UNTIL ONCOLOGISTS ARE ABLE to cure every case of bladder cancer, treatment won’t rise to the level we envision. But the development of therapies for people with the disease is moving in the right direction — and remarkably swiftly.

Until 2016, it had been 30 years since the approval of a new bladder cancer treatment. Since then, the Food and Drug Administration has given the green light to five immunotherapies to treat metastatic disease. All are checkpoint inhibitors, drugs that have generated excitement by showing activity in many cancer types. They disable certain proteins made by the body, freeing up the immune system to recognize and attack cancer.

®, we discuss this exciting treatment in bladder cancer. Our article lists the recently approved immunotherapies, explains how they work and who is most likely to benefit from them, and considers how they might be combined with other therapies.

We also delve into the thriving area of treatments for kidney cancer. Twenty targeted drugs and immunotherapies have emerged over the past decade, and treatment questions now revolve around how best to sequence or combine the agents.

Finally, our cover story sheds light on the complexities of treating prostate cancer. In a disease that lacks screening methods and predictors of aggressiveness, it’s important to understand genetic drivers so doctors will know when more radical treatments are called for. As scientists research this, doctors are working with newer hormonal drugs that have become the mainstays of treatment, while the targeted PARP inhibitors already used in ovarian cancer represent a new frontier.

By detailing the latest science guiding the treatment of genitourinary cancers, we hope we have answered your questions and generated others that will shape what you ask your medical team. Along with all these facts, we hope we’ve conveyed a sense of the hope that is growing along with the ever-increasing array of options for treating oncologic diseases. As always, thank you for reading.

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From the Chairman

UNTIL ONCOLOGISTS ARE ABLE to cure every case of bladder cancer, treatment won’t rise to the level we envision. But the development of therapies for people with the disease is moving in the right direction &mdash; and remarkably swiftly.
 

Therapy for Bladder and Kidney Cancers Is Swiftly Improving as Many New Treatments Emerge

MONITORING YOUR HEALTH WHEN you have cancer? Yeah, there's an app for that.

While your doctors may have asked you to record your symptoms in a health diary, that can become labor-intensive when your illness and treatment are already demanding time and concentration.

Enter Cancergraph, the brainchild of Malecare, a nonprofit men’s cancer survivor advocacy and support organization. One of many free apps available to help patients with cancer to track their treatments and health, its goal is to make it easy to use smartphones to record symptoms, side effects or emotional issues, even at the worst times.

Patients can even snap a photo of a rash and be sure it won’t get shared with their vacation photos. The app turns the information into graphs that show how symptoms vary over time.

Cancergraph works not just for patients with cancer of the prostate, but also for those with any form of the disease, and is available for iPhone and Android devices. So far, it’s been translated into Italian, Spanish, Chinese and French.

Sharing specific symptom information with doctors can lead to more precise treatment dosages and even offer the real-time opportunity to save lives. For example, if a patient is throwing up repeatedly, Cancergraph sends a message to a doctor or caregiver, who can then communicate with the patient through the app. An upcoming version will allow doctors to design a more automated set of alerts for common symptoms, streamlining patient management.

In addition, Cancergraph posts are showing up in online health-related social networks, where patients use the information to compare their experiences. “There are a lot of opportunities to understand the progression of disease relative to treatment, as well as for the patient to understand what’s going on and protect themselves,” says Malecare Founder and Executive Director Darryl Mitteldorf, LCSW.

The app is being used in two clinical trials to collect anonymous data, but Mitteldorf also hopes it will increase clinical trial participation.

In his experience, the emotional and bureaucratic hurdles for clinical trial enrollment are significant enough that patients who get rejected the first time often don’t try again. Cancergraph can match patients' profiles — including geographic location and medical history &mdash; to a clinical trials database and alert them when relevant studies open up. Once a patient opts in to this feature, he doesn’t have to do anything else &mdash; trial information will be delivered electronically.

Side Note

Cancergraph, a smartphone app, helps patients track their symptoms and report them to doctors.

Cancer Symptoms? There's an App for That

Destroying part of the prostate to treat prostate cancer may be just as effective as removing the entire organ, but without many of the distressing side effects that tend to accompany the more invasive operation, according to investigators in the United Kingdom.

Based on the results of a feasibility study, the researchers are moving forward with a randomized controlled trial that will compare partial prostate ablation with radical prostatectomy in patients with intermediate-risk prostate cancer, according to a presentation at the American Urological Association’s 2017 Annual Meeting, held in May in Boston.

In partial ablation, the portion of the prostate gland containing the tumor is destroyed through one of several types of “focal therapies,” while the rest of the organ is left intact. In the feasibility study, investigators used high-intensity focused ultrasound to achieve partial prostate ablation. In the randomized trial, they hope to also include cryotherapy (freezing), focal brachytherapy (radiation) and vascular targeted photodynamic (light-activated) therapy.

The investigators have hypothesized that partial ablation using minimally invasive therapies can not only achieve organ preservation but can also reduce the incidence of side effects, allowing men to maintain good voiding and sexual function without any compromise to cancer health outcomes. “The data certainly suggest fewer side effects in the partial ablation arm early on,” said lead study author Tom Leslie, M.B., Ch.B, D.Phil, a consultant urological surgeon at Oxford University Hospitals. “The aim of the study is to see whether these benefits can be balanced with the oncological outcomes.”

The phase 3 PART (Partial prostate Ablation versus Radical prosTatectomy) trial would be the first to compare the two procedures in the context of intermediate-risk, unilateral, clinically significant, localized prostate cancer and could improve understanding of how to treat this disease, the researchers said. Previous studies generally assessed these treatments in low-risk prostate cancer, which can alternatively be treated with watchful waiting.

The feasibility study was conducted at five large urology clinics in the U.K. and targeted men amenable to partial ablation or radical prostatectomy. The group included some men whose cancerous cells were abnormal enough to receive a score of 4 on the five-point Gleason scale. Other participants had contralateral insignificant (very low-risk) disease. The patients were diagnosed by multiparametric magnetic resonance imaging (MRI), along with biopsy, and randomized to receive either partial ablation or prostatectomy. “When we were designing this study, the diagnostic pathway was rapidly evolving, so we tried to move with the times by incorporating prostate MRI, targeted biopsies and fusion biopsies (which combine MRI and ultrasound images),” Leslie said.

The investigators randomized half the men to partial ablation and half to radical prostatectomy, and collected data on quality-of-life factors, primary treatment failure (the need for whole-gland ablation or secondary therapy), long-term side effects, disease progression and diseasecaused mortality. According to Leslie, they also paid attention to cases in which focal therapies were tried but then prostatectomy or radiotherapy were required due to progressing disease.

The feasibility trial recruited the targeted 80 patients. Half of the men who were considered wanted prostatectomy and therefore were not included in the study. Others preferred brachytherapy, cryoablation or chemotherapy and also could not participate. “These were men who couldn’t be randomized because they knew what they wanted, and that’s perfectly fair,” Leslie said. Ultimately, 52 men were randomized; however, in a future analysis of the study, the number of men evaluated will increase to 82, once researchers have been able to follow some later recruits, Leslie said.

