Challenges of PARP Inhibitor Selection and HRD Testing in Ovarian Cancer

Challenges of PARP Inhibitor Selection and HRD Testing in Ovarian CancerA continuing medical education session at the Society of Gynecologic Oncology’s 2018 Annual Meeting on Women’s Cancer (March 24-27, 2018; New Orleans, LA) offered insight for optimal selection and administration of poly (ADP-ribose) polymerase (PARP) inhibitors, as well as homologous recombination deficiency (HRD) testing in ovarian cancer.

With many available therapeutic options for treating ovarian cancer, along with many more in the pipeline, the treatment landscape for ovarian cancer can be difficult to navigate. Three individuals attempted to provide some clarity to this challenge: Bradley Monk, MD, FACS, FACOG, professor of gynecologic oncology, University of Arizona; Michael J Birrer, MD, PhD, director, University of Alabama Birmingham Comprehensive Cancer Center; and Ursula A Matulonis, MD, director of gynecologic oncology, Harvard Medical School.

The presenters implored the audience to share their prior knowledge of clinical trials relating to the PARP inhibitors olaparib, rucaparib, and niraparib. The discussion was then directed to when best to use PARP inhibitors in the treatment paradigm, molecular markers for guiding treatment, eligible patients, and inhibitor characteristics to inform treatment decisions.

Genetic alterations are directly related to the homologous recombination repair pathway in up to 50% of epithelial ovarian cancer cases, explained Dr Monk, which is why identifying the germline and somatic mutations involved in homologous recombination DNA repair is a crucial determinant for when to use PARP inhibitors. However, the approved PARP inhibitors are unique and must be assessed individually to ensure optimal utilization. Dr Monk shared a few ongoing and promising trials for PARP inhibitor combinations, including bevacizumab and  inhibitors with immunotherapy as well as triplet therapy with inhibitors, immunotherapy, and bevacizumab.

Dr Birrer then addressed HRD testing in ovarian cancer, stressing the fact while BRCA1/2 are the most common mutations, many other mutations have been uncovered that factor into ensuring patients receive the optimal therapies. A few trials were shared that helped support this argument, including the NOVA trial, in which patients with BRCA mutations responded best with niraparib, though patients with non-BRCA mutations also demonstrated good results.

“All patients with ovarian cancer should undergo genetic testing,” Dr Birrer said, especially now that HRD assays are available.

To read this full article on Journal of Clinical Pathways, please click here.

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What is HIPEC?

What is HIPEC?Ovarian cancer most commonly follows a pattern of intraperitoneal spread, and even in the setting of bulky extra-ovarian disease, it can be thought of as being largely localized to the peritoneal compartment. This forms some of the rationale for performing extensive cytoreductive surgery (CRS) on ovarian cancer metastatic within the peritoneal cavity, and also some of the rationale for delivery of cytotoxic therapy directly to this compartment (intraperitoneal or “IP” chemotherapy). To be most effective, IP chemotherapy should be able to contact all peritoneal surfaces and be exposed to very low volume tumors (ideally no thicker than 2-mm implants).

There is a large body of evidence demonstrating the benefits of conventional IP chemotherapy in women who have received complete or “optimal” CRS to disease measuring less than 1 cm3.1 However, IP chemotherapy is complicated by difficult administration and can be difficult for patients to tolerate. It is associated with significant toxicity, more so than what is seen from intravenous chemotherapy, and this toxicity is drawn out over the 18 (or more) weeks of therapy. It requires placement of an intraperitoneal port, and there are many problems associated with this foreign body including infection, malposition, and even erosions into underlying visceral structures. There are also concerns regarding the ability of the intraperitoneal infusions to reach all peritoneal surfaces when postoperative adhesions may have formed to pocket-off areas of the peritoneal cavity.

