Leah Lawrence

When Jo Anne Schatz, 69, talks about the latest treatment she received for her endometrial cancer, she describes it as an “eraser.”

“It was amazing,” Schatz says. “It just wiped my cancer out.”

The drug, Keytruda (pembrolizumab), is a type of cancer treatment called immunotherapy, designed to harness a person’s immune system to identify and destroy the cancer. It is just one of the targeted treatments approved by the Food and Drug Administration (FDA) for or being developed for the treatment of endometrial cancer.

Unlike traditional chemotherapy, which acts against cancer cells and healthy cells alike, targeted treatments are aimed at specific aspects of the cancer cells.

Keytruda hitting its target is what Schatz credits with saving her life.

Schatz, a former addiction specialist from Philadelphia, received a diagnosis of endometrial cancer in May 2015 after experiencing unexpected vaginal bleeding. She had never heard of the disease.

“My primary care doctor told me to contact my gynecologist; within two weeks, I was seeing a specialist at Fox Chase Cancer Center and headed in for a complete hysterectomy,” Schatz says.

Endometrial cancer is a disease in which cancer cells form inside the lining of the endometrium, or uterus. Vaginal bleeding and pelvic pain are common symptoms.

“Endometrial cancer is the most common of all gynecological cancers in the United States,” says Dr. Christina S. Chu, professor in the Department of Surgical Oncology at Fox Chase Cancer Center in Philadelphia. “Fortunately, the vast majority of endometrial cancers can be treated surgically with the removal of the uterus, ovaries, fallopian tubes and cervix. Most are cured with this surgery plus or minus radiation.”

Some patients — 13% — who receive a diagnosis of endometrial cancer, however, will have their disease recur. After surgery, Schatz underwent several rounds of radiation and chemotherapy to destroy any remaining cancer cells. After a brief remission, her cancer recurred, metastasizing to the peritoneal lining, and her physicians began to look for more targeted treatment options.

“When we started to get down to the genomic levels of these tumors, we realized that just because some endometrial cancers may look (similar) under the microscope, they may still behave biologically different based on genomic signature,” says Dr. Emily M. Ko, assistant professor of obstetrics and gynecology at Pennsylvania Hospital of Penn Medicine in Philadelphia. “Based on that genomic signature, there may be biologic pathways that we can target.”

That is what happened to Schatz, who was told that her type of endometrial cancer had a genetic component called MSI-high.

MSI stands for “microsatellite instability.” When disease is MSI-high, the cancer cells have a high number of mutations within microsatellites, which are short, repeated sequences of the DNA. These signify abnormalities in DNA repair, which can be targeted with certain drugs.

In 2017, the FDA approved Keytruda for use as a treatment for any solid tumor that was MSI-high, had progressed after prior treatment and had no satisfactory alternative treatment options.

“This was important for patients with endometrial cancer because (approximately) 30% of patients with endometrial cancer will have tumors that are MSI-high,” explains Dr. Shannon N. Westin, associate professor in the Department of Gynecologic Oncology and Reproductive Medicine at The University of Texas MD Anderson Cancer Center in Houston.

One study evaluating the use of Keytruda in patients with MSI-high tumors showed that among a small group of women with endometrial cancers, more than half saw their tumor respond to the treatment, and the majority had at least some clinical benefit.

“A larger proportion of patients with endometrial cancer will have microsatellite-stable disease,” Westin says. “For those patients, there is a newer FDA-approved targeted therapy combining Keytruda with Lenvima (lenvatinib).”

Indeed, in late 2019, the FDA approved the immuno- therapy Keytruda with Lenvima for patients with endo- metrial cancer that is not MSI-high and whose disease has come back after prior chemotherapy. Lenvima is a multiple-receptor tyrosine kinase inhibitor. The drug works by blocking the action of abnormally activated proteins that signals cancer cells to multiply. A study of this combination showed that approximately one-third of endometrial tumors responded.

Finally, some patients with endometrial cancer may qualify for treatment with a drug targeting NTRK gene fusions, which are estimated to occur in only a small percentage of endometrial cancers. Rozlytrek (entrectinib) and Vitrakvi (larotrectinib) are approved for adults who have solid tumors with this specific genetic alteration.

“Not every endometrial cancer that comes back or spreads will have one of the characteristics to qualify for the currently available targeted treatments. These women may want to ask their physicians about potential alternatives,” Ko says.

Kim Bryant, 61, a former special education teacher from Texas, did just that when she was told in May 2019 that her endometrial cancer had spread. After receiving her diagnosis in March 2016, Bryant initially underwent surgery and radiation for the cancer. After its first recurrence a year later, she had additional surgery followed by radiation and chemotherapy.

“At that point, my local oncologist said he had done all he could and referred me to MD Anderson,” Bryant says. “I was given a choice between two trials. I was enrolled in one for about a year and my cancer progressed. I have had more success with the second trial.”

The second clinical trial is testing a three-drug combination of the hormone therapy Femara (letrozole); Afinitor (everolimus), a drug designed to target a protein called mTOR that promotes cell growth; and Kisqali (ribociclib), a CDK 4/6 inhibitor that is designed to interrupt the cell cycle that drives growth of cancer cells.

“CDK 4/6 inhibitors have been studied in breast cancer and are thought to potentially be synergistic when used with other hormonal drugs,” Ko says.

For her first clinical trial, Bryant had been making a four- hour drive once a week from Dallas to Houston to receive treatment. On the current trial, all three drugs are oral and can be taken at home.

