Lauren M. Green

With the FDA approval of two new PARP inhibitor drugs since last year’s Ovarian Cancer National Conference, it’s no surprise the topic was of great interest at this year’s meeting in Chicago, and a standing-room-only crowd was on hand July 8 to hear the latest news on this practice-changing class of drugs.

“There is a dizzying amount of data with respect to how effective they are, how tolerable they are, and when it’s best to use them,” noted John Moroney, M.D., the expert on hand to lead the discussion.

Three of these oral agents have been FDA-approved for specific indications in ovarian cancer: Lynparza (olaparib) in December, 2014, Rubraca (rucaparib) in December, 2016, and Zejula (niraparib) in March, 2017. These drugs continue to be the topic of investigation for expanded use in ovarian cancer, and Moroney mentioned two other PARP inhibitors in development: veliparib and talazoparib.

As just one indication of the impact of these agents on the research landscape, Moroney said that when he went on clinicaltrials.gov that morning, there were 57 active trials involving PARPs. That’s a big number, but it includes some smaller trials. Moroney, who is an associate professor of obstetrics and gynecology specializing in gynecologic cancers at University of Chicago Medicine, added that the majority of the phase 3 trials in patients with ovarian cancer are for those who respond to platinum chemotherapy.

Inhibitors of the enzyme poly ADP ribose polymerase (PARP), work specifically in women with BRCA mutations. Encouragingly, PARP inhibitors are also proving valuable for some patients who don’t have BRCA gene mutations.

The first approved PARP inhibitor, Lynparza, is indicated for women with germline BRCA-mutated advanced ovarian cancer who have had three or more lines of chemotherapy. The trial that led to the drug’s approval reported an objective response rate of 34 percent, and 55 percent of patients were free of progression at six months.

Rubraca is approved for the treatment of BRCA-positive advanced ovarian cancer after at least two lines of chemotherapy. With this drug, BRCA-positive status can be due either to a germline mutation or a mutation in the tumor itself, known as a somatic mutation. The FDA also approved a companion diagnostic to detect deleterious BRCA mutations in tumor tissue. Rubraca’s approval was based on data from 106 patients across two trials; in a pooled analysis of the data, the objective response rate was 54 percent.

The latest approved addition to the PARP class of drugs is Zejula. This drug can be prescribed as maintenance treatment following a partial or complete response to the patient’s most recent platinum chemotherapy, and it can be used in women who do not harbor BRCA mutations.

With PARP inhibitors now established as an efficacious ovarian cancer treatment option for many women, Moroney discussed some of the questions patients may have about them, including what side effects to look out for and when is the best time to use them. There is also interest in whether they may be used in combination with other drugs.

Moroney said that when PARPs first came to market, it was assumed the oral agents would be nothing like chemotherapy in terms of adverse events: “With more experience, we’ve learned that by and large, they are significantly more tolerable than many of the first-line chemotherapies,” but he cautioned that there are still some side effects.

He highlighted three gastrointestinal side effects — nausea, constipation, and abdominal pain – observed with all three FDA-approved PARPs, but few are the serious grade 3 or 4 adverse events that can result in treatment disruption or hospitalization. He did say, however, that when grade 2 toxicities persist over time for any drug, they can be very distressing for patients and deserve more attention.

Similar to the way chemotherapy can affect hemoglobin and platelets, Moroney explained that all of the PARP inhibitors can have some hematologic toxicities, principally involving decreased hemoglobin. Fatigue is another frequently reported side effect, which, Moroney acknowledged, “is much underappreciated by most oncologists, including me.” All of the agents can cause some fatigue, he said, but less than 10 percent of patients have had to stop the medication as a result.

Moroney said the answer to this question is not yet clear. PARP inhibitors were initially studied in the platinum-sensitive and platinum-resistant setting, but studies are being conducted of the agents as primary treatment. There are no FDA approvals in the primary setting yet, but Moroney anticipates that findings from these studies will help to determine whether PARPs are an option as primary treatment, with some expected to report results in approximately 18 months.

