Immunotherapy Combinations Have Mechanistic Rationale in Ovarian Cancer

Immunotherapy Combinations Have Mechanistic Rationale in Ovarian CancerImmunotherapy combinations with PARP inhibitors or checkpoint inhibitors may represent the future of treatment for patients with ovarian cancer, said Samir N. Khleif, MD, during the 2017 ASCO Annual Meeting.

Alternatives to chemotherapy are needed for the treatment of ovarian cancer because despite an 80% response to chemotherapy, recurrence is universal with few options available following recurrence. Ovarian cancer is an immune-dependent cancer; ovarian cancers with T-cell infiltration within the tumor microenvironment are associated with superior progression-free survival and overall survival.

Multiple tumor-associated antigens have been defined, from which a number of vaccines have been developed and tested. “Most have approached the vaccine as a single agent rather than as a combination agent, either in a specific antigen, either synthetic, naked DNA, RNA, bacterial, or viral; whole-cell lysate, or anti-idiotype vaccine, and it is either given by itself or given in the context of a dendritic cell,” said Khleif, director of the Georgia Health Sciences Cancer Center in Augusta. Unfortunately, vaccines have demonstrated limited efficacy in this setting.

Ovarian cancer is an immune-driven tumor, but because of the immune-suppressive environment within it, T cells are activated and captured by various mechanisms, leading to an inability of the T cells to generate a proper immune response. These mechanisms include accumulation of intratumoral T regulatory cells (Tregs) that block an immune response, production of the enzyme IDO (leading to activation of suppressive populations of Tregs) by tumor cells, and suppression of effector T cells by engagement of PD-1 with PD-L1.

“When we think of our approach to vaccines, it’s pretty naïve to think that a vaccine is going to generate T cells, and the T cells are going to be taking care of a tumor that is that immune suppressive,” said Khleif.

Accordingly, the use of PD-1 inhibitors and other checkpoint inhibitors in ovarian cancer has been proposed, but so far, the data are scant. The expression of PD-1 in ovarian tumors is dependent on the grade of the tumor, with high-grade tumors having higher expression.

Hamanishi et al studied the activity of nivolumab (Opdivo) at 2 dosages (1 or 3 mg/kg every 2 weeks) in 20 patients with platinum-resistant ovarian cancer, producing 2 complete responses and 1 partial response.2 Levels of PD-L1 expression did not seem to influence response, “which might be a little bit different than other diseases like lung cancer,” he said.

A phase Ib study of avelumab (Bavencio), 10 mg/kg, in 124 patients demonstrated an objective response rate of 9.7% and stable disease in 44%.3 Another study of nivolumab in 17 patients with recurrent/refractory epithelial ovarian cancer, showed 1 partial response and 2 patients with stable disease after treatment. “As a single agent, so far, we have some responses but we did not break that tolerance yet,” Khleif said, and noted that the responses rarely lasted very long.

Multiplication of effort is probably needed to address the immune suppressive state of the tumor microenvironment in ovarian cancer, he said. “That is why combination immune therapy is going to be, and is, the name of the game.” Chemotherapy is known to induce PD-L1 expression and lead to enhanced infiltration of CD8-positive cells in the tumor, possibly enhancing the efficacy of checkpoint inhibitors.

Khleif’s team has found that Tregs and T conventional cells (Tconvs) are differentially regulated by PI3K isoforms. Tregs are primarily dependent on the PI3K-delta isoform, whereas in Tconvs, PI3K-alpha and -beta provide a redundant pathway to PI3K-delta. This dichotomy can be exploited to target Tregs by inhibiting the PI3K-delta isoform while leaving Tconvs intact.

In a mouse model of lung cancer, co-administration of an inhibitor of PI3K-delta with a tumor-specific vaccine decreased the number of suppressive Tregs and increased the number of vaccine-induced CD8 T cells within the tumor microenvironment, resulting in a large reduction in tumor volume. The results “offer a mechanistic rationale to employ PI3K-delta inhibitors to selectively target Tregs and improve cancer immunotherapy,” the authors concluded.