“All three oral treatments (are) so much easier because there are no infusions,” Bryant says. “I only have to go down once every three months for bloodwork and other testing.”

Bryant remains on treatment and says that, so far, the cancer is responding well.

In addition to mTOR and CDK 4/6 inhibitors, clinical trials are also testing a class of drugs that inhibit poly (ADP-ribose) polymerase — more commonly known as PARP inhibitors. This class of drugs is approved for certain breast and ovarian cancers that have an inherited mutation in the BRCA gene

or have a certain genomic instability called homologous recombination deficiency (HRD), a type of DNA repair defect.

“There are a number of trials exploring these drugs alone or in combination with other targeted agents to see if there is activity in endometrial cancer,” Westin says. “Probably about 20% of endometrial cancers have mutations in BRCA or other abnormalities in HRD pathway members, but there may be other abnormalities in endometrial cancer that predict benefit, so none of the trials (is) being selective.”

There are also trials exploring other immunotherapy drugs that target a protein called PD-1 or PD-L1, immunotherapy drugs in combination with chemotherapy or other targeted agents, and agents targeted against other disease pathways such as the PI3K or MEK pathways, Westin says.

Right now, these targeted therapies are considered second- line treatments — given after a first disease recurrence — because they are not as effective as primary chemotherapy for most patients, according to Chu.

“Trials are ongoing to test targeted therapies in combination with chemotherapy in the first-line setting, though,” Chu says.

There have not been any completed clinical trials yet comparing the standard chemotherapy with these new targeted treatments, but they are in progress, according to Ko.

“What we are learning is that perhaps side effect profiles may be better in targeted treatment, meaning it may be worthwhile to consider an alternative targeted therapy up front in treatment rather than saving it for down the road,” explains Ko.

For example, immunotherapy drugs such Keytruda do not have the traditional side effects seen with chemotherapy, such as hair loss, nausea or vomiting. Because the drug works by attempting to stimulate the immune system, many of the side effects seen with Keytruda are related to the immune system, Chu says. Similarly, side effects seen with Lenvima, which works by affecting blood vessels, can be related to a patient’s blood vessels, such as high blood pressure.

Schatz says that during her treatment with Keytruda, she experienced muscle aches, pains and fatigue. Other common side effects associated with Keytruda include headache, fever, skin rash, constipation, loss of appetite and diarrhea.

“On chemotherapy, I was often sick for a full week, then a little better before preparing to go back for another treatment,” Schatz says. “On the trial, I was able to cook and care for myself and establish a routine.”

Bryant says that side effects during her most recent clinical trial also have been tolerable.

“I have had some decrease in appetite and some fatigue, but not enough that it keeps me from doing what I want to do,” Bryant says. “It has only slowed me down some.”

Many of the side effects related to targeted therapies can be managed easily if caught early, Westin says.

“This takes good communications between a patient and their health care team — and preparation — so that a patient knows what to look for,” Westin says.

In addition to a patient’s tumor having the right “target,” the health care team will consider these possible side effects in their decision on whether a patient might qualify for treatment with a targeted therapy.

“We look at the best data we have available, the tumor characteristics and the overall health of each patient to decide if a targeted therapy is best,” Ko says.

Schatz credits much of her progress not only to targeted therapy but also to advocating for herself and her treatment. She had one doctor who encouraged her to continue treatment, whereas another told her to stop. Since stopping treatment with Keytruda, Schatz has follow-up scans every four months, as well as other regular monitoring. “I am also healthier,” she says. “I am on a ‘cancer-fighting’ plant-based diet. I take it one day at a time, but I am grateful to be alive and can feel my creativity coming back.”

Bryant, too, has been able to maintain an upbeat, “glass-half-full” attitude throughout her cancer journey, she says.

“I have surrounded myself with my faith, family and friends,” she says.

Westin applauds patients such as Schatz and Bryant for raising their voices and sharing their stories about endometrial cancer.

“Other tumor types get more attention, but endometrial cancer is one of the only cancer types where the incidence is growing,” Westin says. “A lot of women with endometrial cancer will be cured, but we have to be aware of their sisters in diagnosis who do not do as well and together raise our voices to shine more light on this problem. Hopefully that will allow us to get more funding and more companies interested in exploring new agents to treat endometrial cancer.”

For more news on cancer updates, research and education, don’t forget to

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As more is learned about the biology of endometrial cancer, new treatment possibilities emerge.

Targeted Therapies Take Aim at Endometrial Cancer

Alisa Brenes, 63, is a 20-year survivor of lung cancer, and she spends a lot of time worrying about COVID-19. “I first became aware of COVID-19 through my lung cancer community, which was discussing this new disease and how it affects the lungs,” Brenes recalls. “At first, I didn’t feel any panic, (as) most of the local cases were in Westchester, (New York), but shortly after that my office told us we were going home and New York City was going on pause.”

Brenes, a legal assistant living in Manhattan, is just one of the many hundreds of thousands of people in the United States who have survived lung cancer or are facing a new diagnosis and are trying to understand their risks in what has become the COVID-19 era.

What's The Risk of Cancer Care During COVID-19? 

According to the Centers for Disease Control and Prevention (CDC), COVID-19 is a respiratory illness caused by a virus that can spread from person to person, and its symptoms can range from mild or none to severe illness. The virus cells first infect the respiratory and nasal lining, causing inflammation, explains Dr. David M. Jablons, chief of general thoracic surgery at the University of California, San Francisco and a professor of thoracic oncology at its Helen Diller Family Comprehensive Cancer Center.