Initial responses suggested fewer side effects for patients who received partial ablation, compared with radical prostatectomy. However, as the study progressed, there was no significant difference in patient perception of essential function and quality of life, particularly concerning erectile dysfunction and incontinence. “The overall impression was that, early following treatment, quality of life was improved in the partial ablation arm, but as time went, the two arms came together — i.e., as the surgical patients recovered, so did their quality of life,” Leslie said.

Features

A clinical trial will test whether partial prostate ablation matches radical prostatectomy in effectiveness &mdash; with fewer early side effects.

Less May Be More in Prostate Cancer Treatment

THE FREQUENCY OF BLOOD tests to check levels of prostate-specific antigen as a screen for prostate cancer is no longer dropping, according to the results of a recent nationally representative study published in 

The test is not being conducted quite as frequently as it was before the drop, but numbers have leveled off, with approximately one-third of men aged 50 or older receiving routine PSA tests, the researchers found.

In 2008, the U.S. Preventive Services Task Force (USPSTF) recommended against PSA-based prostate cancer screening among men 75 or older, and in 2012, it recommended against routine testing for men of all ages. Possibly as a result, PSA screening rates declined from 37.8 percent in 2010 to 30.8 percent in 2013 among men 50 or older.

The task force recently suggested that men aged 55 to 69 should speak to their doctors about whether to screen, but its earlier recommendation against the imprecise screening test was meant to prevent overtreatment of prostate cancer — invasive testing or treatment in men who either don’t have the disease or in whom the cancer would never cause a problem if left alone.

As expected, the recommendations resulted in substantial declines in reported prostate cancer incidence. However, another recent study suggests that this decline may have led to some treatable cancers being overlooked until they became advanced.

That study revealed a modest short-term increase (from 2011 to 2013) in the incidence of metastatic prostate cancer and a significant increase in distant metastases at diagnosis in men 75 or older. Its authors noted that this may have been a result of the 2008 and 2012 USPSTF recommendations against prostate cancer screening in this patient population. The researchers also found that, in participants younger than 75, the proportion of men who had distant metastases at diagnosis increased from 2.7 percent to 4 percent, and the proportion with intermediate- and high-grade prostate cancers at diagnosis from rose 46.3 percent to 56.4 percent.

In the JAMA study of PSA screening rates, investigators gathered data on 19,690 men aged 50 or older from the 2010, 2013 and 2015 National Health Interview Survey databases. A total of 16,196 men were included in the analysis, after the exclusion of those who reported a history of (or were missing data on) prostate cancer diagnosis (1,115 men) or PSA testing (1,574) or who had undergone PSA testing for non-screening reasons (805).

Of the 16,196 respondents, more than half (59 percent) were aged 50 to 64; 26 percent were 65 to 74; and 15 percent were older than 75. While data was missing for 10 respondents, 75 percent had visited a primary-care physician in the past 12 months. Among men 50 or older, unadjusted routine PSA testing rates in the past year decreased from 38.3 percent in 2010 to 31.5 percent in 2013 and then remained stable at 32.1 percent through 2015.

Adjusted analyses were similar, with PSA testing in the past year significantly lower in 2013 than in 2010 but not significantly different between 2015 and 2013. That pattern was similar across age groups.

The researchers concluded that previously reported declines in PSA testing have not continued in recent years, with approximately a third of men aged 50 or older still receiving routine testing, and noted the need for continued evaluation on how testing patterns influence prostate cancer outcomes over the long term.

After a drop, the frequency of PSA screening for prostate cancer has stabilized.

PSA Screening Rates Are No Longer Dropping

RUBRACA (RUCAPARIB), A DRUG APPROVED for the treatment of ovarian cancer, might also be used to treat patients with metastatic castration-resistant prostate cancer (mCRPC), pending the results of a phase 3 study.

Rubraca (rucaparib) is a targeted drug known as a PARP, or poly (ADP-ribose) polymerase, inhibitor. The pill inhibits the ability of certain tumor cells to repair their own DNA. In December 2016, the Food and Drug Administration approved it for women with recurrent ovarian cancer that expresses BRCA gene mutations.

Now, the drug is being tested in men whose prostate cancer expresses similar mutations, is metastatic and has progressed despite treatment with an initial therapy. The multicenter, randomized TRITON3 clinical trial (NCT02975934) is evaluating Rubraca as a single agent, comparing its effectiveness with that of doctor’s choice of one of three standard drugs: hormonal treatments Zytiga (abiraterone acetate) or Xtandi (enzalutamide), or the chemotherapy drug docetaxel. The trial, now enrolling, seeks to address an unmet clinical need: No standard of care has been established for men with mCRPC and mutations to genes such as BRCA that are associated with hereditary cancers, known as homologous recombination gene deficiencies.

Rubraca selectively targets tumors with these deficiencies, which prevent cancer cells from repairing their DNA. To compensate, the cancer cells rely on the protein PARP to facilitate DNA repair. Rubraca inhibits PARP, so that, when the cell attempts to divide, it cannot repair its DNA, and dies.

“In the world of prostate cancer, we have preliminary data that PARP inhibitor therapies have activity in this group of patients with BRCA1, BRCA2 and ATM mutations, but PARP inhibition has not been tested definitively and validated as a standard-of-care therapy,” said Charles Ryan, M.D., professor of clinical medicine and urology and associate director for clinical sciences at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center, and principal investigator of the North American branch of the TRITON3 study.

“There are conflicting data now on the efficacy of abiraterone in a BRCA-mutated population, and this will potentially highlight some of the overlap between hormone sensitivity and DNA repair alterations.”

The trial is designed to test the efficacy of Rubraca in patients who have received either Zytiga or Xtandi as initial treatment for mCRPC, but have not received chemotherapy. Eligible patients will also have a deleterious mutation in the BRCA1, BRCA2 or ATM genes.

An estimated 400 patients will be randomized 2:1 to receive Rubraca monotherapy or physician’s choice of therapy based mainly on prior treatment. The trial will record the genetic alterations in patients’ tumors and their therapeutic outcomes, focusing on time until disease progression, to better understand who within this patient population is most likely to benefit from PARP inhibitors. Patients whose disease progresses on the arm receiving physician’s choice of therapy will be allowed to cross over to receive Rubraca.

According to Ryan, the main side effects the investigators expect to see with Rubraca are common to PARP inhibitors, and are primarily hematologic, including anemia. Other side effects observed in past trials of PARP inhibitors include fatigue, leukopenia (a reduction in white blood cells), thrombocytopenia (a drop in the number of blood platelets) and neutropenia (a dip in the number of neutrophils, a type of protective white blood cell).

In the concurrently running phase 2 TRITON2 trial (NCT02952534), led by principal investigator Wassim Abida, M.D., Ph.D., a medical oncologist at Memorial Sloan Kettering Cancer Center, investigators are determining how patients with the same disease and gene mutations respond to Rubraca as a monotherapy.

