Ovarian Cancer Pipeline Review: Sponsors Plan Frontline Punch, Smart Combinations

Combination studies of drugs for ovarian cancer have heavy focus on PARP, PD-1/L1 and VEGF mechanisms.

Ovarian cancer treatment has been rejuvenated in recent years by the introduction of the PARP inhibitors, starting in relapsed disease for patients with BRCA mutations. Now, sponsors are tackling ovarian cancer in earlier stages with the goal of boosting initial remissions.

The pace of research in ovarian cancer has accelerated in the past few years – moving beyond BRCA and beyond monotherapy toward earlier lines of disease and "smart combinations," in a bid to change the stark fact that 14,000 women die of the disease every year in the US, AstraZeneca PLC VP-US Medical Affairs for Oncology Andrew Coop noted in an interview.

Current Treatment Options

In addition to mainstay treatment with platinum-based chemotherapy, three PARP inhibitors are approved as monotherapy second-line maintenance treatments for recurrent ovarian cancer that is still responsive to platinum-based chemotherapy – AstraZeneca/Merck's Lynparza, Clovis' Rubraca and Tesaro's Zejula.

Roche's VEGF inhibitor Avastin gained a new indication for use with chemotherapy in first-line Stage III/IV ovarian cancer in June, having already been approved as a maintenance therapy in recurrent platinum-sensitive disease. (Also see "FDA Finally Approves Avastin In First-Line Ovarian Cancer" - Pink Sheet, 13 Jun, 2018.)

Advancing To The Frontline

Among PARP inhibitors, AstraZeneca's Lynparza (olaparib), partnered with Merck & Co. Inc., is the closest to the market for first-line treatment of advanced ovarian cancer.

In October, AstraZeneca and Merck impressed the European Society for Medical Oncology annual meeting with data suggesting Lynparza could be a new standard of care for maintenance therapy in first-line ovarian cancer. (Also see "Stellar Survival Data For AZ's Lynparza Hailed At ESMO" - Scrip, 22 Oct, 2018.)

AstraZeneca and Merck have been counting on influencing prescribers with the full release of SOLO-1 data while simultaneously working to get a new indication approved; filings have been submitted in Europe, Japan and China and a priority review is under way at the US FDA. (Also see "AZ's Lynparza PARP Lead Likely To Lengthen With FDA Priority Review " - Scrip, 12 Nov, 2018.)

The data are quite convincing to drive the use of the drug, Scot Ebbinghaus, vice president of clinical research at Merck Research Laboratories, told Scrip.

"Lynparza is likely to be the first of its class to obtain a 1L label, which we believe will help solidify its class-leading position," Deutsche Bank analyst Richard Parkes said in an Oct. 22 note.

Meanwhile, the Phase III PAOLA-1 study of Lynparza with platinum/taxane chemotherapy and Roche's VEGF inhibitor Avastin (bevacizumab) is ongoing in unselected first-line ovarian cancer patients, with results expected in 2019.

And a new Phase III study led by the sponsors with the German Gynecological Oncology Group (AGO) called DUO-O is set to start dosing at the start of 2019. DUO-O will test AstraZeneca’s PD-L1 inhibitor Imfinzi (durvalumab) with chemotherapy and Avastin, followed by Imfinzi/Avastin/Lynparza maintenance therapy in newly-diagnosed advanced ovarian cancer.

Debating Frontline Use

There has been debate in the about whether it will be best to use everything new together up front or to hold off.

Bradley Monk, director of the division of gynecologic oncology at the Creighton University School of Medicine, however, said that that holding off would be akin to keeping the best players on the bench until the team is behind and needs to be rescued. Instead, the best players should be used at the beginning to get a lead and maintain it in cancer treatment, he said.

Currently, it's unclear how patients would be managed after they got a PARP inhibitor in the frontline setting, though Sharyn Lewin, director of gynecologic oncology at the Holy Name Medical Center, said "there is definitely a lot of emerging data that will definitely help us figure out how to sequence these things in the future."

Clovis Oncology Inc. CEO Patrick Mahaffy told Scrip that patients may discontinue treatment for a range of reasons, not necessarily related to treatment failure or disease progression, but rather treatment fatigue. Clovis expects that if Lynparza is used in the first-line setting, doctors will still be retreating with another PARP inhibitor in subsequent lines of therapy.