“That is why some patients can get a cough or shortness of breath, and in severe cases, people can develop pneumonia or interstitial lung disease,” a group of disorders that can cause progressive lung scarring, Jablons says.

Everyone is at risk for getting COVID-19, but certain groups, including older adults and those of any age with serious underlying medical conditions, might be at a higher risk for severe illness if they contract the virus, according to the CDC.

Lung cancer itself likely does not put people at increased risk of contracting COVID-19, but some of the other illnesses or treatments associated with the malignancy may increase the severity of the virus, according to Dr. Joshua K. Sabari, a medical oncologist at NYU Langone Health’s Perlmutter Cancer Center and an assistant professor at its NYU Grossman School of Medicine in New York City. One of those conditions is simply age, as the average patient who receives a diagnosis of lung cancer is 70 years old.

“Other pulmonary comorbidities (coexisting illnesses) associated with lung cancer, such as chronic obstructive pulmonary disease and the use of certain cytotoxic chemotherapies to treat lung cancer, may also increase risk compared with targeted therapies or immunotherapy and chemotherapy combined,” Sabari says.

Although chemotherapy leaves patients with lung cancer immunocompromised, meaning that their bodies are more prone to infection, study results have been mixed about whether the treatment contributes to the risk of contracting COVID-19 or having a severe case.

Some of the best data available on the relationship between lung cancer and COVID-19 are from the TERAVOLT global registry study. Recently published data from TERAVOLT showed that patients with stage 4 non-small cell lung cancer face a higher risk of complications and death if they get COVID-19. When various factors were looked at independently, the study showed that older age, treatment with chemotherapy and the presence of comorbidities were associated with an increased risk of death among these patients. However, in an analysis of multiple factors looked at together — typically considered a more accurate measure — only smoking history was associated with an increased risk of death.

Another study, this one conducted by researchers at Memorial Sloan Kettering Cancer Center in New York City, analyzed the cases of 102 patients who had both lung cancer and confirmed COVID-19; they found that the virus was severe in 62% of the patients but accounted for only 11% of the deaths among the group studied. Chronic obstructive pulmonary disease and smoking status were associated with increased severity of COVID- 19, but recent chemotherapy was not.

Most patients with early-stage lung cancer found incidentally through screening or on a chest X-ray prior to another surgery are likely not at any increased risk from COVID-19 compared with the general population, Jablons says, adding that he is not aware of any patients with lung cancer at his cancer center who contracted COVID-19 since the pandemic started.

Although her evaluation is anecdotal rather than scientific, Brenes has seen a similar trend: None of her close friends from the lung cancer community have told her they had the virus, and Brenes has heard through the grapevine of only a handful of people within that community who have been sick with the illness.

One important thing to remember is that cancer will not “shelter in place” when people do, Jablons says.

“In the past few months, there have not been as many incidental early-stage cancers found through screening because people are avoiding going to the hospital or for routine health care,” he says. “That may be a bigger risk to someone’s long-term survival than COVID-19.”

Brenes admits that she delayed some of her regularly scheduled follow-up appointments.

“I was a few months late for my routine low-dose CT (scan),” she says, referring to a screening test for individuals with a history of smoking that checks the lungs for lesions. “I was afraid to go to my cancer center — Mount Sinai in New York — which was a COVID-19 hospital. I was afraid to take mass transportation or to take a cab.”

To lower her risk for exposure, Brenes eventually called to have her scans scheduled at a private radiology center within walking distance and asked to have the first appointment of the week after the CT scanner had been out of use for 48 hours over the weekend.

Sabari, who practices in New York City, says he knows of a lot of patients who are fearful of in-person health care visits.

“We definitely missed opportunities to diagnose patients early and cure their disease,” Sabari says. “We have also seen a lot of mortality in lung cancer patients from not accessing care or getting the correct care during the pandemic.”

Right now, in any area with lower COVID-19 rates, patients should not delay treatment, he says. Even during the peak of the pandemic, he continued to treat patients with stage 2 or 3 disease, for whom the goal of chemotherapy is to cure the cancer.

Even in those areas with higher rates of COVID-19, patients should actively communicate with their health care teams on the best way to approach treatment, according to Dr. Konstantinos Leventakos, a medical oncologist and an assistant professor of medicine and oncology at Mayo Clinic in Rochester, Minnesota.

For some patients with advanced disease, the recommended treatment approach may include enrolling in a clinical trial. Fortunately, most centers have these studies up and running again. “Some trials halted enrollment at the start of the pandemic, but we are now able to reopen them safely,” Leventakos says.

The requirements of each clinical trial are different, and some may mandate that patients undergo COVID-19 testing before they receive treatment. Other changes made to the design of some trials during the pandemic aim to make participation more accessible, for instance, by requiring fewer cancer center visits than would otherwise be expected or using televisits or local providers when possible. “We have to constantly balance the risk of potentially life-threatening infection in patients with lung cancer with the short- and long-term consequences of delaying cancer care,” Leventakos says. “That is why good communication with your oncology team is the only way to make the best decision.”

According to Jablons, if required to come onsite, patients are safe at most treatment centers, especially at high-volume centers of excellence where thorough precautions have been put into place to prevent transmission of the virus. If concerns exist, patients should inquire about the safety precautions that are being taken for both employees and patients at the facility.

Tiffany Fagnani, 39, said she has experienced some cancellations or rescheduling of treatment and follow-up appointments at Fox Chase Cancer Center in Philadelphia since the pandemic began, but that she feels safe going in when necessary because the center has been able to maintain a COVID-19-free status.

