October 2019 Edition Vol.11, Issue 10

PARP Inhibitors Win, Place, and Dramatically Show at ESMO 2019

By Neil Canavan

“This is a paradigm shift in the first-line treatment for advanced ovarian cancer patients.”

-Ana Oaknin, MD, PhD, Vall d´Hebron Institute of Oncology, Barcelona, Spain

Once you drill down into the data, hyperbole often dies, but at ESMO 2019, three distinct clinical trials using three different PARP inhibitor agents in the setting of advanced ovarian cancer prompted most, if not all observers that a new standard of care in front-line treatment had just been established.

The trials, with the code names PRIMA, PAOLA, and VELIA – highlighted herein – provided clear evidence of improved survival for nearly all patient subtypes, and this, without significant impact on patient quality of life.

Primo Prima

First up, PRIMA, a phase III investigation of the PARP (Poly ADP Ribose Polymerase) inhibitor, niraparib, in patients with newly diagnosed, advanced ovarian cancer. “I’m going to show you results of the trial that should change how we treat ovarian cancer,” said PRIMA lead investigator, said Antonio González-Martín, MD, co-director, Department of Medical Oncology, Clinica Universidad de Navarra, Spain. “For the first time you will see positive data for PARP inhibitors in patients in front line – not only for BRCA mutations, but also for patients whose tumors are BRCA wild type.”

As González-Martín’s comments suggest, such progress is big news. Of the roughly 22,000 new cases of ovarian cancer diagnosed each year, 61% of patients will present in an advanced state. Even though most of these women will respond to initial treatment with platinum-based chemotherapy, approximately 85% will experience a disease recurrence; thereafter, treatment options are few.

Enter the PARPs, of which there are now four FDA-approved agents indicated for breast cancer, or ovarian, or both. Of the approved agents discussed here, the use of oliparib (PAOLA) requires the presence of a BRCA mutation, while niraparib (PRIMA) does not. (Veliparib, from the VELIA trial, is investigational.)

The presence of a BRCA, or similar type mutation in the patient’s tumor is key, since the mechanism of action of all PARPs is to inhibit the repair of DNA damage – damage such as that incurred by chemotherapy or radiation.

For PRIMA, patients eligible for enrollment had high-grade serous, or endometroid pathology, stage III or IV disease, who experienced a partial, or complete response to first-line platinum treatment; patients with no visible evidence of residual disease after primary debulking surgery were excluded. After enrollment, all patients were tested for mutations in homologous recombination (HR) repair enzymes, and stratified as “deficient” (HRd) or “proficient” (HRp) in the trial results.

Patients were randomized in a 2:1 fashion to maintenance treatment with niraparib (200mg-300mg QD, depending on weight; n=484) or placebo (n=244), for 36 months, or until disease progression. The primary endpoint for PRIMA was progression-free survival (PFS).

The treatment arms were balanced for the presence of BRCA mutation (30%), and HRd (51%). Almost all patients with stage III status had residual disease after surgery.

Results for niraparib maintenance treatment for the overall patient population at the 18-month time point showed an impressive increase in PFS of 13.8 months for niraparib vs 8.2 months for placebo. That said, the results for patients with HRd status were even more striking, with an increase in PFS of over 10 months for the PARP inhibitor, as compared to placebo (21.9 vs 10.4 months), with a hazard ratio of 0.43 (P<=0.043) (Fig. 1).

“This translates into a 57% reduction in the hazard of relapse or death with niraparib,” said González-Martín.

Regarding all patient subtypes, the best results were observed in the BRCA mutation positive (BRCAmt)/HRd setting (HR=0.40), whereas the worst outcomes were seen with HRp individuals (HR=0.68) (Fig. 2).

Perhaps most interesting was the group of BRCA wild type (wt)/HRd patients, where “…Niraparib provided similar clinical benefit in the HRd subgroups, whether BRCA mutant, or wild type,” González-Martín reported.

For overall survival, though data are not yet mature, a pre-planned interim analysis shows a numerical superiority for niraparib vs. placebo.

The adverse events observed in the niraparib treatment arm were deemed, “manageable, and consistent with the PARP inhibitor class.”

“Niraparib is the first PARP inhibitor to demonstrate benefit in patients across biomarker subgroups after platinum-based chemo,” said González-Martín. “Based on these results, niraparib monotherapy after first-line chemotherapy should be considered a new standard of care.”

PAOLA-1

A second phase III investigation of a PARP inhibitor, that being olaparib, looked at efficacy in combination with the anti-angiogenic agent, bevacizumab (BV) in the same patient population as did PRIMA.

“PAOLA-1 is the first phase III trial to evaluate maintenance therapy with a PARP in patients with advanced ovarian cancer – regardless of BRCA status – who are receiving first-line treatment with standard or care (SOC), plus bevacizumab,” said PAOLA investigator, Isabelle L. Ray-Coquard, MD, PhD, of the Centre Leon Bérard, Lyon, France.

For PAOLA, eligible patients received SOC plus BV (this use is on-label), and were then randomized in a 2:1 fashion for maintenance therapy with either olaparib (300mg BID for 2 years) plus BV (15mg/kg every 3 weeks for 15 months; n=537) or placebo/BV (n=269).

