bevacizumab and placebo plus bevacizumab arms (4% and 3%, respectively).
Alexandra Leary, MD, PhD:
ATHENA is a 4-arm phase III study of rucaparib maintenance vs placebo in patients with newly diagnosed, stage III/IV, high-grade ovarian cancer who achieved a CR or PR following cytoreductive surgery (R0 permitted) and 4-8 cycles of first-line platinum-doublet CT. The primary endpoint is investigator-assessed PFS in ITT.
Initial results presented at the 2022 ASCO Annual Meeting for the rucaparib monotherapy arm B and placebo arm D, ATHENA-MONO, showed a significant improvement in PFS with rucaparib maintenance compared with placebo alone.20
Alexandra Leary, MD, PhD:
At the 2022 ESMO Congress, Kristeleit and colleagues presented additional results from the ATHENA-MONO trial.21 This included a disease-risk subgroup analysis to help identify which patients benefited most from PARP inhibitor maintenance.
In the HRD and ITT subgroups of ATHENA-MONO analyzed by surgical outcomes, the subgroup with a complete resection (eg, R0) had a PFS HR of 0.52 and 0.60, and patients with an incomplete resection (eg, non-R0) had a PFS HR of 0.29 and 0.41, respectively. This suggests that patients with ovarian cancer and either good or poor risk after surgery will benefit from rucaparib maintenance. Likewise, with the caveat of small patient numbers, the PFS benefit with rucaparib was seen across analyzed subgroups of FIGO stage III/IV (HR: 0.64/0.40), timing of surgery of primary/internal debulking (HR: 0.64/0.44), and CA-125 at baseline of normal/above normal (HR: 0.55/0.26).
In view of these data, we can say that regardless of whether patients were at high or low risk of relapse, they benefited from maintenance with rucaparib in the ATHENA‑MONO analysis. These data continue to add evidence that patients with stage III/IV ovarian cancer will benefit from a PARP inhibitor.
Alexandra Leary, MD, PhD:
ARIEL4 is an ongoing phase III trial comparing rucaparib as treatment (not maintenance) vs CT in patients with relapsed ovarian cancer and deleterious germline or somatic BRCA1/2 mutation.22 In this study, 349 patients with no previous PARP inhibitor exposure were randomized to receive rucaparib 600 mg twice daily vs either weekly paclitaxel or platinum-based CT (single agent or doublet), depending on whether patients at relapse were resistant, partially sensitive, or fully sensitive to CT. Previous results showed a PFS benefit for rucaparib vs standard-of-care CT in these patients with heavily pretreated, BRCA‑mutated ovarian cancer.22
Alexandra Leary, MD, PhD:
At the 2022 ESMO Congress, Oza and colleagues presented the final OS results from ARIEL4.23 As stated before, this patient population was heavily pretreated, with up to 40% of patients having received 3-5 previous CT regimens. Of importance, 49% of patients randomized to receive CT crossed over to rucaparib on progression, including >82% with platinum-resistant or partially platinum-sensitive disease.
The final OS data from ARIEL4 showed a nonsignificant trend in favor of standard-of-care CT in the ITT population (HR: 1.313). Of note, the platinum‑resistant population had worse median OS in the rucaparib arm than in the CT arm (14.2 months vs 22.2 months, respectively; HR: 1.511). OS results were similar in the partially (HR: 0.972) and fully platinum-sensitive (HR: 1.243) subgroups.
In my opinion, these results are not completely surprising. Most oncologists who treat ovarian cancer are slightly concerned that patients who progress on a PARP inhibitor will not do well with subsequent CT, especially platinum, due to overlap in resistance mechanisms.1 Nevertheless, this study does validate earlier data from phase II studies showing a benefit to using a PARP inhibitor (rucaparib) as treatment for patients with heavily pretreated, BRCA‑mutated ovarian cancer.
Alexandra Leary, MD, PhD:
Fortunately, as with other studies already mentioned, the toxicity profile was reassuring, with MDS or AML reported in only 7 patients (3%) initially randomized to receive CT. In my opinion, these results suggest that PARP inhibitors are better used as early as possible in frontline treatment. Dr Lorusso, what do you think?
Domenica Lorusso, MD, PhD:
These results for PARP inhibition in the treatment of active ovarian cancer in the recurrent setting were completely unsettling, especially given the amazing results seen in the first-line and maintenance settings. It is difficult to make a judgment about this study because nearly 70% of patients initially treated with CT received a PARP inhibitor after progression, resulting in 90% of the total patient population receiving rucaparib. Conclusions seem based on sequence instead of comparison, per se. It also is difficult to understand why approximately 42% of patients in the rucaparib arm did not receive any other treatment after progressing on this trial.
Elisabeth Diver, MD:
Currently, we do not have head-to head data on PARP inhibitors for ovarian cancer, and I do not know that we will. I tend to choose a PARP inhibitor based on toxicity profile and the patient’s experience of CT. For example, did they have issues with thrombocytopenia during treatment?
Available length of follow-up data also is influential. Some drugs have been around longer, and healthcare professionals might have more experience using them. But all 3 PARP inhibitor regimens (olaparib, olaparib plus bevacizumab, and niraparib) that are approved by the FDA in ovarian cancer have excellent activity.
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