Fagnani, a nurse case manager living in Pennsylvania, received a diagnosis of stage 4 lung cancer with brain metastases in July 2017. Today, even though the disease is stable, she understands the importance of not delaying care.

“I know that I still have to go in for certain appointments, and for others I am able to talk with my team using telehealth,” Fagnani says. She sees this compromise as the best way to prioritize her care while still being cautious.

When Fagnani goes out, she wears a mask and checks to make sure everyone around her is doing the same. If they are not, she avoids going near them. She also avoids crowded spaces where social distancing is not possible.

One challenge for Fagnani was that she was in the process of having a new home built when the pandemic hit.

“When we did walkthroughs, I asked that it only be me, my realtor and the builder,” she says. “We were all masked, and we were all socially distanced.”

In the more crowded setting of New York City, Brenes also takes precautions. “I always wear a mask if I have to leave my apartment or even for the laundry room, to get mail from the lobby or to get a home delivery,” Brenes says.

“I wear a disposable mask with a reusable lung cancer awareness mask over it.”

As many public service announcements have emphasized throughout the pandemic, frequent hand washing and keeping fingers away from the face are also important. Another way to protect health is to keep the lungs and body as healthy as possible, Leventakos says.

“At home, a healthy lifestyle can help overall health: Make healthy choices in order to keep your body strong,” Leventakos recommends. “Get enough sleep so that you wake feeling rested. Choose a healthy, balanced diet. Aim to get exercise most days of the week.”

Importantly, he says, find healthy ways to reduce stress.

“I do have high anxiety, and it has affected my mental health,” Brenes notes. To help manage her anxiety, Brenes has signed up for meditation and chanting classes on Zoom, which help her relax. When she feels anxious, she tries to focus on her breathing. Brenes also turns to the lung cancer community and its Zoom chats to talk about her fears and concerns.

Patients in need of support can turn to online communities like LUNGevity, which offers weekly virtual meetups for patients, survivors and caregivers across the country. Similarly, the GO2 Foundation for Lung Cancer has moved its Lung Cancer Living Room, a monthly patient education and support series, to a virtual plat- form. Fagnani says that she still sees some friends in person, at least the ones she knows are following all appropriate COVID-19-related precautions. She has also found a renewed joy in cooking.

“I have been doing grocery delivery, and sometimes there are certain things that you
can’t get,” Fagnani says. “I have learned to open the cupboard and see what I have to create a new meal or new recipes. I have really enjoyed that.”

As winter months approach, Sabari says that patients with lung cancer should be cautious but not fearful.

“I recommend that all patients get a flu shot, and if you are 65 or older, get the high-dose flu shot,” Sabari says. “We can’t become complacent. We have to continue to wear masks, wash hands routinely (and) socially isolate and distance when possible.”

He also emphasizes that, with all that health care experts have learned about COVID-19 since earlier this year, the benefits of treating lung cancer far outweigh the risks of the virus.

“Take every possible precaution that you can, but until we have a vaccine or until a greater proportion of the population has antibodies, COVID-19 is something that is going to remain with us, and dealing with it has to become a new normal,” Sabari says.

Leventakos agrees. He recommends that all patients and their families or caregivers get familiar with the COVID-19 precautions at their clinic or hospital and closely monitor the levels of the virus in their local area.

Finally, he says, it is important to remember that each patient’s experience is unique.

“Even though, statistically, COVID-19 might cause more complications in patients with cancer, and lung cancer, specifically, every patient has a different course,” Leventakos says. “This is why it is important for patients to communicate any change in their health with their oncology team.”

Patients with lung cancer should take all recommended precautions against COVID-19, but they must also keep up with their cancer care, doctors advise.

Patients With Lung Cancer Should Be Cautious, But Not Fearful of COVID-19

Darryl Elzy, 60, an Air Force retiree from North Carolina, has been living with prostate cancer for about 12 years and has been a participant in clinical trials almost as long.

“Every time they offered me a trial, I said, ‘Sign me up!’” Elzy says.

Earlier this year, Elzy completed a clinical trial — his third — testing PARP inhibitors, a class of drugs that is new to the treatment of prostate cancer. PARP is an enzyme in cells that helps repair DNA when it becomes damaged. The inhibitors can block PARP in cancer cells, keeping them from repairing their damaged DNA and causing them to die.

PARP inhibitors were first approved by the United States Food and Drug Administration (FDA) in 2014 to treat certain ovarian cancers and, more recently, to treat breast cancers. In May, two PARP inhibitors became the first in their class approved as therapies for certain metastatic prostate cancers, ushering in a new era of treatment with targeted drugs. 

While drugs that suppress the hormones that fuel metastatic prostate cancer are the mainstay of treatment, PARP inhibitors can help certain patients whose disease has become resistant to those medications.

In particular, the patients most likely to benefit from PARP inhibitors are those who have tumors with DNA repair defects. It is for those patients that Lynparza (olaparib) and Rubraca (rucaparib) are intended.

“Our bodies have mechanisms in place to repair damage that happens to our DNA,” explains Dr. Veda N. Giri, director of cancer risk assessment and clinical cancer genetics at the Sidney Kimmel Cancer Center at Thomas Jefferson University in Philadelphia. DNA damage happens on a daily basis and can be caused by things such as exposure to ultraviolet light, radiation, cell turnover or substances in the environment.

“DNA houses genes that act as the control center for our cells and tell the cells what to do,” Giri says. “If DNA is damaged in the region that houses those genes — called DNA repair deficiency — it can lead to improper signals and result in disease conditions such as cancer.”