The trial differs from TRITON3 in a few key areas: It is a single-arm (not randomized) study for patients with mCRPC who previously received Zytiga and/or Xtandi, as well as docetaxel, and patients are being screened for mutations not only in BRCA1, BRCA2 and ATM, but in 12 additional genes. An estimated 160 patients will receive Rubraca daily, with the primary endpoints being objective response rate and prostate-specific antigen (PSA) response. Higher levels of PSA in blood can be an indicator of the presence or growth of prostate cancer.

Prior studies have shown efficacy of PARP inhibitors in mCRPC. In the phase 2 TOPARP-A trial, investigators assessed Lynparza (olaparib) in patients with mCRPC who had received prior treatment with docetaxel, the majority of whom (98 percent) had also received Zytiga or Xtandi. Out of 49 evaluable patients, 16 (33 percent) had a response, and 12 received treatment for more than six months. Among men with BRCA1, BRCA2 or ATM mutations, the overall response rate to Lynparza was 87.5 percent. The study concluded that this PARP inhibitor sparked a high response rate in patients with mCRPC and DNA repair mutations whose disease was no longer responsive to standard treatments.

Another phase 2 study, presented at the 2017 Annual Meeting of the American Society of Clinical Oncology, tested the experimental PARP inhibitor veliparib combined with Zytiga and prednisone versus Zytiga and prednisone alone in patients with mCRPC. There was no statistically significant difference between the two arms of the trial in terms of overall survival, progression-free survival or PSA response rate. However, in a secondary analysis of patients with DNA repair mutations versus those without them, the PSA response rate in the veliparib arm was statistically significant compared with Zytiga and prednisone alone. Those with DNA repair mutations had a PSA response rate of 90 percent across both trial arms, while those without mutations logged a 56.5 percent PSA response rate.

Rucaparib is being developed by Clovis Oncology, which is sponsoring the TRITON2 and TRITON3 trials. TRITON3 “is a registrational trial, as well, so, pending positive results, it would be reasonable to expect that the FDA would review rucaparib as a standardof- care treatment in patients with mCRPC (with DNA repair deficiency) who have progressed after prior abiraterone- or enzalutamide-based therapy,” Ryan said.

A targeted drug for women with ovarian cancer may also benefit men with prostate cancer who have similar genetic mutations. A phase 3 trial is designed to find out.

Can an Ovarian Cancer Drug Work in Prostate Cancer?

In localized prostate cancer, radical prostatectomy early in the course of the disease did not significantly reduce deaths from all causes or specifically from prostate cancer compared with observation through nearly 20 years, according to longterm follow-up results from the phase 3 Prostate Cancer Intervention Versus Observation Trial (PIVOT). The findings, most notable for men diagnosed with low-risk disease, were presented at the 2017 American Urological Association Annual Meeting held in May in Boston.

“We previously demonstrated no significant difference between surgery versus observation in all-cause or prostate cancer mortality (in this population) through 12 years; however, treatment decisions often require information about very long-term mortality,” said Timothy J. Wilt, M.D., M.P.H., professor of medicine at the University of Minnesota School of Medicine and core investigator at the Minneapolis VA Center for Chronic Disease Outcomes Research, in his presentation at the conference.

The PIVOT study, a randomized, controlled trial for patients with clinically localized prostate cancer, began recruitment in 1994. The followup analysis sought to determine whether radical prostatectomy reduced mortality compared with observation. This is a crucial question for patients, because prostatectomy can cause side effects including incontinence and erectile dysfunction.

The study measured death from any cause, with death from prostate cancer as the secondary endpoint. In the 12-year follow-up, according to Wilt, investigators also addressed bone metastases; disease progression; patient-reported outcomes; and erectile, urinary and bowel dysfunction. The study recruited men who were 75 years or younger, diagnosed within the previous 12 months and were expected to live at least 10 years. Patients could have any grade of prostate cancer, including early-stage disease, as long as they were viable candidates for radical prostatectomy. The levels of prostate-specific antigen (PSA) in their blood, which doctors can use to help determine whether prostate cancer may be present or growing, had to be less than 50 ng/mL.

Based on these criteria, 731 patients were randomized to receive either a radical prostatectomy (n = 364) or observation (n = 367). Observation in the PIVOT study included palliative therapy for symptomatic progression, Wilt said, which is different from commonly used PSA-based monitoring and biopsy-based active surveillance programs with delayed radical intervention. The patients in the observation group were offered palliative therapy or chemotherapy for symptomatic or metastatic disease progression. In this group, while PSA was checked regularly, investigators discouraged its use in treatment decisions unless it reached 20 ng/mL. They also advised against repeated prostate biopsies or eventual treatment with prostatectomy, in order to avoid associated potential harms. However, participating doctors were allowed to monitor and treat patients as they saw fit.

The average participant in the observation arm was 66.8 years old and had a mean PSA of 10.2 ng/mL. The average man in the surgery arm was 67 years old and had a mean PSA of 10.1 ng/mL.

Study: To prolong survival in early-stage prostate cancer that is low-risk, observe instead of operating.

Active Surveillance Is Best Bet for Low-Risk Prostate Cancer

Twenty-five years ago, the FDA approved the first systemic therapy for renal cell carcinoma (RCC), interleukin-2. But it would be another 13 years before a powerful surge in treatment developments arose.

The initial breakthrough occurred when the agency approved Nexavar (sorafenib), the first targeted therapy for RCC. Since then, there's been a steady hum of FDA approvals — more than 20 new treatments for the disease, including additional targeted drugs and immunotherapy agents that prolong overall survival (OS) and even offer the potential for a cure in a subset of patients.

The newer drugs are generally for stage 4 disease, because earlier-phase kidney cancer tends to be treated primarily with surgery and radiation. Chemotherapy drugs aren’t typically used, because they do not have activity against kidney cancers. Luckily, targeted drugs do, and while they have different mechanisms, the basic goal of treatment remains the same: Find a way to cure the patient’s cancer while preserving quality of life. The downside of this progress is that the rapid pace of drug approvals for RCC has left oncologists with many unanswered questions about the optimal way to use the new agents, including the order in which to administer them, says Robert A. Figlin, M.D.

Figlin, the Steven Spielberg Family Chair in Hematology-Oncology at Cedars-Sinai, in Los Angeles, hashed out those issues recently as moderator of a panel of experts in genitourinary malignancies at a Peer Exchange hosted by 

®. The panelists reviewed data from clinical trials that can help guide treatment decisions in the firstline setting and beyond.

“New data continue to emerge to help us navigate a pathway for each individual patient, often through multiple lines of therapy,” Figlin said.

After kidney removal (nephrectomy) and before medication is started, medicine may not even be needed. It’s reasonable to consider active surveillance of disease spread in some — particularly those with slow-growing cancer, a small number of lesions and metastasis that is focused in the lungs, especially if the patients are otherwise healthy and active, the panelists agreed.