Hyperthermic intraperitoneal chemotherapy (HIPEC), at the time of CRS, is a strategy that has been explored to overcome some of these challenges.2 HIPEC has the most history as an adjunct to the surgical management of gastrointestinal cancers (particularly appendiceal and colorectal). The technique first described by Dr. Paul H. Sugarbaker for gastrointestinal tumors remains similar to that performed in ovarian cancer.3 Patients first undergo extensive CRS until there is no macroscopic residual disease. Immediately following cytoreduction, catheters are placed into the peritoneal cavity, the main incision is temporarily closed (to prevent spillage), and an infusion of cytotoxic agents (commonly cisplatin, often with a second agent such as mitomycin C or doxorubicin) is warmed and then distilled into the peritoneal cavity until it is “moderately distended.” The patient’s body is then rolled back and forth to “wash” down the entire peritoneal cavity. All peritoneal surfaces can be touched by the agent as this procedure is happening intraoperatively prior to adhesion formation.

The “H” in HIPEC stands for hyperthermic, which is a key differentiator from traditional intraperitoneal and intravenous chemotherapy administration. Some chemotherapy agents, such as cisplatin, have a synergistic effect with hyperthermia. Some of these effects include increased oxygen free radical formation, increased cellular uptake of drug, reversal of mechanisms of drug resistance, and increases in DNA damage. The ideal range of hyperthermia is between 41° C and 44° C. At higher temperatures, infusions rates can be faster; however, higher temperatures are associated with more toxicity, particularly of the small bowel.4

Toxicity is a concern with HIPEC.5 Cytoreductive surgery for ovarian cancer can be associated with substantial morbidity, and exposing patients to prolonged operative time, extended periods of hyperthermia, and high doses of cytotoxic agents is a concern. When performed by high volume, experienced practitioners, approximately 12% of patients experience serious (grade 3-5) toxicity after CRS with HIPEC, with a procedure-related mortality of 1.2%. The majority of major toxicities were bone marrow suppression and nephrotoxicity (which in some cases can result in patients requiring hemodialysis in the immediate postoperative period). It is for this reason that most HIPEC protocols include a routine ICU admission postoperatively to closely monitor patients for major renal toxicity and electrolyte disturbances. These complications are associated with higher doses of administered cisplatin. Febrile neutropenia and gastrointestinal complications (such as bowel perforation, fistula, or anastomotic leak) also comprise the most common major toxicities. Patient factors to consider as higher risk for morbidity and mortality include underlying cardiac or pulmonary disease, poor performance status, extreme obesity, and preexisting renal disease.

While the history of HIPEC was focused around the treatment of GI peritoneal malignancies, in more recent years, the technique has been applied and studied in women with ovarian cancer.

The indications for use can vary from the upfront setting (at the time of primary CRS), following neoadjuvant chemotherapy (at the time of interval CRS), or in the recurrent setting (at the time of secondary CRS).2 Possibly the most compelling study exploring HIPEC in ovarian cancer was published earlier this year in the New England Journal of Medicine.6 This study explored the use of HIPEC at the time of interval CRS following three cycles of neoadjuvant platinum and taxane intravenous chemotherapy. Two hundred and forty-five patients were randomly assigned at the time of optimal interval CRS to either CRS alone or CRS with HIPEC with cisplatin administered over 90 minutes. All patients received three additional cycles of intravenous platinum and taxane chemotherapy. Death was observed in a significantly higher proportion of patients in the non-HIPEC group (62% versus 50%). HIPEC was associated with a hazard ratio for death of 0.67 (P = .02). In this study, a similar number of severe adverse outcomes were observed in the two groups, though specific information was lacking, particularly with respect to renal toxicity.

These findings are intriguing and have energized interest in HIPEC by many gynecologic oncology providers; however, there are some concerns regarding the results. Patients in this study received not one intervention, but in fact three interventions (hyperthermia, an additional cycle of chemotherapy, and the peritoneal administration of chemotherapy). Any one of these three variables could explain the outcomes and it is difficult to know if all three (in the form of HIPEC) are necessary to see this observed benefit. Others have questioned the finding of no added toxicity when HIPEC is applied. This is inconsistent with what has been presented elsewhere. It is unclear from the data whether or not the nephrotoxicity was comparable between the two groups or more severe among those who received HIPEC.

An additional concern regarding HIPEC is the feasibility. Additional operative times (by up to 90 minutes), increased duration of hospitalization (including ICU admission), and additional equipment and specialized personnel are required for this technique. This may further hinder its uptake and routine practice. In the meantime, we continue to await further clinical trials that will better define the ovarian cancer patient population who might benefit from this technique and provide further data regarding its risk/benefit profile.