PARP is an important target in ovarian cancer. PARP inhibitors have been shown to have clear beneficial effects on clinical outcomes in the treatment of ovarian cancer in several clinical trials. The combination of a PARP inhibitor with CTLA-4 blockade improved overall survival in a BRCA1-deficient murine ovarian cancer model compared with treatment with CTLA-4 or PD-1/PD-L1 monoclonal antibodies alone.

A PARP inhibitor enhanced apoptosis and tumor volume shrinkage within the tumor microenvironment when given in addition to a PD-1/PD-L1 blocker. PARP inhibition was able to attenuate anticancer immunity via upregulation of PD-L1, and blockade of PD-L1 re-sensitized the PARP inhibitor-treated cancer cells to T-cell killing, the authors found. Multiple trials combining PARP inhibitors and checkpoint inhibitors are ongoing, said Khleif.

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Women With BRCA Gene Mutations Given Clearer Picture of Breast and Ovarian Cancer Risk

Women With BRCA Gene Mutations Given Clearer Picture of Breast and Ovarian Cancer RiskWomen who carry the BRCA1 or BRCA2 gene mutations now have the clearest picture yet of their risk of developing breast and ovarian cancer.

An Australian study led by the University of Melbourne, Peter MacCallum Cancer Centre and Cancer Council Victoria tracked almost 10,000 women with these mutations for up to 20 years.

What they found has given clinicians “enormous power” to assess a carrier’s risk of developing these cancers.

It will also provide carriers with greater confidence in the decisions they make about prevention strategies including surgery, says the oncologist Prof Kelly-Anne Phillips, founder of the Peter Mac Breast and Ovarian Cancer Risk Management Clinic.

“This is the largest and most scientifically rigorous study to date without question,” Phillips said. “We used data from a large number of studies running internationally in over 18 around the world.”

The study published in JAMA: The Journal of the American Medical Association found that women with BRCA1 mutations have on average a 72% risk of developing breast cancer by the age of 80.

For BRCA2 mutation carriers, the risk of breast cancer is 69%.

The average lifetime risk of ovarian cancer is 44% for BRCA1 and 17% for BRCA2.

It was also found that the location of where the abnormality is found in the gene and family history influenced the risk.

“So women who had these gene mutations who had more people in their family who’d been affected with breast and/or ovarian cancer had a higher likelihood of developing these cancers than women with the same mutation who had less of a family history,” Phillips said.

She said the findings also had significant implications for older women with these mutations. The study found cancer risk increased rapidly at a young age and peaked in the 30s for BRCA 1 mutation carriers and in the 40s for BRCA 2 mutation carriers.

But it remained as the woman aged, overturning previous thinking that the risk reduced when a woman turned 60 without a diagnosis.

“Our study really showed that the risk reaches its highest level in a woman’s 30s and remains well into their 80s,” Phillips said.

Further analysis of the data will examine whether modifiable lifestyle-related factors such as timing of pregnancies, contraceptive use or alcohol and smoking can influence the risk of cancer for these women.

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Tumor Marker Associated With Poor Ovarian Cancer Outcomes

Tumor Marker Associated With Poor Ovarian Cancer OutcomesWomen with advanced ovarian cancer who expressed the tumor antigen NY-ESO-1 demonstrated shorter PFS and OS than those without the antigen, according to study results published in Gynecologic Oncology.

However, patients with NY-ESO-1–expressing tumors who enrolled in immunotherapy trials had significantly improved OS, researchers reported.

“The most significant finding of the present study is we have identified a biomarker for aggressive ovarian cancer that is not only highly expressed, but is targetable with immunotherapy,” Kunle Odunsi, MD, PhD, FRCOG, deputy director and chair of the department of gynecologic oncology at Roswell Park, told HemOnc Today.

Ovarian cancer is the most lethal gynecological malignancy in the United States, accounting for about 14,000 deaths in 2016, and only incremental improvements have been made in survival rates. In their study, Odunsi and colleagues at Roswell Park aimed to provide an update on the prevalence of NY-ESO-1 expression in ovarian cancer, assess the association between NY-ESO-1 expression and clinical outcomes, and evaluate the survival impact of targeting NY-ESO-1 with immunotherapy.

From Jan. 1, 2002 to June 30, 2016, researchers tested 1,002 patients (median age, 61 years; 62.8% stage IIIc, 13.2% stage IV) for NY-ESO-1 expression.