Patients were stratified by BRCA status, and SOC treatment outcomes. The primary endpoint of the trial was investigator-assessed PFS. The median follow-up for the study was 23 months.

In the intent to treat population, PAOLA demonstrated a PFS of 22.1 months for olaparib vs. 16.6 months for the control arm (HR=0.59; P<0.0001).

For patient subgroups, the best results were seen for patients with BRCAmt status – a PFS of 37.2 months for the oliparib combination vs. 21.7 months for placebo (HR=0.31) (Fig. 3).

For the HRd/BRCAmt patients, a stellar improvement was observed in PFS: 17.7 months for the control group vs 37.2 months in the oliparib arm (HR=0.33) (Fig. 4).

For the HRd/BRCAwt patient cohort, the hazard ratio favoring oliparib was 0.43 – which, mechanistically, shouldn’t surprise. “Homologous recombination repair deficiency is not limited to BRCA mutations, and is present in roughly 50% of high-grade serious ovarian tumors,” said Ray-Coquard. As contrast to that, results for patients determined to be HRp were dismal, and “non-significant.”

Efficacy did come at some cost to patient comfort. The discontinuation rate due to treatment-emergent adverse events were 20% in the oliparib arm vs. 5% with BV alone.

Despite this downside, Ray-Coquard concluded that, “The results reveal a patient population beyond BRCA (mutations) who are HRd positive, that experience substantial benefit from maintenance therapy with bevacizumab.”

VELIA

“It’s a great day for women with ovarian cancer.” So began Robert L. Coleman, MD, of the MD Anderson Cancer Center as he embarked on his presentation of the efficacy results for VELIA, a phase III study of front-line carboplatin/paclitaxel (SOC) combined with veliparib, followed by veliparib maintenance in patients with newly diagnosed, advanced ovarian cancer (N=1140).

The trial had three treatment arms, randomized in 1:1:1 fashion: veliparib/chemo, followed by veliparib, called “veliparib throughout”; veliparib/chemo followed by placebo; and SOC, with placebo maintenance. The primary endpoint was PFS for veliparib Throughout vs. control.

Treatment arms were balanced for BRCAmt status – 31% for patients in Throughout vs. 27% for control, and HRd – 63% for both groups.

Results for efficacy rivaled those for oliparib, and niraparib. The PFS for the intent to treat population was 23.5 months for Throughout vs. 17.3 for the control arm (HR=0.68; P<0.001) – which is promising, but the results for BRCAmt patients were just as extraordinary as those seen with the other two PARPs in this report: for BRCAmt patients, the PFS was 34.7 months for Throughout vs. 22.0 for the control group (HR=0.44; P<0.001) (Fig. 5).

For the HRp patients, unfortunately, the results for VELIA were as grim as those in the PAOLA, and PRIMA trials, with non-significant improvements in PFS.

Quality of life was reported in this trial, but did not differ significantly between treatment arms; adverse events were also roughly equivalent, with neutropenia, anemia, and thrombocytopenia being the most common.

Fail

So as not to give the impression that all the news for ovarian cancer patients at ESMO was good, there is this: the results from FORWARD, a study of the investigational drug, mirvetuximab soravtansine (MIS), an antibody-drug conjugate (ADC).

This trial enrolled platinum-resistant ovarian cancer patients that were folate receptor alpha positive (FRa+) – to which MIS is targeted. Enrolled patients were randomized in a 2:1 fashion to either MIS (n=248) or investigator’s choice chemotherapy (paclitaxel, topotecan, or pegylated doxorubicin; n=118). The primary endpoint was PFS.

The patient characteristics were reported, as was dosing, and schedule, and the choices physicians made, and so on but none of that mattered because the trial failed – no improvement in PFS, no nothing – because of a fundamental problem with the trial design. (ADCs – a targeting antibody attached to a toxic payload – are a promising technology, and prior data strongly suggested there should have been as least some efficacy in this setting.) So what went wrong?

Patient selection. For reasons not explained at ESMO, to determine FRa+ status in their patients the trial’s sponsor (ImmunoGen) used a “10x” scoring method, which is rather subjective, as opposed to “PS2+” scoring, which is more stringent. This choice resulted in an enrichment of the “FRa+ high” estimation of the overall patient population, a skewing that would not have occurred with PS2+ scoring. Since the drug works best in FRa+ high patients, this was a problem.

As was pointed out by the study presenter, Kathleen Moore, MD, University of Oklahoma Health Sciences Center, if one were to re-score the patients FRa+ status according to the PS2+ criteria, and then reanalyze those numbers, the trial was positive.

Thus, MIS will next be tested, using the PS2+ scoring, in the phase III, MIRASOL trial, due to launch in Q4 2019.

In the meantime, the biotech company Sutro, which is working on a very similar drug, is taking heed: “We are in the process of developing our own IHC assay that quantitates both frequency and intensity of FRa expression level,” says Sutro CEO  William Newell. “We will be factoring in the learnings from the recently released data at ESMO as we finalize our assay.”

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