Mutations in DNA repair genes can be acquired, meaning that the mutation develops in the tumor as it grows, or they can be inherited, meaning that the glitches are present throughout the body in all of a patient’s cells.

“Reports state that about 25% to 30% of men with metastatic prostate cancer have acquired, tumor-only DNA repair deficiency mutations, and about 12% to 17% of men have inherited mutations,” Giri says. “For men with earlier-stage prostate cancer, about 5% to 7% have inherited mutations.”

Among the most common DNA repair deficiency mutations are BRCA1 and BRCA2 gene mutations and a mutation in ATM, a “BRCA-like” gene also involved in DNA repair, Giri says.

DNA repair deficiencies affect signaling pathways, strings of chemical reactions that pass messages to a cell from its environment about how to behave. Pathways are associated with proteins encoded by specific genes.

When cancer cells have a DNA repair deficiency in the BRCA pathway, for example, the cells adapt and use an alternative pathway to repair themselves. PARP is one of those pathways. Using PARP inhibitors in patients who have an existing DNA repair deficiency delivers a one-two punch (known in scientific terms as “synthetic lethality”) to the cancer cells, which leads to cell death.

The exact percentage of men with DNA repair mutations who will benefit from these drugs is still being established, according to Dr. Joshua M. Lang, associate professor of hematology, medical oncology and palliative care at the University of Wisconsin School of Medicine and Public Health in Madison. That is because, for many years, it was thought that genetics were not as important in prostate cancer as in other cancers.

“Fundamentally, this is all a new area in prostate cancer,” Lang says. “In the last five years, we have become aware of genetic changes associated with prostate cancer not just in the tumor cells, but also in genes that can be inherited.”

Previously, the majority of genomic testing was done in samples taken during prostatectomy, meaning the surgical removal of the prostate, Lang explains. While inherited mutations can be found through tests of blood, saliva or tissue samples, experts are learning that acquired mutations — the ones that occur in the cancer as it grows — are not always present in the prostatectomy sample and may only appear later in biopsies taken from metastatic sites.

Elzy received a diagnosis of prostate cancer when he was 48. Although the average age at diagnosis is about 66, men found to have an inherited BRCA2 mutation are more than four times as likely than those without the mutation to receive a diagnosis before that age. Compared with men who don’t have the mutation, the risk of prostate cancer is more than eightfold higher for men who have the BRCA2 mutation and are 65 or older.

Elzy was initially treated with radiation and a prostatectomy to remove the tumor.

“My doctor realized that a portion of my cancer was outside of the margin of being able to remove it, so I knew that there was still the possibility of lingering tumor that we couldn’t reach,” Elzy says.

To address the lingering cancer cells, Elzy underwent chemotherapy, but his blood level of the protein prostate-specific antigen (PSA) — which often rises in response to the growth of prostate cancer — continued to increase. That is when his physician began to look for clinical trials.

“My first two trials both had good results to start, but all of a sudden the PSA would start rising again,” Elzy says.

Eventually, his doctor decided that Elzy should be sent for genetic testing. The National Comprehensive Cancer Center now recommends that all men with metastatic prostate cancer undergo blood tests to determine if they have inherited DNA repair deficiency. Testing can also be done on tumor samples to look for acquired mutations.

Elzy’s results revealed a BRCA2 mutation that his doctors suspect he inherited from his mother, who died of breast cancer in 1992. If genetic testing had been more advanced back then, Elzy, who has no siblings or children, likely would have been advised to undergo genetic testing to find out if he had inherited the mutation.

Dr. Maha Hussain, deputy director of the Robert H. Lurie Comprehensive Cancer Center at Northwestern University’s Feinberg School of Medicine in Chicago, noted that, at the moment, having information about inherited mutations does not change the initial approach to treating newly diagnosed prostate cancer. Similarly, knowing a patient is BRCA-negative when newly diagnosed does not eliminate the possibility that the tumor will acquire a mutation as it grows.

“This could all change as our knowledge improves,” Hussain says. However, in her practice, Hussain says she has begun to send tissue for testing in men with high-risk, 

hormone-sensitive disease or prostate cancer that has recently stopped responding to hormone-suppressing drugs. “Getting prepared and ahead of the game is the best approach,” she says. “Clearly, testing for germline has implications for blood relatives, and I offer patients the opportunity.”

In Elzy’s case, once he learned that he had an inherited mutation, he was quickly recruited into a clinical trial of a PARP inhibitor.

Lynparza and Rubraca are the only PARP inhibitors approved by the FDA so far for men with metastatic castration-resistant prostate cancer (mCRPC), meaning disease that has spread beyond the prostate and has progressed on hormone-suppressing treatments. Lynparza is approved to treat men with cancer that progressed after treatment with one of two hormone-based prostate cancer therapies, Xtandi (enzalutamide) or Zytiga (abiraterone). 

To be eligible, patients must have a mutation in one of the homologous recombination repair (HRR) genes, specifically BRCA1, BRCA2 or ATM, which constitutes a DNA repair deficiency. Patients can be selected as good candidates to receive the therapy based on the results of an FDA-approved companion diagnostic for Lynparza.

Rubraca is approved for men with mCRPC and a BRCA1 or BRCA2 mutation who have received treatment with androgen receptor-directed therapy and a taxane-based chemotherapy.

Lynparza was approved based on the results of a clinical trial comparing the drug against Xtandi or Zytiga. Men with BRCA1, BRCA2 or ATM mutations were assigned to treatment with Lynparza, while men with any of 12 other mutations associated with HRR were given Xtandi or Zytiga. Men treated with the PARP inhibitor went twice as long before experiencing disease progression (7.4 months versus 3.6 months), and early data showed that their overall survival was nearly five months longer than those in the group that received hormonal treatment (19.1 months versus 14.7 months). 