"The ovarian cancer community is used to retreating," Mahaffy noted.

Welcoming In Immunotherapies

Other new options could be coming from a wide range of ongoing combination trials in first-line advanced ovarian, including partnering with immunotherapies (see chart).

Ovarian cancer was not part of the first wave of indications for immuno-oncology, but there is intense interest in what PD-1/L1 inhibitors could do in combination with other drugs, particularly PARP and VEGF inhibitors.

Active first-line ovarian cancer trials include JAVELIN OVARIAN PARP 100 of Pfizer/Merck KgAa's PD-L1 inhibitor Bavencio (avelumab) with Pfizer’s PARP inhibitor talazoparib. (Also see "Immuno-Oncology Outlook: Bavencio Leads PD-1/L1 Pack In Ovarian Cancer" - Scrip, 18 Jul, 2017.) The IMagyn050 study is testing Roche's anti-PD-L1 Tecentriq (atezolizumab) with Avastin.

In November, Merck KGAA and partner Pfizer reported that Bavencio failed to improve progression-free survival or overall survival as a monotherapy or in combination with chemo in the Phase III JAVELIN Ovarian 200 study in platinum resistant/refractory patients, but this is a particularly hard population to treat and the drug still has a chance to work in the first-line setting.

At this year's American Society of Clinical Oncology (ASCO) annual meeting, Merck showed disappointing results for its PD-1 inhibitor Keytruda (pembrolizumab) as monotherapy in the Phase II KEYNOTE 100 study in 386 women with advanced recurrent ovarian cancer. The objective response rate (ORR) for the population overall was 8%, with a median duration of response of 8.2 months; in a cohort that had four-to-six prior rounds of chemo the ORR was about 10%, the duration of response not reached.

 

While these response rates are disappointing compared with what has been reported for some other tumor types, investigators said that it was encouraging that some of the responses were very durable. Merck's Ebbinghaus said that the results highlight the "potential for immunotherapy to be active" in ovarian cancer and that there may be fertile ground for combinations to improve the response rates.

A Long Way From Mice To Man

Clovis linked up with Bristol-Myers Squibb Co. in July 2017 to test its PARP inhibitor Rubraca (rucaparib) with the PD-1 inhibitor Opdivo (nivolumab) as a first-line treatment for ovarian cancer, as well as triple-negative breast cancer and castration-resistant metastatic prostate cancer. (Also see "The PARP Combo Race Is On: Clovis And Bristol Partner On Rubraca" - Scrip, 31 Jul, 2017.) The ATHENA study is testing Rubraca with Opdivo after chemotherapy in about 1,000 patients with previously untreated advanced ovarian cancer.

Clovis CEO Mahaffy said that there is a strong biological rationale for administering a PARP inhibitor with an anti-PD-1 drug; in preclinical models the combination delivers "pretty phenomenal results," the exec said.

"It's a long way from mice to man – we all know that – but there is evidence of synergy, which is what we are hoping to see in the trial," Mahaffy told Scrip.

Enrollment will complete in two years and it will take another 18 months to see data. But Clovis is also set to start a smaller open-label study with a similar design soon that could report as early as August 2019.

Tesaro Inc. is testing Zejula (niraparib) as a monotherapy maintenance treatment after a frontline response to chemotherapy in the all-comer Phase III PRIMA study, with results expected in the second half of 2019, but is also actively developing the drug in combination with the anti-PD-1 mechanism. (Also see "Tesaro's Zejula Expansion Includes Keytruda Combo, Lung Cancer" - Scrip, 5 Jun, 2017.)

In the Phase I/II TOPACIO study of Zejula with Merck's PD-1 antibody Keytruda (pembrolizumab), which was reported at ASCO, the ORR in 60 patients who were platinum-resistant or refractory was 25% and the disease control rate was 67%. (Also see "Tesaro's Zejula Expansion Includes Keytruda Combo, Lung Cancer" - Scrip, 5 Jun, 2017.) Results were similar regardless of mutation status and 63% had previously been treated with Avastin.