What about combination therapy involving PARPs?

Researchers are now investigating the agents in combination, including trials testing Lynparza combined with cediranib maleate in platinum-sensitive and platinum-resistant ovarian cancer. He explained that cediranib is similar to Avastin in that it is an anti-angiogenesis drug that keeps new blood vessels that feed the tumor from forming.

In updated findings from a small phase 3 trial studying the combination that was reported at the annual meeting of the American Society of Clinical Oncology in June, 2017, adding cediranib to Lynparza showed a superior median progression-free survival of 23.7 months, compared with 5.7 months with single-agent Lynparza in 23 women with recurrent platinum-sensitive ovarian cancer, but without a known BRCA germline mutation. The 24 women in the study with a BRCA mutation did not derive the same benefit. “In this trial, patients who were non—BRCA-mutated, actually did better than those who were,” Moroney noted.

PARP-immunotherapy combinations are also being explored, including one phase 1/2 study that is currently recruiting patients that is examining Lynparza with the monoclonal antibody tremelimumab in BRCA 1 and BRCA 2 carriers with recurrent ovarian cancer (NCT02571725).

Articles

The treatment landscape of ovarian cancer continues to change with the recent approvals of new agents.

PARP Inhibitors Changing the Landscape of Ovarian Cancer Treatment

For women with ovarian cancer, the message is clear: participating in clinical trials, even early-phase ones, offers the best hope for better treatments, but efforts are urgently needed at every level to ensure that more of these research opportunities are available.

“Every single major advance in ovarian cancer has come through a clinical trial,” Carol L. Brown, M.D., FACS, said in her presentation July 8, 2017 at the 20

 Annual Ovarian National Conference in Chicago.

The critical importance of expanding the universe of clinical trials in gynecologic cancers was a recurring theme at the meeting. Speaking earlier that day, John Moroney, M.D., of University of Chicago Medicine, stressed that continued progress depends on an expansion of clinical trials focused on gynecologic cancers.

“This is not ‘FAKE NEWS’,” said Moroney, during his presentation. He and Brown both described a crisis in available clinical trials for women with gynecologic cancers and pointed to statistics showing a 90% reduction in patient enrollment in gynecologic cancer clinical trials from 2011-2016.

Why Should I Participate in a Clinical Trial?

Brown, a gynecologic oncologist and associate cancer center director for diversity and outreach at Memorial Sloan Kettering Cancer Center, noted that researchers already have a pretty good idea that a drug being tested in a phase 1 trial will provide some benefit to patients. With the dramatic advances now in cancer science, “Rarely is there a phase 1 trial that’s not going to benefit you at all. That’s important for patients to understand.”

The goal of phase 1 studies, she explained, is to determine a drug’s safety, its maximum tolerated dose and how the treatment is processed in the body. Phase 1 studies are small, however, usually between 20 and 40 patients will be given the new treatment.

Onto phase 2 trials, where Brown told her audience a lot of advances are being made. “The whole field is changing. Phase 2 trials are larger, they are happening more rapidly, and we’re working very hard to make them more accessible.”

While phase 1 trials are still mostly conducted at a specialized center, the base for phase 2 trials — the next stage in proving the anticancer effects of the drug in a larger population – has broadened. “You used to have to go to a cancer center for a phase 2 trial; it was unheard for phase 2 trials to be done in the community. That’s no longer true.”

“Researchers have realized that if we want to get people to participate, we have to take the trials to them. We can’t expect everyone to travel to the big cancer centers.”

Often seen as the “gold standard” of clinical trials, phase 3 studies today typically compare two treatments that researchers already know work well, Brown explained. They are looking to see if they work equally well, as well as at associated quality-of-life side effects like neuropathy and hormonal changes, even cost. Phase 3 findings are what the Food and Drug Administration look to when deciding whether a drug should be approved.

“Participating in a clinical trial gives you access to new drugs and interventions before they are widely available; if the treatment is a success, you are among the first to benefit,” Brown said. Yes, you are also contributing to the larger good and helping other women diagnosed in the future, she continued, but even with a phase 1 trial, “there’s something in it for you.”