In patients who had tumors that could be measured, about one-third of those who received Lynparza saw their tumor respond to the drug compared with only 2% of men treated with the other drugs. When looking at all the men in the study, including those with mutations other than BRCA or ATM, a meaningful delay in disease progression was observed among those who took Lynparza compared with investigator’s choice of treatment (5.8 months versus
3.5 months).

Response to Lynparza also may vary depending on the type of mutation, with the phase 2 TOPARP-B study showing that 80% of patients with a BRCA1 or BRCA2 mutation responded to the treatment while 37% of patients with ATM mutations responded.

Rubraca was approved based on the results of a trial in which all patients received the PARP inhibitor and a hormone-suppressing drug. In this study, 42% of the men who participated saw their tumor respond to the drug. “There are many ways to assess response, including the rate of PSA decline, the shrinkage of tumors and delaying cancer progression,” Hussain said. 

“Based on the PROfound trial, the odds of response to Lynparza as measured by PSA decline of 50% or greater was seen in 43% who had BRCA1, 2 or ATM mutations compared with 8% (six of 77) in the patients who received Zytiga/prednisone or Xtandi. In the overall study population, a PSA response was confirmed in 30% in the Lynparza group compared with 10% in the control group. The data also show benefit in terms of significantly delaying pain progression, which is a critical point from a quality-of-life perspective.”

Patrick McGuire, 73, a retired scientist from Wisconsin, has benefited from PARP inhibitors. McGuire received a diagnosis of prostate cancer in October 2015. After under-going prostatectomy, he learned he had metastatic disease and began to participate in clinical trials. Like Elzy, he found that each trial led to only a temporary improvement in his disease.

Throughout his time in clinical trials, McGuire had been providing blood samples for testing, and after his cancer progressed during the first two trials, Lang had him undergo genetic testing, which revealed a BRCA2 mutation. McGuire did not disclose whether the mutation was acquired or inherited. Lang helped McGuire enroll in a clinical trial testing the combination of Zytiga and a PARP inhibitor.

“The drug that I am on now has helped me significantly,” McGuire says of the PARP inhibitor. “Before I took this drug, I was in a lot of pain and was regularly having to take oxycodone. On this drug, within about a month, the pain went away, and I was able to get off oxycodone.”

Prior to his cancer diagnosis, McGuire and his wife loved to travel, fish, hike and camp. For years, McGuire was no longer able to enjoy these activities, but treatment with the PARP inhibitor has allowed him to start participating again.

Like most cancer treatments, PARP inhibitors do cause some side effects. McGuire says he experiences shortness of breath, which was helped by a dose reduction; the drug also affected his red blood cell production. Other common side effects of these drugs include anemia, nausea, fatigue, decreased appetite, diarrhea, vomiting, cough, rash, constipation and low platelet levels.

It is important that patients discuss these side effects with their physicians, Hussain says.

“When I start someone on these drugs, I try to see them within a few weeks of initiating treatment,” she says. “I want to evaluate them and make sure there are no major side effects. If there are, the earlier we intervene the better the chance of sustainability of treatment.”

While on a PARP inhibitor, Elzy says, he experienced nearly no side effects. But unlike McGuire, who is still 

taking his PARP inhibitor, Elzy has moved on to his next treatment.

“It lowered my PSA level to about 0.3 and it stayed like that for maybe four to five months, but in the last three weeks, my PSA level started going upward bound,” Elzy says of the PARP inhibitor. “That is when the drug was stopped.”

Because PARP inhibitors are so new in the treatment of prostate cancer, many questions about the drugs are still being explored. For example, it is unknown if men without DNA repair mutations might benefit from the drugs. It is also unclear if men with inherited versus acquired mutations benefit more from one PARP inhibitor than another.

“Right now, it seems that some patients who have inherited mutations have cancers that are more sensitive to PARP inhibitors and see long-term response that potentially lasts more than a year,” Lang says. “For those patients whose mutation is only in the tumor, we still see a benefit for the majority of patients, but whether that is going to last for more than a year is less certain.”

While the trials that led to the approval of Lynparza and Rubraca showed significant improvements in survival, Lang and other researchers want to find out if they can do better. “We are just at the tip of the iceberg in terms of developing PARP inhibitors and other therapeutic strategies around this class of medications,” Lang says.

For example, researchers are looking into the possibility of combining PARP inhibitors and immunotherapy. There are also trials exploring combining PARP inhibitors with other treatments that target DNA damage repair, including radiation therapy.

“Combining treatments that target DNA in the cancer cell might be its own way to improve disease control and potentially knock aggressive cancers back for many years,” Lang says.

Another strategy being explored is the combination of PARP inhibitors with Zytiga as an initial treatment for mCRPC. The role of PARP inhibitors alone or in combination with other drugs is also being evaluated for use earlier in the disease, before the metastatic stage. Another question involves the role of platinum, a DNA-damaging agent used in some chemotherapies, as an alternative to PARP inhibitors, Hussain says. There are several case series suggesting potential benefit, though there are no data from a large, prospective clinical trial yet.

Finally, the whole field is faced with the challenge of ramping up testing for mutations in men with prostate cancer, some of whom may benefit from a referral to a genetic counselor to discuss familial risk.