To read this full article by MD Edge, please click here.

AACR 2018: Anetumab Ravtansine Exhibits Additive Effects When Combined With PEGylated Doxorubicin, Bevacizumab, or Copanlisib in Ovarian Cancer

AACR 2018: Anetumab Ravtansine Exhibits Additive Effects When Combined With PEGylated Doxorubicin, Bevacizumab, or Copanlisib in Ovarian CancerAnetumab ravtansine has been shown to exhibit single-agent activity in mesothelin-expressing human ovarian cancer models and to potentiate the activity of chemotherapeutics and targeted agents.

This finding of an in vitro and in vivo evaluation was reported at the American Association of Cancer Research (AACR) Annual Meeting, from April 14 – 18.

Christoph A. Schatz, PhD, of Bayer AG, Berlin, Germany, explained that ovarian cancer remains an area of high unmet medical need, with 239,000 patients newly diagnosed per year.

Dr. Schatz told Elsevier’s PracticeUpdate, “There is still a high medical need for novel therapies in ovarian cancer. Since mesothelin is a well described target for this indication, we decided to investigate anetumab ravtansine, a mesothelin-targeting antibody-drug conjugate, in preclinical ovarian cancer models.”

Internalization of anetumab ravtansine and colocalization with lysosomal markers in ovarian cancer cells was accompanied by rapid resynthesis of mesothelin, which may allow consecutive anetumab ravtansine treatment cycles.

The strong antitumor activity of anetumab ravtansine was preserved during repeated treatment cycles in cells from the ovarian cancer 3 (OVCAR-3) cell line. Mechanistically, treatment with anetumab ravtansine caused mitotic arrest characterized by increased phospho-histone H3 signal and monopolar spindle structures.

Interestingly, anetumab ravtansine monotherapy also induced DNA damage as indicated by focal γH2AX signals. Ultimately, the cells exhibited apoptotic cell death. Strong in vitro monotherapy activity was demonstrated in a set of 11 ovarian cancer cell lines with IC50s from 3 to 90 nM.

In vivo efficacy of anetumab ravtansine dosed intravenously in nine models of human ovarian cancer with varying mesothelin expression levels.

Strong in vivo efficacy was seen in cells from the OVCAR-3 cell line and the patient-derived xenograft model ovarian cancer ST207. Efficacy was greater in tumors with strong mesothelin expression. No activity was seen in mesothelin-negative ovarian cancer models.

The combination of anetumab ravtansine + the PI3K inhibitor copanlisib in OVCAR-3 tumors in vivo resulted in consistently greater efficacy than either treatment alone.

Both single treatments and the combination were well tolerated. Combining anetumab ravtansine with bevacizumab, the only antibody therapy approved for ovarian cancer, also raised in vivo efficacy of the combination and was well tolerated.

Anetumab ravtansine was then combined with PEGylated doxorubicin. This combination proved to be synergistic with significantly improved antitumor efficacy in the OvCa 6668 (patient-derived) model than either therapy alone.

“Strong antitumor activity was demonstrated in mesothelin positive cell-line and patient-derived ovarian cancer xenograft models,” Dr. Schatz said. “Improved antitumor efficacy was obtained when combining anetumab ravtansine with PEGylated doxorubicin, copanlisib, or bevacizumab.”

Dr. Schatz concluded that the data support development of anetumab ravtansine for ovarian cancer and its combination with copanlisib, bevacizumab, or PEGylated doxorubicin.

“A phase I study of anetumab ravtansine + PEGylated doxorubicin is ongoing in patients with platinum-resistant ovarian cancer. Initial results are expected to be presented at an upcoming scientific meeting,” he added.

To read this full article on PracticeUpdate.com, please click here.

Busting Myths Surrounding Cancer and Genetic Testing

Busting Myths Surrounding Cancer and Genetic TestingWhile only 5 percent to 10 percent of cancers are caused by an inherited gene mutation, genetic testing may benefit people with a strong history of family cancer, an expert in genetics suggests.