"Taking patients who don't have a BRCA mutation and giving them a level of response as if they did is transformational, because they don't have an alternative," Tesaro CEO Leon (Lonnie) Moulder said in an interview.

Tesaro's Phase III FIRST study is testing Zejula with its own in-house PD-1 inhibitor TSR-042 as maintenance therapy after standard-of-care chemotherapy in newly diagnosed advanced ovarian cancer. The study allows for use of Avastin in the initial chemotherapy and maintenance phases.

"It actually accommodates the approval of Avastin and will demonstrate the benefit of our PD-1 antibody and Zejula and Avastin and chemo all combined right up front to give patients the best possible chance to alter the entire course of disease," Moulder said.

Moulder stressed the mechanistic synergy between VEGF and PARP. VEGF inhibitors cause decreased oxygenation of the tumor microenvironment, leading to greater DNA-repair deficits in tumor cells, which allows PARP inhibitors to work even better.

Tesaro noted that Zejula is being studied with Avastin – a chemo-free regimen – in the Phase I/II AVANOVA study of recurrent ovarian cancer, which will finish this year.

Zejula also now stands to benefit from having a big pharma partner, following the acquisition of Tesaro by GlaxoSmithKline PLC, announced on Dec. 3.

Clovis is set to start a study of its Rubraca with its investigational VEGF inhibitor lucitinib in ovarian cancer by the first quarter of 2019. The company believes lucitinib has a better toxicity profile than other drugs in its class and that the combination could provide meaningful benefit, including in patients who are resistant to platinum-based chemotherapy.

Mahaffy said that the company is aggressive about considering combinations for PARP beyond PD-1 in ovarian cancer, as well as other tumor types, to either augment activity of Rubraca in those with platinum-resistant or refractory disease who don't respond as well, or to help overcome resistance that emerges after response in those with platinum-sensitive disease.

Clinical collaborations are a "high priority," the exec said. During the company's third quarter earnings call on Oct. 30, Clovis said that it is sponsoring a Phase I/II combination study of Rubraca with Immunomedics' antibody-drug conjugate sacituzumab govitecan (IMMU-132), which contains the active metabolite of the well-established irinotecan, in relapsed platinum-resistant ovarian cancer plus metastatic breast and urothelial cancers. The study will begin enrolling in the first half of 2019.

ImmunoGen's First-Line Ambitions For Mirvetuximab

Meanwhile, Waltham, Mass-based biotech ImmunoGen Inc. believes that its ADC mirvetuximab soravtansine (IMGN853) is suited for a role as a combination partner in earlier lines of disease as well as for monotherapy use in tough-to-treat platinum-resistant ovarian cancer. The candidate joins the anti-tumor agent DM4 to the humanized monoclonal antibody M9346A, which selectively binds to folate receptor alpha-positive cancer, using ImmunoGen's targeted antibody payload (TAP) technology.

The cytotoxic payload is delivered to tumor cells and also diffuses to neighboring cells, so there is a bystander killing effect. That's important because neighboring tumor cells may have lower levels of folate receptor alpha, ImmunoGen Chief Medical Officer Anna Berkenblit explained in an interview.

Mirvetuximab is being targeted at ovarian cancer patients with medium-to-high folate alpha receptor expression – about 60% of the population. Results from the FORWARD-1 study of mirvetuximab versus chemotherapy in folate receptor alpha-positive advanced recurrent ovarian cancer are expected in 2019 and the company is aiming to get approved in the first half of 2020 and then displace single-agent chemo in this setting.

In contrast with PARP inhibitors, which have an issue with myelosuppression that makes it hard to combine with cytotoxic chemotherapy, mirvetuximab is well-tolerated and easy to combine at its full therapeutic dose with a range of other drugs at their full doses, including carboplatin, docetaxel, Avastin and Keytruda, which should help it move into earlier lines of therapy, Berkenblit said.

The treatment landscape is rapidly evolving, noted Monk. "We are going to have some really interesting data about antibody-drug conjugates, checkpoint inhibitors and combination data with anti-angiogenic and PARP inhibitors very, very soon," he said.

