Clovis Oncology Inc.'s win earlier this month that broadened the label for Rubraca (rucaparib) tablets in ovarian cancer put the poly (ADP-ribose) polymerase (PARP) inhibitor on more level ground with competitors Tesaro Inc. and Astrazeneca plc, setting pundits abuzz about the competitive odds and how the market might further slice the PARP pie.

"We're going exactly to that group that has experience with rucaparib and has experience prescribing other PARP inhibitors in this space and making sure they're aware of the really great label we have," said Patrick Mahaffy, CEO of Boulder, Colo.-based Clovis. Beyond that effort with the "growing population" with current PARP inhibitor prescribers, "we, and frankly I'm sure our competitors, need to grow the pool of PARP adopters," he said.

U.S. regulators cleared Rubraca for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. The FDA granted the latest clearance in the second, broader and earlier-line indication, which doesn't require biomarker testing, through a priority review that came about based on positive data from the phase III Ariel 3 trial. Rubraca can now address the same patient population as Waltham, Mass.-based Tesaro's Zejula (niraparib) and London-based Astrazeneca's Lynparza (olaparib) in the same class. In December 2016, gatekeepers gave the nod to accelerated approval of Rubraca to treat women with advanced ovarian cancer who have been treated with two or more rounds of chemo and whose tumors bear a BRCA gene mutation as identified by a companion diagnostic test. (See BioWorld Today, Dec. 20, 2016, and June 20, 2017.)

Mahaffy spoke during a webcast with Evercore ISI analyst Steven Breazzano, who said in an April 6 alert to investors that, with maintenance approval in hand, he "expect[s] Rubraca sales to increase over the course of 2018, with consensus of $133 million in the U.S. and $16 million ex-U.S. ($56 million in sales for 2017). So far, Clovis has maintained its foothold in ovarian cancer (about $17 million per quarter), based on the current treatment label. With a preference for physicians to use PARP inhibitors early and broadly, we expect Clovis sales to increase," though the company will retain only a minority market position, in his opinion.

RBC Capital Markets went deeper into Breazzano's thesis by way of a physician poll back in March. "The second-line maintenance PARP inhibitor market remains largely untreated," wrote analyst Kennen MacKay in a report. "Our survey results indicate that the PARP inhibitors have only penetrated about 30-35 percent of the second-line ovarian cancer addressable market, leaving substantial room for growth." Checks with doctors showed that, "while physicians have broadly adopted PARP inhibitors' use in BRCA mutation patients, treatment initiation in all-comers has lagged, given more limited risk/reward for Tesaro's Zejula and lack of evidence supporting the use of Astrazeneca's Lynparza in these patients (despite the label). We anticipate that Clovis' Rubraca could capture significant share of this market upon launch."

How significant remains open to debate. Piper Jaffray's Christopher Raymond, who covers Tesaro, felt less than comfortable about that company's future with Zejula. Competition and lack of differentiation in the PARP inhibitor space has long been one of his main frets for the drug, and "the approval of a third PARP inhibitor for maintenance in recurrent ovarian cancer does little to quell our concerns," he wrote in a report after the latest decision on Rubraca. "We continue to fear these agents will primarily be differentiated on safety, which we think at this point does not favor Zejula." Although the FDA's OK for the broader label came as no surprise, he said, the move "underscore[s] the intensifying competitive pressure in the PARP space."

Tesaro moved the Zejula needle some Tuesday when the company reported results from the Quadra study, designed to measure benefit of the drug in heavily pre-treated patients. Results hit the pre-specified primary endpoint and showed monotherapy activity in a biomarker-selected patient population. Previous experiments have shown PARP inhibitor activity in the late-line treatment of patients with BRCA mutations, the company noted, and the single-arm Quadra study (n=461) tested Zejula's mettle in the fourth-line-plus treatment of specific ovarian cancer patient populations. Of the 92 percent of Quadra subjects who were PARP inhibitor-naïve, 15 percent turned up a BRCA mutation, more than two-thirds were platinum-resistant/refractory, and 63 percent had received prior Avastin (bevacizumab, Roche Holding AG).

Zejula demonstrated activity in the primary efficacy population of fourth and fifth-line homologous recombination deficiency-positive patients who were PARP inhibitor-naïve, and platinum sensitive (n=45), with an objective response rate (ORR) of 29 percent and duration of response (DOR) of 9.2 months. In patients who were fourth-line or greater with BRCA mutations, including platinum-sensitive, resistant and refractory (n=55), the ORR was 31 percent and the median DOR was 9.4 months. At a starting dose of 300 mg, the most commonly observed adverse events were consistent with prior clinical experience and included myelosuppression, which was generally managed by dose modifications. Tesaro said it plans to discuss a biomarker-focused regulatory submission with the FDA and potentially submit a supplemental NDA in the second half of this year.