Trial participants also will get health care and closer observation by leading physicians in the field of gynecologic cancer research. “When you participate in a clinical trial, you are getting extra CT scans and calls from the doctor or nurse to see how you are doing.”

Advocating for More Gynecologic Cancer Clinical Trials

Brown cited an array of practice-changing advances in ovarian cancer that are the result of clinical trials, including discovery of less toxic drugs like paclitaxel and carboplatin and the availability of targeted therapies in ovarian cancer, such as the oral PARP inhibitors Rubraca and Lynparza.

She noted that in the last three years, four new drugs have been approved for ovarian cancer; that’s compared with four over the previously 15 years: “Things are looking up, things are accelerating, it’s going to happen.”

This optimism is tempered, however, by disturbing trends that show a reduction in gynecologic cancer—focused trials. Brown cited reductions in federal research funding, a move toward smaller biomarker-driven studies, and reorganization of oncology cooperative group research as contributing factors: “Gynecologic cancer is unique and need its own set of resources.”

She urged the audience to advocate aggressively for trial funding and increasing awareness of the importance of gynecologic cancer trials by contacting their elected representatives. The Society of Gynecologic Oncology’s Legislative/Congressional Ambassadors Program is making increased support for the National Cancer Institute a priority and working to expand and integrate its network to educate patients and advocates on how to communicate with Congress.

“We need you to partner with us in this very important effort,” Brown concluded. “Now is the time for action, awareness, and funding,” “Together we have a powerful voice.”

Clinical Trials Are the Way Forward for Ovarian Cancer, but They Need Advocates at Every Level

 Annual Ovarian Cancer National Conference in Chicago, John Moroney, M.D., underscored the challenges that remain in the prevention, earlier detection, and treatment of ovarian cancer, but also the tremendous hope that resides in robust clinical trial research.

“There are numerous early-phase clinical trials with targeted therapies that are by and large more tolerable and do not compromise quality of life that I think are the way forward,” Moroney told a packed ballroom at the conference, held July 7-9. “That is why I am such a proponent of early clinical trials. I think these offer people the best personal option, and then, of course, they have the benefit of helping everyone around you and the people behind you who are getting this diagnosis.”

Moroney, an associate professor of obstetrics and gynecology specializing in gynecologic cancers at University of Chicago Medicine, delivered this year’s Mello Abrams Lecture, established by Jay Schwamm to honor both his wife Judy Mello, who lost her life to ovarian cancer, and ovarian cancer advocate Judith Abrams.

“As survivors and family members you are aware — perhaps too aware – of what it takes to get through this disease,” Moroney said. Nevertheless, he set an optimistic tone for better treatments ahead, but cautioned that such progress will depend on an expansion of clinical trial research focused on gynecologic cancers.

There are about 24,000 new ovarian cancer diagnoses annually, and while the numbers are small compared with other gynecologic cancers, the disease is much more virulent. Eighty percent of patients are diagnosed at stage 3 or 4, and most women diagnosed at advanced stages recur.

“If we could find more stage 1 or 2’s, that would make a huge difference, but the development of an effective strategy for early detection is very challenging,” Moroney said, in part because ovarian is relatively rare compared with breast and endometrial cancers, and unlike colon cancer, there is no predictable pathway from pre-cancer to cancer.

“Most survivors have told me, ‘There was no way to tell that there was something wrong, until it was advanced.’ This is heartbreaking, but a reality for most patients.”

Thus far, studies of early screening methods like annual CA 125 testing, ultrasounds or both have not proven helpful or yielded overall survival benefits, though he acknowledged that there were likely people in the audience whose individual experience defy these statistics on screening.