Of these, 40.7% (n = 408) expressed NY-ESO-1. Women with NY-ESO-1 averaged 3 years older in age (62 years vs. 59 years; P < .001) and appeared more likely to have stage IIIc (62.7% vs. 52%) or stage IV (13.5% vs. 11%) disease.

NY-ESO-1 appeared associated with shorter PFS (22.2 months vs. 25 months; P = .009) and OS (42.9 months vs. 50 months; P = .002).

“NY-ESO-1 appears play a role in ovarian cancer similar to HER-2/neu in breast cancer, where overexpression is associated with a worse prognosis, until trastuzumab (Herceptin, Genentech) became available, and now those patients have improved outcomes,” Odunsi said. “Therefore, we encourage ovarian cancer patients to have their tumors tested for NY-ESO-1.”

Researchers offered 11 immunotherapy vaccine trials to the 408 women who tested positive for NY-ESO-1; 68 patients accepted. Women who enrolled tended to be younger (54.5 years vs. 64 years; P = .002) and had similar stage, grade and histology of disease.

Women who received immunotherapy had longer OS (75.3 months) than women who did not enroll (38 months; P < .001) and women without NY-ESO-1 expression (50 months; P = .046).

“The patients received various forms of NY-ESO-1–targeted vaccine therapies,” J. Brian Szender, MD, MPH, fellow in the department of gynecologic oncology at Roswell Park Cancer Institute, told HemOnc Today. “Our vaccine therapy approaches are focused on ovarian cancer patients in remission or with minimal residual disease burden in order to minimize the risk for relapse. For patients with large-volume disease, we have developed adoptive T-cell therapies using engineered T cells that are programed to bear T-cell receptors that recognize NY-ESO-1 in tumors.”

Researchers encourage patients with NY-ESO-1 expression to participate in vaccine clinical trials to reduce their risk for relapse.

“For patients with recurrent or progressive ovarian cancer who have failed more than two lines of standard chemotherapies, we encourage participation in clinical trials of adoptive T-cell therapy targeting NY-ESO-1,” Odunsi said. “Because NY-ESO-1 is not expressed by all patients, we have developed a clinical trial where NY-ESO-1 expression is enforced pharmacologically, followed by adoptive T-cell therapy with TCR–engineered cells targeting NY-ESO-1.”

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Breast and Ovarian Cancers: Large Study Improves Estimates of Genetic Risk

Breast and ovarian cancers: Large study improves estimates of genetic riskA new study that followed 10,000 women provides more accurate, age-related estimates of the risk of developing breast and ovarian cancer in carriers of mutations of the BRCA1 and BRCA2 genes. It also suggests that family history and the location of the mutations on the gene should be taken into account.

The study – led by the University of Cambridge in the United Kingdom – is reported in JAMA.

The findings should help doctors to improve the advice and counseling they give on treatment options and risk-reducing lifestyle changes, suggest the researchers.

Lead author Antonis Antoniou, Ph.D., of Cambridge’s Department of Public Health and Primary Care, says, “We have been able to provide the most precise estimates of age-specific risks to date. These should provide more confidence in the counseling and clinical management of women with faults in the BRCA1 and BRCA2 genes.”

Cancer develops because of changes to genes that regulate the way that cells work, grow, and divide, causing them to get out of control.

Some of the genetic changes that lead to cancer are inherited, while others can arise during a person’s lifetime, due to either copy errors or environmental factors – such as exposure to tobacco smoke and radiation – that damage DNA.

Higher Risks From BRCA1 and BRCA2

Often, it is an accumulation of hundreds of genetic changes – each of which raises a person’s risk by a small amount – that causes cancer.

However, there are some genes, such as BRCA1 and BRCA2, where we know that mutations or errors in their code can greatly increase the risk of breast and ovarian cancer.

Normally, BRCA1 and BRCA2 help to protect against cancer, but certain mutations in one or both of the genes make cells “more likely to divide and change” more rapidly, giving rise to cancer.

The reason that the new study is significant is that until now, all risk assessments for patients with BRCA1 and BRCA2 mutations have relied on the results of “retrospective” studies – that is, those that look back on groups of patients who already have the disease.