When the time does come to choose a first therapy for metastatic RCC, Toni K. Choueiri, M.D., director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute, in Boston, starts with the kinase inhibitor Torisel (temsirolimus), administered by intravenous infusion, if the patient is hospitalized. For outpatients, he starts with a VEGF-targeted agent that the patients can take at home, as a pill. When the extent of metastatic disease is greater than the volume of disease in the kidney, Choueiri, who is also director of Dana-Farber’s Kidney Cancer Center, considers systemic therapy with a targeted drug to shrink the cancer before surgery.

But what side effects do the drugs bring? Panelist Eric Jonasch, M.D., of the Department of Genitourinary Medical Oncology at the University of Texas MD Anderson Cancer Center, in Houston, said the TKIs Sutent (sunitinib) and Votrient (pazopanib) are equally viable options for firstline systemic therapy, with the greatest differences being in tolerability. Jonasch said that head-to-head trials of the two drugs associated Sutent with higher rates of fatigue, taste changes and hand-foot syndrome, whereas Votrient was associated with a higher risk of hair loss, elevated transaminase levels (which can indicate liver problems) and nausea.

Jonasch also noted that clinicians are increasingly deviating from the standard four-weeks-on/two-weeks-off schedule for Sutent to minimize side effects. A recent study showed that extending the number of weeks off the drug for patients with at least a 10 percent reduction in tumor burden was feasible and did not compromise treatment efficacy. He said the strategies are allowing patients to take Sutent longer, which is translating into improved survival outcomes.

Cabometyx (cabozantinib), another VEGF-targeting agent, may soon also be available as a first-line treatment for patients with metastatic, poor-risk kidney cancer. In a recent study, it improved progression-free survival and overall response in these patients when compared with Sutent.

Although the choice of firstline therapy may be clear, knowing when to switch to another therapy is not, Figlin suggested. “We see many patients who may have had their therapies prematurely stopped and went on to a second-line treatment when they may have still been able to benefit, with some modulation, from the firstline therapy,” he said. Michael R. Harrison, M.D., assistant professor of medicine at Duke Cancer Institute, in Durham, North Carolina, agreed, saying that when he reviews the files of patients referred to him, it is not always clear whether they discontinued a VEGF TKI because of disease progression or side effects that were not optimally managed. In those cases, he said he sometimes puts patients back on a VEGF TKI and finds it effective. One issue that can lead to unnecessary abandonment of a targeted drug is that scans may be misleading, said David I. Quinn, M.B.B.S, Ph.D., director of the University of Southern California Norris Cancer Hospital, in Los Angeles.

“We need to be aware that there’s an oscillation in the disease that should not be confused with progression,” he advised. Jonasch agreed that there is a need for better ways to identify progression, whether via imaging or analyzing specifics in the circulating tumor microenvironment, such as cytokines and angiogenesis factors.

Although many drugs have been approved for second-line therapy, Figlin said, data to guide clinicians in choosing among them are scarce because these agents have never been compared in studies in the second-line setting. Harrison said his choice for patients with progression after a VEGF TKI is generally between Cabometyx and the immunotherapy Opdivo (nivolumab). He said his choice is guided by the patient’s symptoms and quality-of-life concerns, time taking a VEGF TKI, side effects and the potential need for a break from that agent.

“If a patient is symptomatic, especially those patients who have sites of disease in the bone or the liver, I’m thinking a little bit more about (Cabometyx). If (it is) a patient who has clear progression but maybe just in the lung or other sites like lymph nodes, then I’m probably thinking more about (Opdivo),” Harrison explained. Quinn said that, although Cabometyx is “a great drug,” he typically uses Opdivo in the second line because “it’s well tolerated, and I think (patients) want a break from VEGF inhibitor toxicities.” He said he reserves Cabometyx for patients who have contraindications to immunotherapy, such as an organ transplant or an autoimmune disease.

Choueiri added that he uses Cabometyx for patients who are experiencing faster disease progression, especially if they have gut metastases. He said studies have shown a low rate of progressive disease and significant tumor shrinkage with Cabometyx.

“I do not want to lose the battle — I want something to hold the patient quickly and effectively,” he said. Choueiri concurred with the other panelists that Opdivo is a good option for patients who have struggled with the side effects of a VEGF TKI, for whom there is no immediate urgency to treat, and who are willing to go to the clinic for treatment.

Although the targeted drug Afinitor (everolimus) is a standard treatment for patients whose cancer has progressed on other kinase inhibitors, clinical trials have found that it doesn’t match the effectiveness of Opdivo or Cabometyx in that setting. That doesn’t mean Afinitor will disappear from use, but, perhaps, that it will be used even later in the course of treatment.

Using Afinitor upon disease progression becomes more feasible when it is given with Lenvima. That drug was approved last year in combination with Afinitor as a secondline option for patients with advanced RCC. Approval was based on results from a randomized phase 2 study, which showed that adding Lenvima to Afinitor significantly prolonged median overall survival compared with Afinitor alone (25.5 months vs 15.4 months, respectively).

Choueiri said that Opdivo, Cabometyx and Lenvima have never been studied head-to-head, and probably won’t be.

Although Opdivo, Cabometyx and Lenvima are not approved for firstline treatment, the panelists discussed the possibility that they eventually could be. “Firstline immunotherapy may be worth pursuing,” said Quinn, who noted that trials of that strategy are expected to report data soon; changes in practice will occur if they show an overall survival benefit. Other firstline options that may emerge are immuno-oncology agents or vaccines combined with VEGF TKIs, he said.

Jonasch said that studies are also combining new and older agents, such as the PD-L1 inhibitor Tecentriq (atezolizumab) and the targeted drug Avastin (bevacizumab). Several studies are looking at post-surgical therapy with Sutent, Votrient or other agents in populations with a high risk of recurrence. Limited data show promise, but Jonasch said the trials need to show a survival benefit and that confirmatory studies are needed.

Harrison expressed his hope for discoveries of biomarkers — genetic clues about what drives each case of kidney cancer. “Basically, (we need to be) moving toward precision medicine to develop biomarkers to find the right drug for the right patient at the right time,” he said. Some information in this regard has already been established. So far, there are 16 known genes that cause kidney cancer and at least 13 types of inherited kidney cancer, W. Marston Linehan, M.D., recently told CURE®. That’s why it’s important for patients and their doctors to understand that kidney cancer is not one disease, and that its treatment should be based on the genetic mutations and pathways that drive it in each individual case, said Linehan, chief of the Urologic Oncology Branch of the National Cancer Institute.

Despite that line of study, Figlin said that doctors do not have all the answers they desire. He encouraged patients and physicians never to hesitate “to get another opinion from someone who spends their life — like my colleagues &mdash; thinking about kidney cancer and how to address, answer and ask the right questions for the individual patient.”

The latest drugs for advanced kidney cancer are stirring optimism.