This is especially true in families with a history of breast, ovarian, prostate or pancreatic cancers (especially if you are of Ashkenazi Jewish descent), as well as colon and uterine cancers, said Monique Lubaton. She is a cancer genetic counselor at LifeBridge Health in Baltimore.

Lubaton said there are many myths about inherited cancers and genetic testing.

The first misconception is that a negative test for a BRCA1 or BRCA2 mutation means a person does not have hereditary cancer syndrome.

In the general population, about one person in 500 has a BRCA1 or BRCA2 mutation. That compares to about one in 40 among the Ashkenazi Jewish population (Central or Eastern European).

While these mutations are the most common cause of hereditary breast or ovarian cancer, a negative genetic test does not mean there is no hereditary cancer risk, Lubaton explained.

“There are a number of other genes that are associated with hereditary cancer syndromes,” Lubaton said in a LifeBridge Health news release.

Another myth is that having an inherited genetic mutation guarantees a person will develop cancer. While most hereditary cancer syndromes have “moderate-to-high” risk levels, the risk can be reduced “with guided management,” according to Lubaton.

Signs of hereditary cancer syndrome include cancers found before age 50; the same type of cancer in three or more members on the same side of the family; and one or more family members with multiple cancers. People with rare cancers like medullary thyroid cancer and male breast cancer, or a history of more than 10 colon polyps, may also have hereditary cancer syndrome.

Some people think a woman can’t get a genetic mutation from her father. That’s wrong, Lubaton said.

Nearly all hereditary cancer syndrome mutations can be passed down by either mother or father. But inherited mutations in these genes increase female carriers’ risk of breast and ovarian cancers, she added.

Another misconception is believing that if you’ve already had cancer, there’s no need to find out whether you have an inherited gene mutation.

People with such mutations are at increased risk for multiple cancers over a lifetime, so it’s important to know about these mutations, according to Lubaton.

“Also something important to know, there are now targeted therapies for individuals with genetic mutations,” she said.

Lubaton said genetic testing is more affordable than most people think and insurance often covers the cost.

To read this full article on HealthDay, please click here.

Study Finds Relationship Between PTEN Loss, Potential For Immune Response In BRCA 1/2-Deficient Ovarian Cancer

Study Finds Relationship Between PTEN Loss, Potential For Immune Response In BRCA 1/2-Deficient Ovarian CancerThe protein known as phosphatase and tensin homolog (PTEN) is frequently mutated or affected by cancer as tumors develop. Now a new study from the Basser Center for BRCA at the Abramson Cancer Center of the University of Pennsylvania shows PTEN may serve as a marker for whether a patient with BRCA 1-2 deficient ovarian cancer is likely to respond to checkpoint inhibitor therapy. Researchers found the tumors that had PTEN loss were less likely to generate an immune response than tumors that maintain PTEN levels. They will present their findings at the American Association for Cancer Research Annual Meeting in Chicago on Wednesday (Presentation #5729).

BRCA1/2-deficient ovarian cancer is a specific subset of ovarian cancer. Genes known as BRCA1 and BRCA2 are involved in cell growth and the repair of damage to DNA. Mutations or deficiencies in these genes can cause DNA to go unrepaired, which increases the chance of developing cancer. These cancers are often initially susceptible to treatments that damage the tumor’s DNA, such as platinum chemotherapy, but most develop resistance and require other treatment strategies. One strategy is the use of anti-PD1/PDL1 immunotherapies. Although clinical trials have collectively shown a disease control rate of approximately 45 percent using this approach in ovarian cancer, they have yet to establish selective benefit in BRCA1/2-deficient cancers, which should generate stronger anti-tumor immune responses given their higher mutation rate.

Researchers in the Basser Center for BRCA analyzed data on 86 ovarian tumors, from the Cancer Genome Atlas (TCGA—68) as well as from Penn (18), to evaluate potential immunosuppressive mechanisms in BRCA1/2 deficient tumors and to identify factors that may determine response to PD1/PDL1 inhibitors.