Being “after the fact,” retrospective studies are prone to inherent problems such as bias and inaccuracies in recording and reporting of the desired information.

The new study is a prospective cohort study – it recruited a large group of nearly 10,000 cancer-free women with risk versions of BRCA1 and BRCA2 and followed them over a period, during which some of the women developed breast and ovarian cancer, while some did not.

Previous prospective studies of BRCA1 and BRCA2 have been done, but they have been very small – for example, the largest one had just 64 cases of breast cancer.

Age-Related Risk Profiles

When they analyzed the results, Dr. Antoniou and colleagues found that for carriers of BRCA1 mutations, the rates of breast cancer rose rapidly until the age of 30 to 40 years and then remained at the same level until the age of 80.

In the case of BRCA2 mutation carriers, the rates of breast cancer rose rapidly until the age of 40 to 50 years, and then also stayed at the same level until the age of 80.

The team found that the risk of developing breast cancer before the age of 80 was 72 percent for women carrying a faulty BRCA1 gene, and 69 percent for women carrying a faulty BRCA2 gene.

Similarly, the researchers found that the risk of developing ovarian cancer before the age of 80 was 44 percent for women carrying a faulty BRCA1 gene, and 17 percent for women carrying a faulty BRCA2 gene.

The risk of contralateral breast cancer – or developing cancer in the opposite breast – 20 years after having it diagnosed in the first breast was found to be 40 percent for carriers of a faulty BRCA1 gene, and 26 percent for carriers of a faulty BRCA2 gene.

However, in both breast and ovarian cancer, having a family history such as a relative diagnosed with one of the cancers would raise the risk. The amount of increase went up with the number of first- and second-degree relatives diagnosed with breast cancer.

Finally, the researchers discovered that the degree of cancer risk varies by position of the mutation within the BRCA1 or BRCA2 gene.

Dr. Charles Shapiro, director of Cancer Survivorship and Director of Translational Breast Cancer and Research at the Tisch Cancer Institute at Mount Sinai in New York City, NY, comments on the value of the new study:

A single-institution [study] has too few of these women with inherited germ-line mutations to have sufficient numbers for valid statistical analysis. However, this study pooled the several results of several institutions leading to a relatively large sample. This combined analysis means there is more confidence in the results.”

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Study Shows Zejula’s Benefit in Treating Ovarian Cancer

Study Shows Zejula's Benefit in Treating Ovarian CancerSuperior progression-free survival (PFS) was seen in patients with ovarian cancer who previously had a partial response (PR) to platinum-based therapy when they took Zejula (niraparib). This response was seen in patients with or without germline BRCA mutations, according to data from the ENGOT-OV16/NOVA trial presented at the 2017 ASCO Annual Meeting.

Investigators set out to explore the effect of the PARP inhibitor Zejula on PFS in patients with recurrent ovarian cancer who were in response (either complete response [CR] or PR) to their most recent platinum-based therapy after a minimum of our cycles in ENGOT-OV16/NOVA, a phase 3 multicenter, randomized, double-blind, placebo-controlled study.

At the time of unblinding, 45 percent in the Zejula group who were positive for mutant BRCA achieved PFS, compared with 72 percent of patients in the placebo group. In the non-BRCA mutant cohort, 56 percent of patients had PFS versus 80 percent in the placebo group.

“We had half of the population in both groups who had only partial remission and wanted to know how they were doing. We tried to show the patients who were in partial remission have the same PFS as the whole group,” lead investigator Mansoor Raza Mirza, M.D., chief oncologist in the Department of Oncology in Rigshospitalet, Copenhagen University Hospital, Denmark, and medical director of the Nordic Society of Gynecologic Oncology-Clinical Trial Unit, said in an interview with CURE. “PFS is actually better in the non-germline BRCA group because patients with active disease in the placebo group are progressing much faster so you see a better split as a hazard ratio [HR].”

Roughly half of the total study population (272 patients) responded to had a to their last platinum-based therapy. These patients were segregated by BRCA mutation status and assigned to either daily 300 mg Zejula daily or placebo until disease progression or unacceptable toxicity. In the germline mutant BRCA cohort, 67 out of 138 patients in the Zejula arm (49 percent) and 32 out of 65 patients in the placebo arm (48 percent) entered the trial with a PR.