Branded Drug Combinations In Development For Advanced Ovarian Cancer, Select Studies
Phase III
Study	Sponsor(s)	Disease Setting & Treatment
JAVELIN OVARIAN PARP 100 (NCT03642132): anti-PD-L1 Bavencio (avelumab) and PARP inhibitor talazoparib	Pfizer	First-line ovarian cancer; Bavencio with chemo followed by maintenance Bavencio/talazoparib
FIRST (NCT03602859): PARPi Zejula (niraparib) and anti-PD-1 TSR-042	Tesaro with European Network of Gynaecological Oncological Trial Groups (ENGOT)	First-line ovarian cancer; standard of care chemo with TSR-042 followed by TSR-042/Zejula maintenance
IMagyn050 (NCT03038100): anti-PD-L1 Tecentriq (atezolizumab) with anti-VEGF Avastin (bevacizumab)	Roche with Gynecologic Oncology Group (GOG) Foundation and ENGOT	First-line ovarian cancer; standard of care chemo with Avastin/Tecentriq and Avastin/Tecentriq maintenance
ATHENA (NCT03522246): PARPi Rubraca (rucaparib) with anti-PD-1 Opdivo (nivolumab)	Clovis with Bristol, GOG, ENGOT and Foundation Medicine	First-line ovarian cancer, maintenance after front-line chemo response
PAOLA-1 (NCT02477644): PARPi Lynparza (olaparib) with Avastin	Arcagy/Gineco	First-line ovarian cancer; Avastin/chemo and Lynparza maintenance
ANITA (NCT03598270): Avastin and Zejula	Grupo Español de Investigación en Cáncer de Ovario with Roche and Apices Soluciones S.L.	Recurrent ovarian cancer; Chemo +/- Avastin and Zejula maintenance
ATALANTE (NCT02891824): Tecentriq and Avastin	Arcagy/Gineco with Roche	Late relapse ovarian cancer
Phase II
OPAL (NCT03574779): Zejula with TSR-042 and Avastin	Tesaro	Recurrent ovarian cancer; multicohort study
NCT03326193: Zejula and Avastin	Tesaro	First-line ovarian cancer; maintenance therapy with Zejula/Avastin
NCT02873962: Opdivo with Avastin	Dana Farber with Bristol	Relapsed ovarian cancer
OCTOVA (NCT03117933): Lynparza +/- anti-VEGF cediranib	University of Oxford with AstraZeneca	BRCA-mutated, platinum-resistant ovarian cancer
BAROCCO (NCT03314740): Lynparza and cediranib	Mario Negri Institute for Pharmacological Research with AstraZeneca	Recurrent ovarian cancer
CAPRI (NCT03462342): Lynparza and ATR inhibitor AZD6738	University of Pennsylvania with AstraZeneca	Platinum-sensitive or resistant recurrent ovarian cancer
Phase I/II
AVANOVA (NCT02354131): Avastin and Zejula	Nordic Society for Gynaecologic Oncology with ENGOT and Myriad	Platinum-sensitive ovarian cancer
TOPACIO/KEYNOTE-162 (NCT02657889): Zejula with Keytruda	Tesaro with Merck	Recurrent ovarian cancer or advanced triple negative breast cancer
NCT02208375: Lynparza with anti-mTORC1/2 AZD2014 or AKT inhibitor AZD5363	MD Anderson with AstraZeneca and National Cancer Institute	Recurrent ovarian or triple-negative breast cancer
MITO25 (NCT03462212): Avastin and Rubraca	Fondazione IRCCS Istituto Nazionale dei Tumori, Milano with Foundation Medicine	First-line ovarian cancer; chemo/Avastin with Rubraca maintenance
Phase I
FORWARD II (NCT02606305): Antibody-drug conjugate mirvetuximab soravtansine with Avastin and Keytruda	ImmunoGen	Folate receptor alpha-positive advanced ovarian cancer
NCT03552471: Mirvetuximab soravtansine and Rubraca	Ohio State University with ImmunoGen and Clovis	Recurrent folate receptor alpha-positive recurrent ovarian cancer
NCT03162627: Lynparza and MEK inhibitor selumetinib	MD Anderson with AstraZeneca	Solid tumors, including ovarian cancer
Source: ClinicalTrials.gov