“Now there are thousands and thousands of men who need testing, and it will take a lot of hard work to catch up,” Lang says. “We also face a national shortage of genetic counselors, so the field isn’t entirely prepared, but hopefully we will see improvements in the coming years.”

Experts agree that more genetic and genomic testing for men with advanced prostate cancer is likely taking place at major academic centers compared with community cancer centers. It is important that men are educated about genetic and tumor genomic testing, their implications, timing and whether they are eligible.

“Every patient with advanced prostate cancer, and particularly mCRPC, should discuss with their oncologist the role of tumor genomic testing and if they qualify for these treatments, the timing of treatment (and) what to expect in terms of side effects,” Hussain says. “Do not turn to the internet unless it is sources of information that are well-vetted.”

Throughout his treatment, McGuire turned to the Prostate Cancer Foundation, which was active in the funding of studies that helped reveal the role of inherited mutations in prostate cancer. Its website, pcf.org, offers information and resources about genetic testing.

FORCE (Facing Our Risk of Cancer Empowered) is an organization established to improve the lives of individuals and families affected by hereditary breast, ovarian and related cancers. This includes prostate cancer, and the organization’s website, facingourrisk.org, includes information on the disease and the genetic mutations that might increase someone’s risk of developing it.

Elzy and McGuire have faced their diagnoses with the steadfast help of their wives and with a positive attitude.

“I always say, ‘I have cancer, but cancer doesn’t have me,’” Elzy says. “I can’t let it consume me. When I was diagnosed in 2008, my first doctor told me to get my affairs in order, and I’m still here.”

They both credit participation in clinical trials for extending their lives.

“If you have metastatic cancer, I tell people to go find a doctor and a hospital you have confidence in and participate in clinical studies,” McGuire says. “In my view, these trials have basically saved my life.”

Primed to knock out cells vulnerable due to DNA-repair problems, PARP inhibitors are ushering in a targeted-drug era in prostate cancer treatment.

PARP Inhibitors Demonstrate the Value of Targeted Treatments in Prostate Cancer

When Honora Miller, 53, wondered how to explain her cancer-related fatigue to her son, a friend recommended using an analogy involving spoons. The spoon theory held that Miller would start each day with a certain number of the utensils, each one representing energy. Each daily activity cost a spoon.

“Let’s say I only have 10 spoons today, but I do more than I should, in a sense borrowing from tomorrow’s spoons. I know that tomorrow will have to be a rest day because I won’t have enough spoons,” Miller says she told her son. “It has become a shorthand for us. My 14-year-old understands that is why some days after I pick him up I have to go home and go to sleep.”

Miller has multiple myeloma, a cancer involving malignant plasma cells that grow abnormally in bone marrow, and has had to adapt to the day-to-day management of fatigue that accompanies the disease and its treatments. Cancer-related fatigue can be defined as a distressing, persistent sense of physical, emotional and/or mental tiredness or exhaustion related to cancer and/or its treatment that is out of proportion to recent activity and interferes with usual function. People with all kinds of cancer report this common side effect, and many surveys of patients with advanced cancer rank fatigue as the most disturbing symptom.

“Unlike other forms of fatigue or tiredness, cancer-related fatigue is not relieved by your typical rest,” says Dr. Carmen Escalante, professor and chair of the department of general internal medicine at The University of Texas MD Anderson Cancer Center in Houston. “These people do not wake up feeling refreshed after a good night’s sleep.”

Between 80% and 100% of people with cancer report experiencing fatigue, and sometimes the symptoms extend years into survivorship.

Experts such as Escalante do not yet know the exact cause or why certain patients experience more cancer-related fatigue than others. “There are a lot of factors to consider when evaluating for fatigue, including the cancer’s stage, the extent of the disease, and past and current treatments,” Escalante says. “Patients with more extensive disease and those who have undergone multimodality treatments, like combinations of chemotherapy, radiation, hormonal therapy and surgical treatments, do seem to have more cancer-related fatigue.”

Some study findings suggest that the number of markers in the blood that indicate inflammation, such as C-reactive protein or certain fatty acids, could also increase the risk of cancer-related fatigue.

Miller experienced debilitating fatigue before she knew she had cancer. She recalls taking her son to a museum and napping on a bench while he looked around; before that, she’d had enough energy to hike and bike for miles. Her inability to do what she normally could prompted her persistence to find out what was behind the fatigue. After receiving her diagnosis and starting treatment for myeloma, Miller discussed her fatigue with her specialists. Outside of clinical trials, doctors do not always administer specific questionnaires to diagnose cancer-related fatigue.

“Often, we start by looking at fatigue as a subjective experience,” says Leigh Kinczewski, a certified registered nurse practitioner in the supportive oncology and palliative care program at Fox Chase Cancer Center in Philadelphia. “It is something that is emotional, cognitive and germane to how the patient is feeling and is not well captured with bloodwork, imaging and other objective measures.”

In some cases, Kinczewski says, a simple numeric scale is used. “I may ask the patient to think back over their last seven days to capture how they have been feeling recently,” she says. “A response of 0-3 is mild fatigue; 4-6, moderate fatigue; and 7-10, severe fatigue.” Patients with moderate to severe fatigue may be asked follow-up questions to identify patterns or assess its duration.

Miller also underwent a thorough assessment with a palliative care team to determine if other factors were contributing to her fatigue. Cancer-related fatigue rarely occurs on its own and is often diagnosed along with symptoms such as pain, depression, anxiety, anemia and sleep disturbances.

“The consensus, almost without exception, is that depression is consistently associated with fatigue at an at least moderate level, but it is unclear whether being fatigued causes people to be depressed, if the depression is causing the fatigue or if they are occurring in different pathways,” Kinczewski says.