In the non-mutant germline BRCA cohort, 117 out of 234 patients in the Zejula arm (50 percent) and 56 out of 116 in the placebo arm (48 percent) entered the trial with a PR. Randomization was further stratified based on time to progression after completion of the penultimate platinum regimen, the use of Avastin (bevacizumab), and the best response (CR or PR) during the final platinum regimen. Each patient had received at least two prior courses of platinum-based chemotherapy but no prior treatment with a PARP inhibitor.

Disease assessment included imaging performed at baseline every eight weeks through cycle 14, and then every 12 weeks until treatment was discontinued. Disease progression was determined via central review using RECIST v1.1 criteria or clinical assessment. Increased levels of CA-125 alone were not considered to indicate progression. Researchers determined that the safety profile of Zejula-treated patients with a PR was similar to that of the overall study population. The concluded that, overall, treatment with Zejula provided a statistically significant benefit in patients with a PR, with a treatment effect similar to that observed in the overall study population in both the germline BRCA mutant and non-mutant cohorts.

In March 2017, the FDA approved Zejula 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 approval was based on the overall findings from the ENGOT-OV16/NOVA trial, in which Zejula reduced the risk of progression or death by 74 percent compared with placebo for patients with germline BRCA-positive platinum-sensitive, recurrent ovarian cancer.

The median PFS with maintenance Zejula was 21 months compared with 5.5 months for placebo in patients with germline BRCA mutations. These findings remained consistent across subgroups of patients, including those without BRCA mutations.

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When Your Personal War on Cancer Is Exhausting

By: Susan Gubar

When Your Personal War on Cancer Is ExhaustingBecause ovarian cancer initiated a stealthy assault before I discovered it, it seems the clear aggressor, and I the injured party. Yet as my physicians use their weapons to counterattack, collateral damages mount. Fatigue envelops me.

Sometimes the arsenal deployed against recurrent cancer feels like overkill. Often I wonder what will happen if and when the drug of the clinical trial in which I am enrolled fails to keep my cancer at bay. Will I have the resources to undergo surgery or chemotherapy again?

Paradoxically, rigorous medical protocols can steal some of the time they give us. A small quantity of life may be gained at the expense of a sometimes degraded quality of life. Enormous energy must be spent getting to the hospital, completing paperwork, waiting for vitals and blood work and the oncologist, preparing for scans or radiation, undergoing infusions or transfusions, lining up at the pharmacy, and tackling insurance red tape. Periodically, surgical procedures further weaken a patient sent home with a drug arsenal to offset gruesome side effects — the most prominent being pain, nausea and weakness.

Consider this scenario playing out over years — with no end date set for the tour of duty — and you will understand why besieged patients suffer treatment fatigue. Is treatment fatigue like combat fatigue? The enervation of chemotherapy and radiation — both derived from warfare technologies — demoralizes us as regimens multiply and at times it seems impossible to go on. Does treatment fatigue explain the gung-ho rhetoric that bombards cancer patients and that many of them deploy?

At a conference for ovarian cancer survivors that I attended, every “teal warrior” – teal is the color associated with ovarian cancer — encouraged herself to maintain “a positive attitude” and lauded others for “bravely battling and beating” their disease. These women had endured major insults to the body with extraordinary dignity. Yet their militant commitment to victory seemed at odds with their statistical chances of surviving. (About 45 percent of ovarian cancer patients survive the five-year marker, far fewer at Stage 4.) Had their doctors failed to level with them or had they repressed the prognosis? A number of those treated for late stage disease believed that they were or soon would be “cancer free.”

When I was given a diagnosis of advanced ovarian cancer, the only person in my family who believed I could become “cancer free” was my aged mother. The rest of us attributed her optimism to desperate wishful thinking. Sometimes, refusing to acknowledge the severity of an illness can make the patient feel obligated to fight it. Rather than disabusing my mother, I colluded in a fantasy that comforted. I was determined not to take that solace from her.

For some people, denial serves as a life preserver. And some may channel a passionate determination to beat cancer into working to help others. One reader wrote to tell me about such an experience: He formed an organization to help disadvantaged patients cope with complex and expensive health care problems.