RBC's MacKay called the Quadra outcomes incrementally positive and said his firm's "focus continues to be Zejula's uptake in the larger recurrent maintenance ovarian cancer market and indication expansion," adding that he "continue[s] to see headwinds from competition with Lynparza, and now Rubraca, given that both agents present a more favorable risk/benefit profile in this setting," and taking into account Zejula's myelosuppressive profile. "We look to first-quarter Zejula and competitor Astrazeneca's Lynparza sales results to gauge how these dynamics are evolving," he wrote in a report Tuesday.

Breazzano recognized the pressure mentioned, too. "For us, the Clovis 'outperform' story is based on modest continued growth in ovarian and interim prostate cancer data [with rucaparib] later this year at the European Society for Medical Oncology [ESMO] meeting, which we expect will be positive, given PARP activity in these patients and Clovis' better relative position vis-à-vis the competition," unlike in ovarian cancer, he said. Meanwhile, in preparation for the maintenance label in ovarian, Clovis has worked to expand the Rubraca sales force from 120 to 155.

Immunogen steps 'Forward'

Although picking winners in the space represents a challenge, nobody denies the strength of PARPs, an upside that drug developers aim to refine further as time goes on. Enter Ideaya Biosciences Inc., which in March closed a $40 million series A round. The South San Francisco-based firm seeks to hone the PARP approach with respect to synthetic lethality (SL), a factor that came to the forefront with Lynparza's approval. SL happens when the independent loss-of-function of two unrelated genes – ones that have no significant effect on cell growth and viability on their own – results in cell death when combined. Ideaya is examining SL interactions in genetically defined patient populations and trying to figure out how to exploit tumor susceptibilities. The firm plans to discover and develop small-molecule agents targeting a range of oncology indications. Researchers have since better validated the SL approach pioneered with Lynparza. (See BioWorld Today, Dec. 22, 2014, and March 16, 2018.)

In ovarian cancer generally, the struggle goes on. Most women are diagnosed at an advanced stage, and physicians find few options. Pipelines, though, hold various kinds of hope. At the phase II stage, Tapimmune Inc., of Jacksonville, Fla., has TPIV-200, a vaccine candidate targeting folate receptor alpha (FRa). TPIV-200 consists of five naturally processed peptide antigens derived from the highly prevalent tumor cell surface molecule, which is overexpressed by about 90 percent of ovarian cancer cells and 80 percent of triple-negative breast cancer cells. Higher levels of FRa expression are also associated with cancer recurrence. The phase I study of TPIV-200 included stage II-III ovarian, peritoneal and fallopian tube cancer patients, showing that 95 percent of those enrolled generated robust immune responses and 100 percent turned up T-cell responses lasting six months or longer. The results were published in the Journal of Clinical Oncology.

Immunogen Inc. also owns a platinum-resistant ovarian cancer prospect in mirvetuximab soravtansine, an antibody-drug conjugate (ADC) that targets FRa as a single agent and in combos with such drugs as Avastin (bevacizumab, Roche Holding AG) and Keytruda (pembrolizumab, Merck & Co. Inc.). Data with the former pairing will roll out at Chicago's American Society of Clinical Oncology meeting in June and Immunogen will pop the lid in Munich on results testing the latter at ESMO in October. Meanwhile, the phase III Forward I monotherapy trial should complete enrollment this quarter, setting up for a data readout in the first half of next year. The Waltham, Mass.-based firm likely will provide an update during its earnings call May 4.

While the trial hit the required number of progression-free survival (PFS) events for the futility analysis, the company is still sorting through the results. J.P. Morgan analyst Jessica Fye pointed out that the full analysis will look at "both the entire population as well as a subset with high FRa, and provides a chance to stop the trial early in the event that the hazard ratio is greater than 1 in both of these groups. We would be surprised were that the case, and view the futility analysis as a relative non-event." Immunogen researchers assume a PFS of about six months on drug and about three and a half months on the control arm. "While the trial is enrolling patients with one to three prior lines of therapy against investigators' choice, management noted that the results would be stratified for these factors (one to two prior therapies vs. three priors and the chemotherapy selected pre-randomization). Bigger picture, we see an intriguing clinical profile building" for the compound, Fye wrote in an April 19 report, although "from current levels we struggle to see a meaningful upside case," she added, holding to her neutral rating on the shares.

Halifax, Nova Scotia-based Immunovaccine Inc. and Incyte Corp., of Wilmington, Del., this week added a phase II component to the ongoing phase Ib study testing Immunovaccine's lead candidate, DXP-Survivac, when coupled with Incyte's IDO1 enzyme inhibitor, epacadostat, and low dose cyclophosphamide in advanced ovarian cancer. The phase II will consist of an open-label efficacy study including up to 32 evaluable subjects. DPX-Survivac and low dose cyclophosphamide will undergo testing, with or without epacadostat, in patients with advanced recurrent disease. DPX-Survivac consists of survivin-based peptide antigens formulated in Immunovaccine's delivery technology, and apparently works by eliciting a cytotoxic T-cell immune response against cells presenting survivin peptides. Broadly overexpressed in most cancer types, survivin plays an essential role in antagonizing cell death, the companies noted.