Treating the depression can sometimes lower the level of fatigue, Escalante says.

A thorough general medical history and review of recent treatments and medications can also reveal other sources of fatigue. For example, patients with under- lying conditions such as heart failure, past coronary disease, diabetes, kidney disease, thyroid disorders and anemia may experience fatigue.

“Many of our patients with cancer are 50 or older,” Escalante says. “Often, trying to understand the status of those other comorbidities can be helpful in deter- mining whether they are contributing to the overall level of fatigue.”

Fatigue can also stem from treatment for these conditions, with medications such as beta blockers, opioids, antidepressants, nausea drugs and some antihistamines, Kinczewski adds. “Oftentimes, if I have a patient with fatigue, I will look at their medication list and discuss with them and their providers alternative medications or dose reductions,” she says.

In Miller’s case, her health care team opted to manage her pain before addressing her fatigue. Prior to undergoing a stem cell transplant, a procedure that replaces damaged stem cells with healthy ones, Miller had received very high doses of a chemotherapy drug called melphalan. As a result, she dealt with significant joint pain. “It was really when we managed the pain that I was able to turn my attention to managing my fatigue,” Miller says.

For Charles Tucker, 60, cancer-related fatigue came on gradually as he got deeper into treatment. Like Miller, Tucker has multiple myeloma.

Prior to his 2016 diagnosis, Tucker was an active power walker, runner and long-distance cyclist. Once he began radiation therapy and then chemotherapy, he began to feel as though he was in a fog. “It is hard to describe, but every day, I was taking breaks and taking naps. I was lying down more,” Tucker recalls. “You feel like your body shouldn’t be moving, like it can’t move.”

The only thing that helped, he says, was to do the opposite of what his body told him to do. He got moving.

The many recommended or tested treatments for cancer-related fatigue mostly fall under two categories: pharmaceutical and nonpharmaceutical.

“For pharmaceutical options, there are two primary options we consider: corticosteroids and Ritalin (meth- ylphenidate),” Kinczewski says. “Corticosteroids can work well in certain circumstances but cause side effects such as increased blood pressure or muscle weakness, so we often only use them in short-term situations and for patients who are rather ill.”

Ritalin is a stimulant and classified as a psychotropic drug, as is another medication approved for narcolepsy, Provigil (modafinil). Whereas some evidence backs Ritalin’s effectiveness in alleviating cancer-related fatigue, the data supporting Provigil are less clear-cut.

“The National Comprehensive Cancer Network recommends using Ritalin cautiously,” Kinczewski says. “Provigil and other drugs like antidepressants are not recommended when the primary indication is cancer-related fatigue.”

Nonpharmaceutical options may bring more success. Findings from a study comparing types of treatment for cancer-related fatigue showed that psychological interventions, such as cognitive behavioral and psycho- educational therapy, and exercise improved symptoms but drugs did not.

“The research that has been done, especially in breast cancer but in other cancers too, has been consistent in showing that resistance training together with aerobic exercise is a very worthwhile strategy against cancer- related fatigue,” says Cornelia Ulrich, executive director of the Comprehensive Cancer Center at the University of Utah’s Huntsman Cancer Institute in Salt Lake City.

The frequency, amount and type of exercise vary by study, but everyone agrees that any exercise is better than nothing. “We know that exercise helps,” Escalante says.

After eventually undergoing a stem cell transplant, Tucker actively retrained his body. Initially, exercise meant a lap around the hospital ward. Weeks and months later, he was power walking four to five miles.

“I had to rebuild my body and push myself through times when I felt like what I would really like to do was sit down,” Tucker says. “That sensation is still there, but I realize now that when I do get moving, the value in terms of energy is pretty plain right away.”

Miller agrees that the payoff is almost immediate. “In particular, when I swim, I don’t feel as much pain, and when I am done, I have decent energy,” she says. “I may still have to nap later, but in the time around the swim, I have a boost of energy for the next couple of days.” When she takes a break from regular exercise, her energy declines, she says.

Although there are no specific recommendations regarding the amount of activity, many studies looking into the effects of exercise had participants engage in physical activity about three times a week, Ulrich says.

“What is encouraging, as well, is that the effect seems to be consistent across multiple types of cancer, whether it is breast, pancreatic or prostate,” she says. “Although this fatigue cannot exactly be prevented, what is critical is that these exercise regimens be implemented at the time when patients are experiencing the most fatigue.”

Miller has also tried several pharmacologic solutions. Provigil, she says, gave her the jitters and no energy. She also recently tried Vyvanse (lisdexamfetamine dimesylate), a stimulant for attention-deficit/hyperactivity disorder; it boosted her energy but also kept her awake at night.

“Exercise is what works best for me, but I have also spoken to others where Provigil is the thing that works for them, or Adderall (dextroamphetamine plus amphetamine),” she says. “Different people have different paths.”

A wide variety of other methods to relieve fatigue have been tested in clinical trials with moderate success. These approaches include yoga, massage, acupuncture and acupressure aimed at relaxation rather than stimulation, but Kinczewski notes that these methods are not accessible or appropriate for every patient.

Could diet play a role? Escalante says that there are no effective dietary strategies for cancer-related fatigue, but an individual’s diet can exacerbate symptoms. “If a patient is not eating well or not eating the right foods, I tell them that may be contributing,” she says.

People who have had cancer often contend with deep, pervasive exhaustion. The counterintuitive cure: exercise.

Leah Lawrence

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