The Risk of Ovarian Cancer Algorithm (ROCA), he said, is “probably the way forward,” following on two very large screening trials involving average-risk patients, including one involving 202,000 patients in the United Kingdom. Moroney said that though it did not demonstrate an overall survival advantage, “it did — and this is very important – describe what’s referred to as a ‘stage shift,’” whereby a higher number of patients receiving multimodal screening were diagnosed with early-stage cancers. The proprietary ROCA algorithm yields a score, based annual CA 125 levels along with other demographic factors like age and family history; the score determines what and when additional screening is warranted.

Beyond aging, consensus is lacking on other risk factors for ovarian cancer, Moroney said; for example, obesity and endometriosis are likely contributory, whereas talc use remains controversial, hormone replacement therapy may increase risk, and oral contraceptive use decreases it.

The consensus is clear, however, that heritable gene mutations are a risk factor and responsible for 15 to 25 percent of ovarian cancers. Research is ongoing into other druggable targets beyond BRCA, hyperthermic intraperitoneal chemotherapy (HIPEC), immunotherapy, and drug combinations.

Although there are no FDA-approved maintenance therapies after primary treatment for ovarian cancer in the U.S., it continues to be an area of interest and investigation, Moroney noted, “with multiple clinical trials with drugs vying for this space.”

For recurrent disease, however, the PARP inhibitor Zejula (niraparib) was approved by the FDA in March, 2017, for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. The indication for Avastin (bevacizumab) was expanded by the FDA in December, 2016, for treatment of platinum-sensitive patients in combination with chemotherapy, followed by Avastin maintenance.

Also in December, 2016, Rubraca (rucaparib) was granted an accelerated approval from the FDA to treat patients with BRCA-positive (either germline or the tumor itself) advanced ovarian cancer who have received at least two prior lines of chemotherapy. Olaparib, the first PARP inhibitor on the market, was approved in December, 2014, for BRCA-mutated patients with three or more prior therapies.

In the realm of immunotherapy, early studies on the use of CAR T-cell therapy in ovarian cancer have had disappointing results so far, Moroney said, but, “as the technology behind the therapy improves, we hope that the responses will be better.” Checkpoint inhibition is moving beyond PD-1 and CTLA-4 inhibitors to include a host of new targets, he added.

“There are numerous other targets; this is the hottest area of cancer medicine with respect to new targets…they are not prime time now, but the hope is that some of these inhibitory, inactivating drugs will make a difference.”

Recently reported trial findings showed that the PD-1 inhibitor Keytruda yielded a 10 to 15 percent response rate in biomarker-positive ovarian cancer. What’s notable, however, Moroney said, is that “those patients who did respond tend to have very durable responses. If we can pick the right patients, based on their tumor genomics, we can make a huge difference.”

Opening the 20th Annual Ovarian Cancer National Conference in Chicago, John Moroney, M.D., underscored the challenges that remain in the early detection and treatment of ovarian cancer, but also the tremendous hope that resides in robust clinical trial research.
 

The Road Ahead for Ovarian Cancer

Finding out that you have a BRCA or other mutation that increases your risk of cancer is a frightening and often confusing prospect. One way to deal with this fear of the unknown, however, is to advocate for yourself, so that you can know your options and make informed decisions.

There is no “one-size-fits all” approach to this kind of advocacy, however, explains Karen Malkin-Lazarovitz, of Montreal, Quebec, who eight years ago cofounded the BRCA Sisterhood, a peer support group for women dealing with BRCA and other hereditary mutations.

sat down with Malkin-Lazarovitz at the FORCE annual meeting, where she urged people who have a genetic risk for cancer to be their own advocates. This can take many forms — from consulting an array of experts and soliciting second opinions, to gathering information from groups like FORCE and getting support from peers. She also encourages individuals not to be afraid to ask questions and to know that even one supportive voice can make a huge difference in helping others to navigate this journey.

Can you highlight the presentation you are giving at the FORCE conference, “So You Want to Be an Advocate”?

