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Clinical Trials Point to Broader Role for PARP Inhibitors in Advanced Ovarian Cancer

BARCELONA – Advanced ovarian cancer patients may benefit from early combination or maintenance treatments that include a PARP inhibitor even if they do not carry germline or somatic mutations in the BRCA1/2 genes, according to data from three Phase III clinical trials presented at the European Society for Medical Oncology Congress this past weekend.

Those findings come a year after data from the Phase III SOLO-1 trial were presented at ESMO and were published in the New England Journal of Medicine not long after, prompting the US Food and Drug Administration to approve the PARP inhibitor olaparib (Lynparza from AstraZeneca and Merck) and the Myriad Genetics' BRACAnalysis companion diagnostic for maintenance therapy in BRCA-mutated ovarian cancer patients who had already responded to platinum chemotherapy.

This June, the European Commission followed suit, approving olaparib as a maintenance treatment for platinum-treated advanced ovarian, fallopian tube, or primary peritoneal cancers in women with germline or somatic BRCA mutations.

At the latest ESMO gathering, investigators from the Phase III PAOLA-1, PRIMA, and VELIA trials presented data that may push PARP inhibitors to additional ovarian cancer sub-populations or into earlier treatment for advanced-stage disease.

In the randomized, double-blind PAOLA-1 trial, for example, researchers from France, Italy, and other international centers compared progression-free survival in women with high-grade serous or endometrial ovarian cancer, fallopian tube, or primary peritoneal cancer who were randomized at a ratio of two-to-one to receive maintenance therapy with the VEGF-targeting monoclonal antibody bevacizumab (Genentech's Avastin) for up to two years in combination with the PARP inhibitor olaparib or with a placebo.

That trial included 806 patients with stage III or IV ovarian cancer who received first-line treatment with surgery and platinum-based therapy followed by at least three cycles of bevacizumab in combination with a placebo or with olaparib.

Though the PAOLA-1 investigators did stratify their analyses on specific patient sub-populations — including BRCA mutation carriers — all participants were eligible to get olaparib, regardless of their BRCA status, Isabelle Ray-Coquard, a medical oncologist at the Claude Bernard Lyon University, explained during a press briefing on Saturday.

Across the advanced ovarian cancer cohort, the investigators saw progression-free survival times post-randomization that stretched out from an average of 16.6 months in the placebo-bevacizumab arm to just over 22 months, on average, in the patients treated with both olaparib and bevacizumab as a maintenance therapy.

As expected from current PARP inhibitor use in ovarian cancer, the effect was particularly pronounced for the individuals with mutated BRCA1/2 in their tumors. There, median time to progression reached 37.2 months in the olaparib-bevacizumab arm compared to 21.7 months in the bevacizumab-control arm.

But the team also saw a progression-free survival advantage in patients with homologous recombination deficient (HRD) tumors, as measured using the Myriad myChoice HRD plus assay, even when excluding BRCA mutation carriers.

Progression-free survival reached 28.1 months, on average, in the 97 HRD-positive, BRCA mutant-negative patients who got olaparib and bevacizumab maintenance compared to an average of 16.6 months in the 55 HRD-positive, BRCA-negative individuals on bevacizumab with placebo.

Such results hint that the potential benefits of PARP inhibitor treatment beyond the BRCA-mutated ovarian cancer population, noted Susana Banerjee, a consultant medical oncologist and gynecology unit research lead at the Royal Marsden Hospital-NHS Foundation Trust, who was not involved in the trial.

Commenting on PAOLA-1, Banerjee told reporters that the results suggest that more women with advanced ovarian cancer can benefit from PARP inhibitors. Even so, she noted that such results will inevitably raise new questions about whether HRD or another marker should be used to target the drugs to appropriate patient sub-populations, when to combine the drugs with other treatments, and so on.

Results from two more Phase III trials supported the notion that PARP inhibitors have the potential for wider use in advanced ovarian cancer, while at once adding to the complexity for clinicians wading through PARP inhibitor-based options that may be available in these patients.

In the PRIMA trial, investigators saw a significant decline in disease recurrence or death in an analysis of 733 platinum chemotherapy-responding, advanced high-grade serous or endometrioid ovarian cancer patients who were randomized to maintenance therapy with the PARP inhibitor niraparib (Zejula from GlaxoSmithKline) rather than to the placebo arm.

Progression-free survival came in at 13.8 months in the PARP inhibitor maintenance arm versus 8.2 months in the placebo arm. And in the sub-population of 373 patients with HRD, niraparib maintenance therapy was linked to a lack of progression for 21.9 months, while progression-free survival on placebo was 10.4 months in this sub-population.

First author Antonio Gonzalez-Martin, a medical oncologist at the Clinica Universidad de Navarra, shared PRIMA data during a presidential symposium at the ESMO conference on Saturday. The results appeared online the same day in NEJM.

"In the PRIMA trial, our primary hypothesis was that the clinical benefit of first-line treatment with niraparib could be extended to all patients with advanced ovarian cancer, including those who had tumors with homologous recombination deficiency (with either mutated or unmutated BRCA) and those with homologous recombination proficiency," the authors wrote. "Results of this trial confirm the hypothesis that treatment with niraparib provides a longer duration of progression-free survival than placebo in the overall population."

In July, GlaxoSmithKline announced that that trial had reached its primary endpoint of significantly improved progression-free survival. Earlier this year, Myriad began the process of seeking premarket approval from the FDA to use the myChoice HRD assay as a companion diagnostic for niraparib. The firm's BRACAnalysis CDx is already approved by the American regulator as a companion diagnostic to find germline BRCA mutations in ovarian cancer patients who may benefit from that PARP inhibitor.

Finally, MD Anderson's Robert Coleman outlined results from the Phase III VELIA trial, which looked at the PARP inhibitor veliparib (in development by AbbVie) in combination with carboplatin and paclitaxel chemotherapy for initial treatment of advanced high-grade serous ovarian carcinoma and as a maintenance therapy after this combination therapy.

Like the PRIMA data, the VELIA trial was published in NEJM to coincide with the presentation at ESMO.

After randomizing more than 1,100 patients on this multi-pronged randomization scheme and comparing progression patterns in the BRCA-mutated, HRD, and full patient populations, the VELIA investigators concluded that use of the PARP inhibitor across initial treatment and maintenance stages could increase time to progression overall.

For patients who got veliparib in combination with chemotherapy, followed by veliparib maintenance, the researchers reported a progression-free survival time of 23.5 months. In the arm receiving chemotherapy followed by placebo, it was 17.3 months. Again, though, there were signs that this effect was boosted in the sub-populations with BRCA mutations or other forms of HRD.

Commenting on the trial during a subsequent presentation at the symposium, Copenhagen University Hospital's Mansoor Raza Mirza noted the benefit of incorporating veliparib into treatment for the patients with BRCA mutations but also raised concerns about the additional toxicity associated with using the PARP inhibitor in combination with chemotherapy. 

He suggested that further comparisons will be needed to evaluate optimal treatment approaches in advanced ovarian cancer patients, particularly since the VELIA trial did not include an arm looking only at that PARP inhibitor in the maintenance treatment setting.