“PTEN is a genomic marker we already routinely measure, and based on published data we wanted to know if we could use it to predict which BRCA1/2 mutated tumors are likely to respond to checkpoint inhibitors and which are not,” said the study’s senior author Katherine L. Nathanson, MD, deputy director of the Abramson Cancer Center and director of Genetics at the Basser Center for BRCA. Adam Kraya, Ph.D., a post-doctoral fellow at Penn, was the study’s lead author and will present the findings at AACR.

The TCGA analysis showed tumors with PTEN loss in the background of BRCA1/2 deficiency had lower levels of cytolytic immune molecules and immune-activating pathways that would normally drive immune responses against tumors. In Penn ovarian tumors, the levels of immune molecules like CD3, CD8, FoxP3, and PRF1 were found at significantly lower levels with PTEN loss. These data suggest that immune cells were not able to infiltrate tumors as effectively nor mount anti-tumor responses when PTEN is lost. In other words, PTEN loss correlates with loss of molecules that can generate an immune response.

“This is an effect we’ve seen in other disease types like melanoma and leiomyosarcoma, but this is the first study to identify the effect in BRCA-deficient ovarian cancer,” Nathanson said.

Nathanson and her team are also investigating a similar question in breast cancer.

To read this entire article in MedicalXpress.com, please click here.

‘Personalized’ Ovarian CA Vaccine May Prolong Survival

'Personalized' Ovarian CA Vaccine May Prolong SurvivalA novel cancer vaccine made from autologous whole-tumor and dendritic cells significantly improved survival in women with recurrent advanced epithelial ovarian cancer (EOC), given alone or in combination with standard immunomodulatory therapy, researchers found.

An international pilot study in 25 platinum-treated, immunotherapy-naïve patients with recurrent advanced EOC showed that at 24 months, the overall survival (OS) was 100% in 20 patients who responded to a vaccine developed from autologous dendritic cells pulsed with oxidized tumor lysate.

This rate was compared with an OS of 25% in vaccine non-responders, said Lana E. Kandalaft, PhD, of the University of Pennsylvania in Philadelphia, and the Ludwig Institute for Cancer Research in Lausanne, Switzerland, and colleagues.

Although the median time to progression in responders was more than 15 months, one-third had not progressed at 24 months, the study authors reported online in Science Translational Medicine.

More than 60% of patients who demonstrated potent antitumor T cell responses, including to new epitopes, experienced remission inversion. Over a follow-up period of up to 2 years, 392 doses of the autologous whole-tumor antigen dendritic cell vaccine were administered without serious adverse events, the investigators said.

“[W]e demonstrated that our vaccination approach can effectively mobilize antitumor immunity in ovarian cancer patients,” they wrote. “We conclude that the use of oxidized whole-tumor lysate DC [dendritic cell] vaccine is safe and effective in eliciting a broad antitumor immunity, including private neoantigens, and warrants further clinical testing.”

The autologous whole-tumor antigen dendritic cell vaccine can be made “in sufficient quantities with relative ease,” they added.

“Our results demonstrate that personalized vaccines made out of patients’ own tumors can induce an immune response that correlates with a higher progression free survival and a higher overall survival,” Kandalaft told MedPage Today.

“Furthermore, when our vaccine was combined with SOC [standard of care] drugs, we observed higher survival than in patients receiving drugs alone. These results are very encouraging for patients with ovarian cancer, where there is a clear unmet need.”

The clinical trial with three patient cohorts was conducted at the Abramson Cancer Center at the University of Pennsylvania, and the immunologic analyses were conducted at the Ludwig Cancer Research Institute Lausanne.

In cohort 1, five patients received the vaccine via intra-nodal injection every 2 weeks. In cohort 2, 10 patients received the vaccine plus IV bevacizumab (Avastin; 10 mg/kg) on the day of vaccination. In cohort 3, patients received the vaccine and IV bevacizumab plus IV low-dose cyclophosphamide (Cytoxan; 200 mg/m2) 24 hours prior to each vaccination.

At 12 months, OS was 100% in cohort 3 compared to 60% in an historic control group of 56 matched patients who received standard therapy with bevacizumab and cyclophosphamide but no vaccine (P=0.0094). At 24 months, OS was 78% in cohort 3 compared to 44% in the control group (P=0.046).