There are all different types of advocacy, and my focus in this talk is on patient advocacy. To me, being a patient advocate means being aware of all of your options, knowing who to speak with and where to turn when you’re trying to fact-gather, and basically, to do what’s best for you. There’s no right way to handle any of this, and you have to just do what’s best for you —whether that’s speaking with surgeons or plastic surgeons; whether it’s speaking with oncologists, organizations like FORCE or speaking with peers. That’s really the best way to find out what’s best for you. The more you research and the more information you gather, the more confident you will feel with the decisions you make.

What would you say is the main takeaway from your talk?

So many people are afraid to ask questions. When you’re dealing with a surgeon, for example, there’s that sense that they know best. Yes, they do know a lot, and it’s important that you trust in what they’re saying, but it’s okay to be your own advocate. It’s okay to want to do what’s best for you and get a second opinion. It’s okay to speak to a peer, whether that’s someone who’s had a really positive experience or someone who’s had a negative one. The idea is to feel that you don’t have to navigate this alone. Advocacy begins with your own personal advocacy: gather whatever facts you can, speak with a number of people, and find your own voice to advocate for yourself.

Not everyone who has a mutation likes to talk about it. Some people are sharers, while others like to sit by quietly and observe — both are okay. I have always had a voice, and at least if I’m able to share and help one person to get a little bit of information that can help them, then I feel like I’ve at least been able to pay it forward. I had none of that support almost 10 years ago in Montreal where there really wasn’t a huge network of support at all. I felt quite alone, and I don’t want others to feel that.

Was this the impetus for founding the BRCA Sisterhood?

Absolutely. It was that sense of feeling like nobody else understood what I was going through. Genetic testing was still an unknown world for people who had never done it, and I felt like I constantly had to explain my decisions. I really needed to find other women who “got it” and who I could connect with. We just felt that peer support was the way to do it. We started slowly with this support group of women from different areas of the world and then started reaching out to our communities to let them know that this was something that could help people in their fact-finding missions, and it slowly grew from there. Now, it’s huge, and the group is as successful as it is, because women feel that it is a safe place to be able to share their information.

BRCA Sisterhood is above all a tight-knit support group of women from around the world. There are minimal rules in our group, but they work really well. One of them is, you don’t tell people what to do; you only offer advice. Another one is we don’t discuss any politics, especially in this volatile time right now; it’s not really something that plays a part in our group, and we don’t discuss religion. We also don’t allow posting of “GoFundMe’s.” It really is peer support, and no professional advice. For every type of support you’re looking for, there’s a support group out there. This is solely peer support, and it’s worked really well because of those few rules.

Can you elaborate on the importance of a “safe space” for women to find support and reliable information?

A lot of these women who have dealt with mutations don’t get a lot of support from their families or they get negative feedback, so a lot of them shut down. In the overall scheme of things, it is a small population — we’re talking about 5 to 10% of the world &mdash; but that’s an awful lot of people when you think about it. That safe haven allows them to share what they’re feeling without having to worry about judgment from others. There are even women who have lost partners because their partners don’t understand what they’re going through. It’s a private Facebook group, people are comfortable with Facebook, and nobody outside can see what they’re writing.

What do you see for the BRCA Sisterhood moving forward?

The clinical trial session at this FORCE meeting was quite interesting. They’re not getting all of the participants that they need. We have some ideas about how maybe, with our large voices, we can do something to help, or at least, extend the outreach a bit more. I am hoping that will at least lead to more discussion. Without participants, you can’t get the research that you need. Clinical trials are really the way to see if treatments work; so little is known about clinical trials, and the lack of conversation scares people. Groups like FORCE and BRCA Sisterhood and other organizations throughout the world can help get the message out that all treatments start with clinical trials. We are a strong, powerful voice.

Finding out that you have a BRCA or other mutation that increases your risk of cancer is a frightening and often confusing prospect, but even one supportive voice can make a huge difference.

Lauren M. Green

PARP Inhibitors Changing the Landscape of Ovarian Cancer Treatment

Clinical Trials Are the Way Forward for Ovarian Cancer, but They Need Advocates at Every Level

The Road Ahead for Ovarian Cancer

Paying It Forward, so Others Do Not Have to Navigate Hereditary Cancer Risk Alone

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