Caroline Seymour is your initial point of contact for the 

™. She joined the company in 2018 as an assistant editor, with expertise in video production and print/digital publication. Email: cseymour@onclive.com​ 

The management of metastatic hormone-sensitive prostate cancer continues to evolve as new findings emerge, such as results from the LATITUDE and CHAARTED studies.

The FDA based its recent approval of abiraterone acetate (Zytiga) and prednisone in metastatic high-risk castration-sensitive disease on results from LATITUDE. After a median follow-up of 30.4 months, the median overall survival (OS) was not reached in the abiraterone/prednisone plus androgen-deprivation therapy (ADT) versus 34.7 months with ADT plus placebo (HR, 0.62; 95% CI, 0.51-0.76; 

In CHAARTED patients were randomized to ADT alone or ADT plus docetaxel. After a median follow-up of 28.9 months, the median OS was 13.6 months longer with ADT plus docetaxel versus ADT alone, at 57.6 versus 44.0 months (HR, 0.61; 95% CI, 0.47-0.80; 

 What questions surround abiraterone versus docetaxel in the treatment in prostate cancer?

, William K. Oh, MD, chief, Division of Hematology and Medical Oncology, professor, Medicine and Urology, Mount Sinai School of Medicine, associate director, Clinical Research, The Tisch Cancer Institute, discussed treatment with abiraterone versus docetaxel in patients with prostate cancer, other remaining questions in the field, and what role immunotherapy is poised to play.

One of the biggest developments in the treatment of advanced prostate cancer over the past several years has been the management of metastatic hormone-sensitive prostate cancer. This is primarily in patients who are newly diagnosed. In 2014, a plenary session at the ASCO Annual Meeting presented the results of CHAARTED. The results, favoring the use of early chemotherapy, were subsequently published in the 

. A second study, STAMPEDE, confirmed those findings. At that time, we started using docetaxel in the treatment of newly diagnosed metastatic disease.

How do you approach treatment for these patients?

At the 2017 ASCO Annual Meeting, LATITUDE was presented at the plenary session. LATITUDE was another large, randomized trial of ADT plus or minus abiraterone and showed an extremely comparable benefit for up to 2 to 3 years of abiraterone plus prednisone in the treatment of metastatic hormone-sensitive prostate cancer. An arm of STAMPEDE looked at abiraterone compared with ADT alone and also showed a similar benefit. Now, we have 4 clinical trials that show either docetaxel or abiraterone compared with ADT alone significantly improve survival. The big question remains: which is better?

My practice, like in most practices, adapts new therapies as they come about. In 2014, I administered docetaxel after the data were released. However, the challenge after that study was determining whether one or both treatments should be used. Patients have difficulty understanding the nuances of these questions, but they do have their own preferences. Most patients, if given a choice, may prefer not to have chemotherapy.

What about treatment with enzalutamide (Xtandi)?

Are there any other settings looking at either abiraterone or docetaxel that might make a clearer distinction between the 2 agents?

However, I have had some patients prefer chemotherapy because the treatment, administered 6 times, is over in about 4.5 months. Though a patient may choose abiraterone, it may not be financially feasible for them either because their insurance does not [cover] it, or because the copay can be too expensive. You have to look at the individual characteristics of the patient and incorporate their personal preferences before deciding which treatment best suits them. For most patients, abiraterone has become a more popular choice because it’s an oral therapy and may have a more favorable side effect profile.

Enzalutamide hasn’t been studied in this situation yet. In theory, enzalutamide and abiraterone work similarly mechanistically, so it shouldn't necessarily be any different. It just hasn’t been studied in a large, randomized trial in this setting. There are ongoing studies, and it may have the exact same benefit, but we don't know as of now. 

The use of abiraterone and docetaxel was established in metastatic castration-resistant prostate cancer (mCRPC). Even in that setting, there are a lot of conversations about both combinations. Should we combine them if they both work and are mechanistically different? Is there an optimal sequence? Is abiraterone followed by docetaxel or docetaxel followed by abiraterone any better or worse?

What other agents could surpass abiraterone or docetaxel?

In the mCRPC setting, there’s not a clear answer to that question. Some people believe that abiraterone might have a greater benefit early. That preference may translate to its use in early metastatic hormone-sensitive disease. However, a lot of oncologists have a bias. If your cancer is extremely aggressive or has features that are very poorly differentiated, such as a neuroendocrine kind of cancer that doesn’t make a lot of PSA, maybe that patient would be better suited to receive chemotherapy upfront. Do we have good data on that? Not necessarily, but is it something that I might factor into my consideration of who to give chemotherapy to.

In the hormone-sensitive setting, people are recognizing that this may be a good area to test new agents. That’s partly because developments are made more quickly in this setting. If you wait for a patient who relapses with a rising PSA to develop metastatic disease, and then castration-resistant disease, getting a quick answer will be more difficult with all of the drugs we have approved in that setting.