I respect such activism, but at the conference I silently wondered: Were participants bamboozled by an American brand of you-can-do-it-against-miserable-odds individualism? Or maybe it is nearly impossible to continue submitting oneself to debilitating procedures without hyped hope in their triumphantly restorative powers.

The titles of many cancer books maintain the upbeat martial language of the conference participants: “Knockout,” “Beating Cancer With Nutrition,” “A Cancer Battle Plan,” “You Can Fight Cancer and Win,” “Defeat Cancer,” “Fighting Cancer With Knowledge and Hope.” Such a narrative may work with curable cancers. Even in these cases, though, the generals with the big surgical, chemical and radiological weapons are doctors, not patients. But my hesitations about warfare language go beyond that objection.

Are patients enjoined to vanquish their multiple sclerosis? Are they encouraged to rout their emphysema, A.L.S., rheumatoid arthritis or the macular degeneration of their eyes? Why is this bellicosity so prominent with regard to cancer?

Perhaps one reason for militant cancer language relates to treatment fatigue. It takes grit to subject oneself to injurious rays, toxins and excisions, especially when they harm an existence extended for only a limited period of time. The tedious repetition of successive interventions wearies worn patients. Physicians and relatives must feel the need to rouse the demoralized foot soldier. The worse the prospects the louder the drumming. Consider the alternative, recurring patients are periodically warned.

While dealing with a chronic or terminal condition, however, some people decide to reject medical options that damage the life left to be lived. Those who cease and desist should not be considered cowards, deserters, losers or quitters. Conscientious objectors, they have made their separate peace — if not with cancer, then with their living and their dying. Wearied by treatment fatigue, they want their remaining days or months to consist of more than a war against cancer. They want to consider the alternative.

I am not yet in this place. But I honor those who decide to lay down arms. Deborah Cumming, who died of lung cancer, wrote that she believed that “cancer is an insistent opportunity to learn that in dying we are alive, in living we are dying.” She felt that a “good attitude” is not about “fighting, conquering, winning. It’s about the daily thankfulness. And about peace, not war.”

When coping with metastatic breast cancer, my friend, the pioneering gender studies scholar Eve Kosofsky Sedgwick, acknowledged that she longed to hear four simple words, “You can stop now.”

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Pairing PARP Inhibitors With Other Drug Types the Next Frontier for BRCA-Mutated Ovarian Cancers

Pairing PARP Inhibitors With Other Drug Types the Next Frontier for BRCA-Mutated Ovarian CancersThe idea of interfering with DNA’s self-repair capabilities has been at the heart of this decade’s progress in treating ovarian cancer, and combining the PARP inhibitors that accomplish that with other types of therapies will be the focus of treatment in the decade to come.

Those ideas were fleshed out during a June 10 talk by Elise C. Kohn, M.D., head of gynecologic cancer therapeutics in the Cancer Therapy Evaluation Program within the Division of Cancer Therapy and Diagnostics at the National Cancer Institute. She gave the talk in Orlando, Florida, during the 10th Annual Conference of the patient advocacy group Facing Our Risk of Cancer Empowered (FORCE). FORCE’s mission is to improve the lives of individuals and families affected by hereditary breast, ovarian and related cancers.

Benefiting From PARP Inhibitors

Between the 1990s and today, several classes of treatments have been approved for use in ovarian cancer: platinum-based chemotherapies, taxane chemotherapies and then anti-angiogenesis drugs, like Avastin (bevacizumab), which interfere with the growth of the blood vessels that feed tumors. Since those agents, “PARP inhibitors are the first big things,” said Kohn, who credited the FORCE community for helping to push development of the drugs.

Lynparza (olaparib) was the first PARP inhibitor approved to treat ovarian cancer, in 2014, and Rubraca (rucaparib) followed in late 2016; both are used after treatment with chemotherapy. This year brought the approval of Zejula (niraparib) as a maintenance drug after chemotherapy, and now Lynparza, too, is being considered for use in maintaining response to chemotherapy. All the drugs except Zejula are approved specifically for BRCA-positive women.