A Wave of Optimism for New Kidney Cancer Drugs

THIBEAUX LINCECUM, shown playing with his twin sons at home, wishes his original urologist had reacted more aggressively to his prostate cancer symptoms. - PHOTO BY BOB RIVES

Thibeaux Lincecum wishes he’d fired his urologist more than a decade ago. Lincecum, 46, visited his specialist three years ago, when he noticed a precipitous drop in his semen volume over just a few months. (He’d seen the same doctor a decade before for urinary urgency — another possible symptom of prostate cancer.) He asked for a prostate-specific antigen (PSA) test &mdash; a standard blood test that is often used to screen for prostate cancer, but is controversial due to its lack of specificity in detecting the disease &mdash; yet the doctor gave in only when he learned there was a family history. He ordered tests from two different labs, and both came back high enough to warrant investigation. He dismissed the results and prescribed antibiotics.

Finally, Lincecum decided his doctor “was an idiot.” His next urologist needed only to do a digital rectal exam to express concern and schedule a biopsy. The results were brutal: a maximum Gleason score of 10, indicating an extremely high level of abnormal cells and growth, and a prostate nearly solid with cancer. The only bright side was no sign — yet &mdash; of metastatic disease.

Lincecum was done waiting. When he tried to schedule surgery immediately and was offered a first appointment three weeks out, he began calling around for an earlier time slot. One receptionist noted his biopsy results, consulted a doctor and booked him for early the next morning. Between his age and advanced disease state, Lincecum fit the profile for a clinical trial, so after a radical prostatectomy, he enrolled in what would become the first of many.

His dilemma outlines the fundamental challenge of prostate cancer. It’s often said that men don’t die of prostate cancer, they die with it. This is, in many cases, quite true. But it’s also true that prostate cancer is the second-leading cause of cancer-related death in American men. This is because some men present with aggressive cancer, a higher PSA and higher Gleason scores. They are at greater risk of developing metastases, and their disease is often more resistant to treatment.

“It goes all the way from very low risk to very difficult to treat. There is no disease where risk stratification is more important,” explains urology department head Christopher Kane, M.D., of Moores Cancer Center at the University of California San Diego. “Prostate cancer is one of the most complicated diseases in medicine.”

If you look at 70-year-old men dying of other causes, more than half of them have microscopic, low-grade disease that, under today’s classification system, is called prostate cancer. “The death risk of those men, from prostate cancer, is well under 1 percent,” says Kane. He believes that this low-grade, low-volume prostate cancer — the result of normal aging &mdash; should probably be called something different.

Oncologists struggle to precisely define low-risk prostate cancer. According to National Comprehensive Cancer Network guidelines, the characteristics of low-risk disease include a Gleason grade of 3+3, a PSA under 10 ng/mL and low-volume disease that the doctor can’t feel. “If you meet that criteria, among the various treatment options, the recommended strategy is active surveillance,” says Kane. “Not a potential option, but now THE recommended strategy.” Active surveillance is not to be confused with watchful waiting for either the development of clear metastatic disease or cancer-related symptoms. Active surveillance is more aggressive, beginning with initial classification of low-risk patients according to a specific criterion, and including systematic monitoring with PSA screening, biopsies, physical exams and possibly imaging — and, when needed, a quick shift to aggressive intervention.

Active is the key word. A proportion of men with apparently indolent disease will, over time, either develop more aggressive disease, or will experience a more aggressive disease that was there at diagnosis, but missed. “Following men over time is really important,” says Kane. If you have very low-risk prostate cancer, and you don’t blow off your follow-up appointments, your 10-year prostate cancerspecific mortality is about half of 1 percent.

The biggest challenge remains figuring out which disease will progress and which will remain indolent. Fairly new genetic tools are available, including three tests to analyze tumors: Decipher, Prolaris and Oncotype DX for Prostate Cancer.

“Those three tests have been shown to do a good job of risk stratifying,” says Kane. “They can really help us decide who has indolent prostate cancer and who should be followed.” There are also some methods of risk stratification that are still being studied. Single-nucleotide polymorphism, or cancer susceptibility gene mutation testing (such as looking for BRCA mutations) would uncover any inherited genetic mistakes associated with more or less promising prognoses. Assessing the androgen gene receptor in a man’s plasma might predict whether he will respond well to the hormonal drugs Zytiga (abiraterone) or Xtandi (enzalutamide). Detecting the presence of AR-V7 (an androgen receptor splice variant) in circulating tumor cells could signal that a man with castration-resistant prostate cancer will have a less-than-robust response to hormonal drugs. Finally, what's living in someone’s microbiome, or gut, may affect treatment outcomes.

Predictions will improve as the understanding of prostate cancer genetics continues to emerge, but for now, only a minority of patients are treated with the help of genomic testing and targeting. The work of breaking down the whole population of prostate cancer into subtypes, and figuring out which ones respond best to which drugs, is just beginning. “The promise of genomic testing is to be more individualized, not just for the patients who have advanced and recurrent disease, but right when a man is initially diagnosed,” Kane says. “We have a lot of work to do.”

MARK STEELE has taken more than a dozen new drugs during his ongoing fight against prostate cancer. - PHOTO BY DAVEY MORGAN

One of our major weapons against prostate cancer is a salvo of drugs used to manipulate androgens, male hormones including testosterone. As part of the male reproductive system, prostate tissue is particularly sensitive to these hormones, and testosterone can help fuel prostate cancer at certain stages of the disease; androgen deprivation therapy (ADT) tries to shut those pathways down. Unfortunately, most men don’t like the way it feels, since low testosterone can lead to lower energy levels, including diminished libido, decline in sexual function and other body changes. Prostate cells have different pathways activated by testosterone, so shutting it down completely is pharmacologically difficult. The cancer makes it even harder, spinning off various mutations affecting androgen action that make the disease resistant to ADT. Prostate cancer that doesn't respond to ADT is called castration-resistant disease. While it seems counterintuitive, sometimes high-dose testosterone can help keep advanced prostate cancer in check and counteract its resistance to ADT.

“Right now, I’m on this high-dose testosterone, so I’m feeling pretty good,” laughs Mark Steele, an Atlanta retiree of 70. He’s a few weeks out from the five-year anniversary of his diagnosis, and is planning a party to mark the occasion. They haven’t been easy or disease-free years, but he faces that with a nonchalant, fighting spirit.

Steele’s disease came on fast. When he was 64, his PSA was under 2 (4 or higher is considered abnormal) and, as for evidence of disease, he was all-clear. By the time he was 65, his PSA had leapt to 29, the disease metastatic and already beyond surgery. “Drugs have been my best friend for the last five years,” he says. He often compares notes with a good friend from his tour in Vietnam who is a few years ahead of him with prostate cancer: “We say jokingly — but also quite seriously &mdash; if we live long enough, we’re going to be saved by the new drugs.”

 He’s had a lot of them — more than a dozen &mdash; including a variety of testosterone modulators and two of the more promising approvals of the last five years: androgen inhibitors Zytiga and Xtandi. Zytiga was the most successful for him. Given with prednisone, it was first approved by the Food and Drug Administration in February of 2011 for patients with metastatic disease after chemotherapy, increasing median overall survival from 11 months with just prednisone to 15 months with the combination. By December of 2012, it had also been approved for patients with metastatic disease prior to chemotherapy. In the study on which that approval was based, Zytiga increased median overall survival from 30 to 35 months for those who took prednisone only compared with those who took the Zytiga combination.