Notably, OS was significantly higher at 12 and 24 months in cohort 3 patients who received cyclophosphamide prior to immunization compared to cohort 2 patients who received no cyclophosphamide. OS was also significantly higher than previously reported with bevacizumab-based biological combinations, the researchers said.

“The 2-year survival of the cohort who received the full combination was considered promising, albeit preliminary, compared to literature and historic institutional controls,” the investigators noted.

These results also demonstrated how autologous whole-tumor antigen dendritic cell vaccines might be integrated into standard therapeutic strategies, Kandalaft said. If larger, randomized, placebo-controlled trials produce similar results, a new therapeutic strategy “could be implemented swiftly,” she said in a statement.

“Bevacizumab and cyclophosphamide are routinely used to treat recurrent ovarian cancer. All we did was add the vaccine,” she pointed out. “This means that we should be able to easily integrate this personalized immunotherapy into the current standard of care for recurrent ovarian cancer.”

Kandalaft said she sees a couple of potential therapeutic niches for the vaccine. In patients who have completed surgery and chemotherapy, vaccination could prolong progression-free survival. About 85% of ovarian cancer patients relapse during this period of watchful waiting, she noted.

The vaccine could also help prevent recurrence when used in combination with a checkpoint blockade inhibitor. “Response rates are low for checkpoint blockade inhibitors in this population of patients so the combination of vaccine with checkpoint blockade inhibitors could improve the response rates,” she explained.

“Even though vaccines have not been successful in the last decade, our deeper understanding of the immune system combined with the recent advances in technologies enables us to produce better vaccines,” Kandalaft said. “We now know better how to vaccinate, what population of patients we should vaccinate, and what we should use in combination with vaccines.”

The research team plans to study the vaccine in up to 30 patients with ovarian cancer who have completed chemotherapy and surgery at the University Hospital of Lausanne. That study will open towards the end of 2018, Kandalaft said.

To read this entire article in MedPageToday.com, please click here.

Ovarian Cancer Vaccine Improves Women’s Survival Rates

Ovarian Cancer Vaccine Improves Women’s Survival RatesA personalised cancer vaccine that trains the immune system to attack tumours has had encouraging results in women with ovarian cancer.

Ovarian cancer is one of the most common types of cancer in women – around 7,300 women in the UK are diagnosed with it each year. The disease often isn’t recognised until it has already spread, and even after successful treatment, there is a high risk of the cancer returning. Only half of women diagnosed with ovarian cancer survive for five years or more.

Cancer vaccines have been showing promise in clinical trials, but few worldwide have made it into the clinic for routine use. Many of these vaccines are designed to train immune cells to recognise particular molecules that are often present in cancer cells, but this can fail because tumours vary between different people.

To get around this problem, Lana Kandalaft from the University of Lausanne, Switzerland and her team have created personalised vaccines that are tailored to each individual tumour. To do this, they take samples from a woman’s tumour and kill the cells with acid, which exposes molecules that are normally hidden. These dead cells are then mixed with immune cells from the woman’s blood, and grown in the lab for a few days before being injected back into her.

Extended Survival

To test the safety of this approach, Kandalaft and her colleagues gave personalised vaccines to five women with recurrent ovarian cancer. They also gave vaccines to 20 other women with ovarian cancer, in combination with either one or two chemotherapy drugs. These drugs kill cancer cells, but are also known to boost the immune system.

The women received a dose of the vaccine every three weeks, for 15 weeks, and then monthly injections until their disease progressed or their vaccine supply ran out.

The team found that the vaccine was safe and did trigger immune responses against the women’s tumours. The women who showed stronger immune responses subsequently lived longer than those with weaker ones. The women who received the vaccine alongside both chemotherapy drugs showed the best survival rates – 80 per cent of these women were still alive two years later, compared with around 50 per cent of women with similar stages of cancer who received only the drugs.

Ovarian cancer bounces back in 85 per cent of women who undergo surgery, so Kandalaft thinks a vaccine could be given post-surgery, to women in remission, to reduce the chances of this happening. Kandalaft says her team’s results show that it’s important to keep samples of a women’s tumour when she undergoes surgery, so that a personalised vaccine can be made.

To read this article by New Scientist, please click here.