Kohn explained why PARP inhibitors are appropriate for women with mutations in the BRCA1 and BRCA2 genes. These mutations cause susceptibility to breast and ovarian cancers by allowing problems to occur with the DNA repair process. Once DNA mistakes have ignited disease, these cancers depend on the PARP enzyme manufactured by the body to facilitate DNA repair. Medications that inhibit PARP get in the way of DNA repair and can lead to cancer cell death.

The drugs work particularly well with chemotherapy, since cytotoxic drugs damage DNA and PARP inhibitors prevent repair. “It’s like breaking your leg and never getting it fixed,” Kohn said.

She cited two studies that support the idea of using chemotherapy followed by a PARP inhibitor to help maintain response.

One, the NOVA trial, showed that Zejula improved progression-free survival (PFS) in patients with ovarian cancer following platinum-based chemotherapy. The median PFS was 21 months in BRCA-associated cancers versus 5.5 months with placebo. The SOLO2 trial, conducted only in women who were BRCA mutation–positive, found that maintenance Lynparza sparked a 70 percent improvement in PFS compared with placebo; the median PFS was 30.2 months versus 5.5 months for the control group.

A new trial is testing Lynparza as a maintenance drug in the front-line setting in women with ovarian cancer and a BRCA mutation, Kohn said. None of the studies are mature enough to offer information on whether overall survival was improved.

PARP inhibitor side effects can include nausea, anemia, fatigue, headaches and white blood cell and platelet imbalances.

In studying PARP inhibitors in BRCA-associated cancers, scientists have learned some principles that might apply to the treatment of women who don’t have the mutation. They’ve found that some ovarian cancers, while not associated with BRCA mutations, have patterns of behavior that are similar to those of BRCA-related tumors. For instance, patients with these tumors, which are deemed HRD-positive, did not respond as well as BRCA-positive patients to Zejula in the NOVA trial, but they fared better than patients who were neither BRCA mutation- nor HRD-positive.

Whether the HRD classification will prove meaningful in treatment, however, has not been confirmed. One reason is that, unlike BRCA-associated tumors, those that test HRD-positive may lose those characteristics as they change and evolve during treatment, Kohn said.

Exploring Drug Combinations

Unfortunately, PARP inhibitors don’t work for all patients with ovarian cancer, so researchers are exploring whether combining them with other drugs might lead to broader efficacy.

Kohn’s team studied carboplatin, a platinum-based chemotherapy, in combination with Lynparza and found that “women with germline mutations responded phenomenally and longer,” and, in general, that “women with ovarian cancer were more likely to respond than expected.”

A trial that looked at Lynparza paired with the experimental cediranib — an angiogenesis drug — found that their mechanisms are synergistic. “In women with platinum-sensitive ovarian cancer, many with BRCA mutations, the combination was scary good,” Kohn said, although non-BRCA mutation carriers experienced the most benefit. Now, in the NRG GY-004 study, the team is testing that concept in BRCA mutation–positive women with high-grade serous ovarian cancers, who will take platinum-based chemotherapy, Lynparza or Lynparza plus cediranib.

In a second, related phase 2/3 study, NRG GY-005, the team is studying the responses of women with platinum-resistant ovarian cancers — some of them BRCA mutation–positive — by administering single-agent chemotherapy versus Lynparza, cediranib or a combination of the two.

Studying Newer Drugs

Additional techniques are being studied as potential therapies for ovarian cancer.

The enzyme WEE1 is involved in cell division, and the experimental drug AZ1775, which inhibits that enzyme, is being studied in combination with carboplatin and taxol chemotherapies, Kohn said.

The drug prexasertib inhibits the activity of the proteins made by mutated CHEK1 and CHEK2 genes, and this interference stops cancer cells from dividing. In a study presented at the European Society for Medical Oncology 2016 Congress, results were dramatic in women with high-grade serous or germline mutation-unknown ovarian cancers, Kohn said.

The drug triapine potently blocks ribonucleotide reductase (RNR), which ovarian and breast cancers use to make new DNA or repair DNA injury. The strategy works very well in combination with radiation, Kohn said.

While the immune system tends not to notice cancers caused by germline mutations, adding abnormalities to cells with chemotherapy and PARP inhibitors may wake it up, Kohn said. As a result, she said, combinations of the immunotherapy drug Imfinzi (durvalumab) with Lynparza or cediranib may prove valuable.

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