Steele got 18 months out of Zytiga before the cancer progressed, and then he moved on to Xtandi. It was first approved in 2012 for metastatic castration-resistant disease, and in 2014 its use was also expanded into firstline treatment.

Steele got another year out of Xtandi, then underwent proton beam radiation and, last spring, began a targeted drug, the PARP [poly(ADP-ribose) polymerase] inhibitor Lynparza (olaparib), which disables certain DNA repair enzymes, making it difficult for cancer cells to propagate. But his PSA is rising again, and he figures chemotherapy is probably next in what he knows will be a steep challenge. If his cancer had been diagnosed today, his treatment schedule might have been quite different. In the past year, several trials have reported an encouraging bump in survival when either Zytiga or chemotherapy (docetaxel), along with ADT, is used soon after diagnosis.

For Zytiga plus ADT, two trials showed this early intervention lowered the risk of death by almost 40 percent for men with newly diagnosed metastatic prostate cancer. For docetaxel, two large randomized trials showed survival improvements of about a year (10 and 13.6 months) when the chemotherapy was added to androgen deprivation therapy, instead of the usual practice of using chemotherapy later. The benefit was even higher for those with more disease, and whose cancer was metastatic at initial diagnosis.

“We can use a lot of these drugs a lot earlier,” says Susan Slovin M.D., Ph.D., a prostate cancer specialist at Memorial Sloan Kettering Cancer Center in New York City. Being able to use Zytiga and docetaxel so much earlier is potentially paradigm-shifting, as the patients do much better in terms of disease control. “While chemo is not for every patient, a unique subset with a lot of disease seemed to do very well,” she adds. “We’ve never had this kind of flexibility before.” This timing discovery is exciting, but also emphasizes the challenge of using the drugs correctly. For example, another recently approved drug, the radiopharmaceutical Xofigo (radium 223 dichloride), offers yet another option for patients with bone metastases, yet it’s not universally appropriate, even for that subset of patients. “There are a lot of new drugs that have hit the market, and they have really been challenging in terms of how we strategize them,” says Robert Dreicer, M.D., a prostate cancer specialist and deputy director of the University of Virginia Cancer Center.

Is chemotherapy or Zytiga better overall when doing an early intervention? Will different patients experience different benefits? “We don’t know that one is better than the other,” says Dreicer. In addition to considering the differences in patient eligibility in each of the trials, the treatment choice may be governed by other factors, ranging from side-effect profiles and the patient’s pre-existing conditions all the way to cost. “There is not a definitive answer,” Dreicer says. “It’s still progress, because we’re improving survival and have more options.” With less clear evidence about how to do things, clinical experience matters. Because prostate cancer is common, it’s frequently treated in community hospitals, but its complexity is daunting. “The knowledge base is impossible for anybody to keep up with,” warns Dreicer, so seeking out a second opinion, at least to confirm a treatment paradigm, is becoming increasingly important.

 “Some cancers have very well-defined treatment courses,” he adds. “Prostate cancer is not one of those diseases.”

Hormone therapy targets hormonal receptors to slow prostate cancer, but the more specifically targeted therapy that matches a particular genetic target to a precisely designed drug is only just coming into focus in prostate cancer. For patients with BRCA1 and BRCA2 mutations, as well as mutations in ATM, CHEK2, PALB2, FANCA and HDAC2, a new generation of drugs, PARP inhibitors, offers significant hope. In fact, recent studies have shown that, in those with metastatic disease, upwards of 10 percent of patients may harbor one of these inherited mutations, even in the absence of a family history.

The DNA repair routine is so deeply coded in human cells that even cancer cells repair some of their own damaged DNA. PARP inhibitors block these repair enzymes in some cancer cells, helping to kill them. Though they appear to have the best chance of working in patients with known mutations in BRAC1, BRCA2 and some of the other DNA repair genes, they may also work on some patients without these mutations. Figuring out these exceptions to the rule will help researchers get even closer to a more complete targeted therapy approach.

Already approved for treating ovarian cancer with BRCA-mutation roots and shown to be more effective than chemotherapy in breast cancer with BRCA mutations, Lynparza has been given clearance for use in accelerated clinical trials because of an early study in which one-third of 49 patients with advanced prostate cancer showed at least some response to the drug. Response was 87.5 percent among the 16 participating patients who had DNA-repair mutations.

PARP inhibitors are the first real crack in the genomic profile of prostate cancer that will hopefully allow oncologists to begin carving it into subtypes, matching specific treatments to known genetic profiles of disease. Unfortunately, the other hot frontier of cancer treatment, immunotherapy, has less exciting news to report when it comes to prostate cancer. Slovin feels this frustration intensely, especially every time she sees Keytruda (pembrolizumab) advertisements on TV. “Drives me batty,” she acknowledges.

The success of Keytruda and related checkpoint inhibitors in melanoma, lung and other cancers has led to a broad effort to test their worth in just about every other cancer type. For other genitourinary cancers like bladder cancer, the response has been significant: five checkpoint inhibitors have been approved to treat that disease since last year. But results in prostate cancer have been underwhelming, at best.

An immunostimulant, a vaccine called Provenge (sipuleucel- T, or sip-T), was approved in 2010 for men with lowvolume metastatic disease. It is trained to match a patient’s immune system, but seems to be struggling to find its treatment niche. “We really have no firm data to suggest that, if you give sip-T, you are changing the immune milieu substantially,” Slovin says. As with other recently approved drugs, it may be necessary to find an appropriate pharmaceutical partner, which will involve further research.

With any cancer, it can be hard to reconcile the experiences of its most forward-thinking doctors and its most frustrated patients. With unprecedented choices and rising survival rates, Kane calls prostate cancer “one of the solid tumors we’ve made the most progress on in the last 10 years.” Lincecum tries to channel that positive attitude, but knows those breaks haven’t fallen his way. He wages his battle in full public view, hoping that other men learn from his bad luck and experience.

And he talks openly about the difficult choices that men with this disease must face. Surgery was the clinically recommended choice with his diagnosis, but he’s not sure he made the right decision. “Sometimes I think I’d be happier keeping my erectile function and dying earlier,” he admits.

But still he fights, enjoying his young twin boys and trying to erase the deficit left by the doctors who didn’t read his PSA correctly or comprehend the dark side of his urinary complaints. “It’s just like my second job, learning about prostate cancer. It just never stops,” he says. From his Maryland home, he regularly contacts the experts at Johns Hopkins University, the National Institutes of Health and Georgetown University. He’s always looking for a treatment edge, and currently he’s waiting for the bureaucratic wheels to turn on a phase 1 bone marrow transplant trial. If approved, he’d be the first patient enrolled. “This cancer is not going to go away with normal treatment,” he says plainly. “I need to do something radical.”

