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Practical Considerations for Using PARP Inhibitors in Ovarian Cancer: Key ESMO Congress Updates

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Alexandra Leary, MD, PhD

Medical Oncologist and Team Leader
Gynecology Translational Research Lab
Department of Medicine
Gustave Roussy Cancer Center
Paris, France


Alexandra Leary, MD, PhD: consultant/advisor/speaker: Ability, AstraZeneca, Clovis, GlaxoSmithKline, Merck Sharp and Dohme, Zentalis; researcher: Apmonia; AstraZeneca.


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Domenica Lorusso, MD, PhD

Associate Professor
Gynecologic Oncology Department
Clinical Research Unit
Fondazione Policlinico Gemelli IRCCS
Rome, Italy


Domenica Lorusso, MD, PhD: consultant/advisor/speaker: AstraZeneca, Clovis, Genmab, GlaxoSmithKline, Immunogen, Merck Sharp and Dohme, Novartis, Seagen, Sutro.


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Released: October 19, 2022

Key Takeaways

  • In the SOLO-1 study, maintenance therapy with 2 years of the PARP inhibitor olaparib showed a strong overall survival benefit vs placebo at 7 years of follow-up in patients with stage III/IV ovarian cancer with a BRCA mutation.
  • In the PAOLA-1 study, patients with ovarian cancer with homologous recombination deficiency experienced meaningful benefit from PARP inhibition plus bevacizumab. 
  • In the ARIEL4 study of the PARP inhibitor rucaparib as treatment for ovarian cancer, a progression-free survival benefit was seen vs chemotherapy, but overall survival was not significantly improved.

Treatment for ovarian cancer is continually evolving. In this commentary, Alexandra Leary, MD, PhD, and Domenica Lorusso, MD, PhD, discuss select studies of PARP inhibition in ovarian cancer from the European Society for Medical Oncology (ESMO) Congress 2022 in Paris, France, and their potential influence on the current standard of care.

SOLO-1: Olaparib Maintenance

Domenica Lorusso, MD, PhD:
SOLO‑1 was the first randomized trial to evaluate the approved PARP inhibitor olaparib in ovarian cancer. Patients with stage III/IV high-grade ovarian cancer with a BRCA mutation were randomized to receive 2 years of maintenance therapy with either olaparib or placebo. Initial results of this trial presented in 2018 showed a 3-year increase in median progression‑free survival (PFS) with olaparib. At the ESMO Congress, DiSilvestro and colleagues presented overall survival (OS) results after 7 years of follow-up.

After 7 years, 67% of patients receiving olaparib were still alive compared with 46.5% of patients receiving placebo (HR: 0.55). Moreover, this was despite nearly 45% of patients who initially received placebo crossing over to a PARP inhibitor on progression.

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.

The toxicity profile was reassuringly similar to the initial presentation of data from SOLO-1. In particular, the risk of developing myelodysplastic syndromes or leukemia did not increase. At 7 years, fewer than 2% of patients receiving olaparib presented with myelodysplastic syndromes 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. 

PAOLA‑1 : Olaparib Plus Bevacizumab Maintenance

Domenica Lorusso, MD, PhD:
At the ESMO Congress, Ray-Coquard and colleagues presented final OS results of the PAOLA‑1 trial. 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 homologous recombination deficiency (HRD) status. Initial results showed a significant PFS benefit for the combination of olaparib and bevacizumab in patients with HRD-positive ovarian cancer. In this trial, the myChoice next-generation sequencing assay was used to evaluate HRD.

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. 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. 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 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. I want to also point out that the 5-year safety data from PAOLA‑1 were reassuring, with no significant increase in myelodysplastic syndromes and leukemias.

ATHENA‑MONO: Rucaparib Maintenance

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 complete response (CR) or partial response (PR) following cytoreductive surgery (R0 permitted) and 4-8 cycles of first-line platinum-doublet chemotherapy. Initial results presented at the 2022 American Society of Clinical Oncology Annual Meeting showed a significant improvement in PFS with rucaparib maintenance compared with placebo alone.

At the ESMO Congress, Kristeleit and colleagues presented results from the ATHENA-MONO analysis of rucaparib monotherapy vs placebo. This included a disease-risk subgroup analysis to help identify which patients benefit most from PARP inhibitor maintenance. Patients in the ATHENA-MONO subgroup with a complete resection (eg, R0 and non-R0) had a PFS HR of 0.60, and patients with an incomplete resection had a PFS HR of 0.41. 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 conclusion, 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.

ARIEL4: Rucaparib as Treatment

Alexandra Leary, MD, PhD:
ARIEL4 is an ongoing phase III trial comparing rucaparib as treatment (not maintenance) vs chemotherapy in patients with relapsed ovarian cancer with germline or somatic BRCA1/2 mutation. 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 chemotherapy (single agent or doublet) depending on whether patients at relapse were resistant, partially sensitive, or fully sensitive to chemotherapy. Previous results showed a PFS benefit for rucaparib vs standard-of-care chemotherapy in these patients with heavily pretreated BRCA‑mutated ovarian cancer. At the ESMO Congress, Oza and colleagues presented the final OS results from ARIEL4. This patient population was heavily pretreated, with up to 40% of patients having received 3-5 previous chemotherapy regimens. Of importance, 49% of patients randomized to receive chemotherapy 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 chemotherapy in the intention-to-treat population (HR: 1.313). Of importance, the platinum‑resistant population had worse median OS in the rucaparib arm than in the chemotherapy arm (14.2 months vs 22.2 months, respectively). OS results were similar in the partially and fully platinum-sensitive subgroups.

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 chemotherapy, especially platinum, due to overlap in resistance mechanisms. 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. Fortunately, the toxicity profile was reassuring, with myelodysplastic syndromes or acute myeloid leukemia reported in only 7 patients (3%) initially randomized to receive chemotherapy.

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 treatment of active ovarian cancer were completely upsetting, especially given the amazing results 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 chemotherapy 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.

Your Thoughts?
What are the challenges you experience in your practice when it comes to integrating PARP inhibitors into the treatment of your patients with ovarian cancer? Answer the polling question and join the conversation in the discussion box below.

 

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