Overall Survival Data fails to show superiority in ARIEL4 confirmatory clinical study

Ovarian cancer has a poor prognosis, mainly because it is usually diagnosed at an advanced stage. Approximately 50% of the diagnosed patient die within five years of diagnosis. Heterogeneous nature of ovarian cancer assume significance for diversify causative agents. BRCA oncogene also could be a causative factor for ovarian cancer and ~11% of OC patients have mutation in the BRCA-1 gene, and ~10% have a BRCA-2 gene mutation. Historically platinum based chemotherapies have been main stream treatment options in initial lines of therapy. Evolution of treatment with the breakthrough findings in the form of PARP inhibitors significantly altered the treatment outlook in ovarian cancer. PARP inhibitors are being used as maintaince therapy to newly diagnosed, rather than being used only after other therapies have failed. But Care givers expect as their numbers will grow, so too might their applications.

Chemo resistance for frontline chemotherapies leads to higher recurrence rate in OC. Since there is a paucity of targeted drugs in the advanced line of therapy, care givers tend to change different combination regimen which are used in earlier lines. PARP inhibitors are approved in ovarian cancer mostly for maintenance therapy. But rarely for treatment in fourth or later line of therapy. The efficacy outlook of front-line agents have been poor and care givers feel huge unmet need in relapse or refractory ovarian cancer patients.

In December 2016, the US.FDA approved CLOVIS’ Rubraca as a mono therapy for advanced ovarian cancer patients with deleterious BRCA mutation after progression on at least 2 Lines of therapy. Rubraca is  a “PARP—a protein that helps repair DNA when it becomes damaged” Inhibitor. It was first and only PARP inhibitor approved for Ovarian Cancer. Approval was granted under the FDA’s accelerated approval program based on clinical study data from Study 10 and ARIEL2.

The ARIEL4 is the Phase III confirmatory clinical study, to compare the efficacy and safety of rucaparib versus chemotherapy as treatment for relapsed ovarian cancer in patients with a deleterious BRCA1/2 mutation. The results from clinical study (Overall Survival) data were published at ESMO 2022:

• Median OS were found to be 19.4 months in the rucaparib arm vs. 25.4 months in the chemotherapy arm ( HR, 1.313), which reflects median OS favored the chemotherapy arm
• The overall survival data was more reassuring in chemotherapy arm, if analyzed for  different sub group of ITT population
• In platinum-resistant subgroup of patients median OS was found to be 14.2 months and 22.2 months with rucaparib and chemotherapy, respectively (HR, 1.511)
• In platinum sensitive subgroup of patients median OS was found to be 29.4 months and 27.6 months with rucaparib and chemotherapy, respectively (HR, 1.071)
• Median duration of randomized treatment was found to be longer in the rucaparib vs. chemotherapy group:
  • In platinum resistance patients, 5.6 months vs. 4.4 months;
  • In partial platinum sensitive patients 7.6 months vs. 4.5 months,
  • In full platinum sensitive patients 13.7 months vs. 3.4 months respectively.
• Subsequent treatment of any kind was more common in the chemotherapy vs. rucaparib arm.
• Crossover therapy to rucaparib in chemotherapy was found to be high, 69% patients in the chemotherapy group did crossover to receive rucaparib and continued treatment for more than 6 months
• Median OS was found to be favorable for rucaparib arm, if adjusted analysis performed that excluded patients who crossed over from chemotherapy to rucaparib, median OS were found to be 19.4 months and 9.1 months with rucaparib and chemotherapy arms, respectively. However, if results were censored at crossover, OS outcomes were similar between both the arms (P = .673)
• The objective response rate (ORR) was approximately similar between both the arms, 40.3% in the rucaparib arm and 32.3% in the chemotherapy arm (P = .13)
• Median duration of response in rucaparib vs. Chemotherapy arm were found to be 9.4 months and 7.2 months (HR = 0.59)
• Median progression-free survival (PFS) in rucaparib vs. chemotherapy arm were found to be 7.4 months and 5.7 months, respectively (P = .002). It reflected that rucaparib was Superior in PFS Analyses. However, in sub groups of patients with BRCA reversion mutations, the median PFS were found to be 2.9 months and 5.5 months (HR = 2.77), respectively
• In terms of second progression (PFS2), both arms resulted in similar outcomes, for platinum resistance patients (HR, 0.968). While slightly favoulable in rucaparib arm for both partial (HR, 0.65) and full platinum sensitive patients (HR, 0.88)
• There were no new safety signals noted

According to updated OS data at ESMO 2022, increase risk of death was found in rucaparib arm. Discouraged with the overall clinical findings, the Clovis chose to voluntarily withdraw the approval of rucaparib from both the US and European market for advanced ovarian cancer patients with deleterious BRCA mutation after progression on at least 2 Lines of therapy. Analyst estimates that such recalls will adversely impact revenue market share of rucaparib in both OC and other indications. Rucaparib’s withdrawal will certainly be worrisome to both patients and caregivers as it once again leaves a huge void in the treatment paradigm of relapse/refractory ovarian cancer.

As updated data from ARIEL4 study failed to impress, the Clovis’s prospect, in sNDA submission for “first-line maintenance” treatment in OC based on ATHENA-MONO trial data, may also face hindrance from regulators. US.FDA has already advised the drug makers, that they should not submit the first-line maintenance sNDA until OS findings from the ATHENA-MONO trial are as much as 50% mature. The FDA’s advice pushes the sNDA submission to a minimum delay of two more years.

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