It’s a spirit that Steele understands, and even wears on a blue rubber wrist band: NEVER GIVE IN. “I’ll never be cured, but (I’ll do what) I can (to) live a longer life, with quality of life,” he says.

In his support group, he counsels newly diagnosed men, trying to replace their deer-in-the-headlights look with temper and resolve. “You’ve got time. Study. You make the decision. Once you make it, don’t look back,” he advises. “The best thing you can do is start getting educated. If you really want to live, you’ve got to take control of your fate. You’ve got to understand what’s going on.”

Scientists are looking for more and better ways to identify the prostate cancers that are most likely to become aggressive.

Better Calculating the Aggressiveness of Prostate Cancer

Treated in a clinical trial for his bladder cancer, DAVE DIMICK had a complete response to the immunotherapy Imfinzi. - PHOTO BY ADENA STEVENS

Four months after Dave Dimick entered a clinical trial for the immunotherapy drug Imfinzi (durvalumab) in 2015, his doctors told him he’d had a “complete response.” He figured it was good news from the smiles on their faces, but he was afraid to ask for more details, because ever since he had been diagnosed with stage 4 bladder cancer two years earlier, he had heard nothing but bad news. Prior to the trial, his cancer had spread to his lymph nodes, and two chemotherapy regimens had failed to keep the disease in check.

“I Googled ‘complete response’ and learned that it meant I was in remission,” Dimick recalls. He stayed on Imfinzi for a year, receiving the drug by infusion once every two weeks. His only side effect was joint pain, which was treated with anti-inflammatory agents. Although remissions are not always permanent, every imaging scan taken since Dimick stopped taking the drug has shown no trace of his cancer. “I’m one of the lucky ones,” says Dimick, 61, who lives in Hasbrouck Heights, New Jersey, and works in the fencing business. “I haven’t felt this good in four years.”

Imfinzi was approved by the Food and Drug Administration in May 2017 for patients with advanced or metastatic bladder cancer whose disease has progressed despite platinum-based chemotherapy. It’s one of five new drugs approved to treat bladder cancer since 2016 — all of which work by blocking “checkpoints,” such as the naturally occurring proteins PD-1 and PD-L1, that normally rein in the immune system and prevent it from recognizing and attacking cancer. Before 2016, there hadn’t been a new treatment approved for bladder cancer in 30 years.

Initially approved to treat some types of melanoma and lung cancer, checkpoint inhibitors look promising in a number of cancer types. The rapid expansion of the number of these drugs available to patients with metastatic bladder cancer has revolutionized the treatment of the disease, oncologists report. “Before, we could offer chemotherapy, which was hard for patients to tolerate, and for many, the cancer ultimately returned,” says Elizabeth Plimack, M.D., chief of the Division of Genitourinary Medical Oncology at Fox Chase Cancer Center in Philadelphia.

“Now, we have a wealth of immunotherapy treatments. When they work, the quality of the response can last for months or years.”

The other immunotherapy drugs approved over the past year and a half are Tecentriq (atezolizumab), Bavencio (avelumab), Keytruda (pembrolizumab) and Opdivo (nivolumab). All work by inhibiting PD-1 or PD-L1, and all are approved for the treatment of patients who previously received chemotherapy. Keytruda and Tecentriq are also approved for patients who are not eligible for chemotherapy.

CRAIG BROWN's bladder cancer has gone into remission on the immunotherapy Tecentriq, without side effects. — PHOTO BY MIKE PETERS

The side effects reported in the trials of these drugs included fatigue, nausea, itching, kidney injury and pneumonia, and a small percentage of patients developed immune disorders like thyroid disease, diabetes and hepatitis.

Craig Brown is happy to report that he has not experienced any noticeable side effects while taking Tecentriq. 

Diagnosed at age 61 with stage 4 bladder cancer that had spread to his ribs, Brown enrolled in a clinical trial of the drug after undergoing six months of chemotherapy. After three immunotherapy treatments, his bladder tumor disappeared, and he’s now in remission. He continues to get the drug every three weeks, along with scans every 12 weeks. He is among about one-quarter to one-third of eligible patients with cancer who respond to immunotherapy. 

“There are no side effects at all,” says Brown, an accountant who lives in North Caldwell, New Jersey. “That makes it possible for me to do everything I always used to do,” such as boating and spending time with his family, he says. “I’m extremely grateful.” 

In bladder cancer, Keytruda stands out among immunotherapies because it was the first of the new crop to be granted a full approval by the FDA, rather than an accelerated approval, says Dean Bajorin, M.D., a medical oncologist at Memorial Sloan Kettering Cancer Center in New York. Bajorin was one of the investigators in the large phase 3 studies that compared Keytruda with chemotherapy and led to the drug’s full approval. The other drugs were given the green light after smaller phase 2 studies, but will need to undergo larger, randomized trials in order to gain final full approval. 

The results of the phase 3 Keytruda studies were impressive. In patients whose cancer had previously progressed despite chemotherapy, Keytruda reduced the risk of death by 27 percent. Survival at 18 months was 36 percent for patients receiving Keytruda versus 20 percent for those treated with additional chemotherapy; median overall survival for those patients was 10.3 months with Keytruda versus 7.4 months with chemotherapy. “That trial showed unequivocal superior response rates and tolerance of therapy,” Bajorin says. “In another trial, which enrolled patients who were not eligible for standard chemotherapy, Keytruda achieved an objective response rate of 29 percent. Those results are also encouraging.” 

Although the other four approvals were granted based on similarly impressive results from small trials, recent data from a larger trial of Tecentriq have raised some questions about whether all five medicines will prove equally effective over the long run. In May, a phase 3 trial comparing Tecentriq with chemotherapy failed to show an improvement in overall survival. Analysis of the trial data is ongoing, with full data expected later this year. 

Even though the menu of immunotherapy options for bladder cancer patients has expanded over the past year, oncologists still recommend chemotherapy as the firstline treatment for patients with metastatic disease who are otherwise healthy enough to tolerate it. In the meantime, studies are being conducted to determine whether immunotherapy should be used as a firstline treatment. For instance, a planned phase 2 study will consider pre-surgical treatment with durvalumab and tremelimumab for patients who aren’t eligible for cisplatin. 

Standard treatment with chemotherapy involves choosing from among a few regimens, including cisplatin plus gemcitabine; cisplatin and gemcitabine plus paclitaxel; and MVAC (methotrexate, vinblastine, doxorubicin and cisplatin). In more recent years, a protocol called dose-dense MVAC has gained popularity, because it can be administered in two-week cycles versus three- or four-week cycles for classic chemotherapy treatments. A recent trial of 166 patients comparing dose-dense-MVAC with two older regimens found similar efficacy, but the rate of toxic side effects was 32 percent with the newer dosing schedule versus 55 percent for classic MVAC. 

For patients with localized disease, surgery is also an option. Early-stage disease, or “non-muscle invasive” bladder cancer, can sometimes be treated by removing the tumor without needing to remove the bladder, but if the cancer has invaded the muscle, chemotherapy and removing the entire bladder and nearby lymph nodes may be required. A newer technique involves reconstructing the bladder with a “neobladder,” a piece of intestine that’s connected to the urethra, allowing for normal urination. 

When surgery and chemotherapy aren’t effective enough, the cancer can spread to other parts of the body. This is when the new immunotherapy options come into play. Choosing the right drug, however, can be challenging. Measuring bladder tumors for high PD-L1 expression is a way of helping to predict the likelihood that a patient will respond to a PD-1 inhibitor, and there are diagnostic tests available to do just that. 

But oncologists are divided on the question of whether tumoral PD-L1 levels should be measured in patients at all. In one early trial of Keytruda in bladder cancer, 38 percent of patients with high PD-L1 responded well to the drug. Similarly, the overall response rate in an early Imfinzi trial was 31 percent, while the response rate in patients with high PD-L1 levels was 46 percent. 

The monkey wrench, Bajorin says, is that some patients in the trials had complete responses even though their tumors had no PD-L1 expression. PD-L1 testing, he says, “is not ready for prime time. We do not think it should be employed for clinical decision-making because of its inaccuracy in predicting clinical response.” 

One big advantage of immuno-oncology treatments, oncologists agree, is that they don’t produce the harsh side effects that are common with chemotherapy drugs, such as vomiting and hair loss. For that reason, many patients are asking to skip chemotherapy as a firstline treatment altogether and go straight to one of the newly approved immune-boosting drugs. 

 That presents a challenge, because it was not clear whether there was a survival benefit with immuno-oncology drugs compared with chemotherapy in second-line treatment until the results of the Keytruda trial came in, says Joaquim Bellmunt, M.D., Ph.D., associate professor at Harvard Medical School and director of the bladder cancer center at Dana-Farber Cancer Institute. Some disappointment came when the Keytruda and Tecentriq trials arrived at opposite conclusions on survival.

“Why one trial is positive and the other is negative is a big question,” Bellmunt says. Ongoing analyses are trying to determine whether trial design and patient selection are the reasons behind this lack of benefit for Tecentriq in the phase 3 trial. Another possibility is that drugs that block PD-1 versus PD-L1 may have different levels of effectiveness. 

That’s not the only area of research when it comes to the best use of the newer treatments for bladder cancer. Several trials are underway, not only comparing immuno-oncology treatments with chemotherapy for firstline treatment, but also testing whether giving the two treatments together might be more effective than either by itself. Combining Keytruda with chemotherapy is already approved for treating lung cancer, for example, and the drug is now being combined with gemcitabine and cisplatin in a trial of bladder cancer patients who have not undergone previous systemic chemotherapy. 

A trial of Imfinzi combined with radiation therapy in bladder cancer patients is being planned, and a similar study will be conducted that combines Keytruda and radiotherapy. In addition, that and another upcoming trial are combining Imfinzi with tremelimumab, an experimental immunotherapy that blocks a different checkpoint called CTLA-4. This combination recently produced disappointing results in a lung cancer trial, failing to improve progression-free survival when compared with chemotherapy, but oncologists who treat patients with bladder cancer still hold out hope for such immuno-oncology cocktails. “We’re looking to improve outcomes by combining immunotherapeutic agents,” Bellmunt says. 

One closely watched trial combines Keytruda with the targeted drug epacadostat, an experimental compound that blocks an enzyme called IDO1. The enzyme suppresses the immune system by blocking the activation of certain T cells, which in turn allows tumor growth. A small trial presented at a meeting in June showed that, in 40 patients, the Keytruda/epacadostat combination produced an objective response rate of 35 percent. The study is ongoing, and a phase 3 trial is also planned. 

“There’s a keen interest in combining checkpoint inhibitors with something else to help the immune system work better,” Plimack says. Combination approaches could help two categories of patients: those who haven’t yet been treated with immunotherapy, and those who have but who have become resistant to it. Imfinzi is now being tested in combination with several different types of drugs, including Lynparza (olaparib), which inhibits a tumor-promoting enzyme called PARP, and AZD4547, an experimental compound that inhibits the activity of fibroblast growth factor receptor (FGFR) proteins that would otherwise help drive bladder cancer. 

Treatments that disable FGFR, PARP and IDO1 are examples of targeted drugs, an approach that continues to generate interest. These drugs tamp down the effects of damaging genetic mutations in tumors. FGFR3 mutations are a focus because they are found in 75 percent of early-stage bladder tumors and 20 percent of muscle-invasive cases. Among the FGFR3 inhibitors that have recently entered clinical trials are LY3076226 and B-701, the latter of which is being tested in combination with Keytruda. 

An emerging target called nectin-4 is also being investigated. Nectin-4 is a protein that’s found in high concentrations in 65 percent of bladder tumors. The experimental agent enfortumab vedotin is an antibody connected to a toxic compound that seeks out nectin-4 and destroys tumor cells that contain the protein. In an early trial in 71 bladder cancer patients, the drug produced a 41 percent objective response rate, and three patients went into remission. A phase 2 trial started this year. 

In addition, data presented in September demonstrated that adding the targeted drug Cyramza (ramucirumab) to the chemotherapy docetaxel in patients with previously treated metastatic bladder cancer delayed median time to disease progression by over a month. 

Despite the promise of targeted treatments, however, many oncologists predict it is immunotherapy that will find an ever-expanding role in the treatment of bladder cancer. Trials are already underway to answer a pressing question: Could checkpoint inhibitors prevent early-stage bladder tumors from spreading? 

“Normally, bladder cancer that’s limited to the surface of the bladder can be treated” with surgery or topical drugs, Plimack says. “But when persistent tumors keep coming back, those patients are at risk for having the cancer grow and spread. So, addressing the cancer early is attractive. We hope checkpoint inhibitors will allow these patients to remain cancer-free with their bladders intact.” 

Michael Molnar’s disease is more advanced than that, and he is grateful to be benefiting from a combination of targeted and immunotherapy approaches. 

A patient with bladder cancer from the Lehigh Valley, in Pennsylvania, Molnar was out of options when he entered the trial for Keytruda plus epacadostat in the fall of 2016. He had been diagnosed with bladder cancer in 2014 that was later found to have spread to his lymph nodes. After treatments administered within the bladder failed to eradicate the cancer, the decision was made to remove the bladder, and then Molnar underwent chemotherapy, which initially worked. But nine months after his treatment, the cancer returned. 

Molnar receives Keytruda by infusion once every three weeks, and takes epacadostat in pill form twice a day. After just one treatment with the combination, Molnar’s tumors shrank by 50 percent. Two of the three tumors he started with have disappeared, and the third is tiny. Molnar expects to stay in the trial through at least 2018. The side effects of the two drugs are so minor, he says, “it’s like taking vitamins.” Molnar, 53, who works in the cable communications business, is able to walk and swim for exercise. “This has given me my life back,” he says. 

Immunotherapies known as checkpoint inhibitors are so promising in bladder cancer that many patients want them as first treatments &mdash; before they’ve been proven in that setting.

GU Special Issue | CURE