What are your thoughts on immunotherapy in prostate cancer?

However, in a setting where patients present with metastatic disease, their overall outcomes may be more limited. With ADT alone, they may progress, on average, within 1.5 years, but as agents such as abiraterone and/or docetaxel crowd the treatment landscape and become the new standard of care in the metastatic hormone-sensitive setting, it may be more difficult to get a survival endpoint. This is because these patients are getting subsequent therapies for CRPC, such as radium-223 dichloride (Xofigo), sipuleucel-T (Provenge), or cabazitaxel (Jevtana).

We've been left off of the immunotherapy train, relatively speaking, and that’s ironic because prostate cancer was one of the first diseases where immunotherapy was approved with sipuleucel-T. The checkpoint inhibitors do have a response rate in prostate cancer, but it’s very modest. The small studies that have been completed so far suggest that the rate is approximately 10% to 20%. We are waiting for the large studies, such as KEYNOTE-199, to tell us what the more accurate response rate is.

We all recognize that this is not going to be a disease such as melanoma or lung cancer where there will be very high response rates. That said, there is some hope that combinations in prostate cancer will make a difference, namely combinations of vaccines, such as sipuleucel-T with checkpoint inhibitors. There’s potential for combinations with checkpoint inhibitors.

Some people forget that prostate cancer was one of the first diseases after melanoma that ipilimumab (Yervoy) was tested in. Even though that was a negative randomized trial, it suggested that there was some subset of patients who would benefit. In the rest of the field, the issue of PD-L1 staining remains a somewhat unclear biomarker for predicting response or benefit from checkpoint inhibitors. In prostate cancer, it may be the thing that puts us over the top. We are going to see more immunotherapy in prostate cancer in the very near future, but it has been a tougher slog for us to be able to get these drugs to our patients. 

Fizazi K, Tran N, Fein L. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. 

 2017;377:352-360. doi: 10.1056/NEJMoa1704174.

Sweeney C, Chen Y, Carducci M. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. 

 2015;373:737-746. doi: 10.1056/NEJMoa1503747.

Articles

William K. Oh, MD, discusses treatment with abiraterone versus docetaxel in patients with prostate cancer, other remaining questions in the field, and what role immunotherapy is poised to play.

Expert Discusses Docetaxel Versus Abiraterone in Hormone-Sensitive Prostate Cancer

Approximately 40% of melanoma cases harbor 

 mutations that are able to be targeted, and with the advent of the combination of dabrafenib (Tafinlar) plus trametinib (Mekinist) demonstrating impressive outcomes in patients with 

 mutations, physicians are no longer using BRAF inhibitors alone, but rather in combination with MEK inhibitors due to the improved efficacy.

With a median overall survival (OS) improvement of about 5 months with dabrafenib/trametinib, the safety profile of the combination is significantly more manageable versus BRAF monotherapy, according to Paul B. Chapman, MD.

 State of the Science Summit™ on Melanoma, Chapman, a medical oncologist at Memorial Sloan Kettering Cancer Center, said that while most tumors will develop resistance to the combination therapy, there are also tumors that will remain sensitive to them for longer amounts of time.

Overall survival outcomes were improved in patients enrolled in a phase III trial, especially in those with elevated serum lactate dehydrogenase levels and those whose melanomas contain 

 The combination was also linked to an increase in objective response rate at 69% with the combination versus 53% for BRAF monotherapy. The median time to disease progression was 11 months with dabrafenib/trametinib versus 8.8 months for BRAF monotherapy. Patients also demonstrated fewer secondary squamous cell carcinoma and/or keratoacanthoma lesions.

During the 2017 World Congress on Melanoma, data presented regarding targeted adjuvant therapy revealed 3-year OS to be slightly better in patients who received adjuvant dabrafenib/trametinib versus placebo, at 86% and 77%, respectively.

 The looming question remains whether to administer treatment immediately following surgery or to wait to see whether patients relapse.

Intermittent combination therapy with varying regimens is an approach currently being explored. A 2013 study conducted by Das Thakur and Stuart,

from Novartis Institutes for Biomedical Research, on the evolution of melanoma resistance revealed that intermittent, rather than continuous, therapy with a BRAF inhibitor may prolong acquired resistance. In the phase II randomized COMBAT study, patients are randomized to the combination of dabrafenib plus trametinib followed by nivolumab (Opdivo) plus ipilimumab (Yervoy) at disease progression versus nivolumab plus ipilimumab followed by dabrafenib plus trametinib at disease progression (NCT02224781).

Additionally, the SWOG S1320 study is looking at intermittent dosing, with patients taking 150 mg twice daily of dabrafenib and 2 mg 4 times daily of trametinib during an 8-week lead-in period, and randomizing patients without disease progression at the end of the lead-in period to either continuous dosing or to intermittent dosing with a 5-weeks-on/3-weeks-off schedule (NCT02196181). Combination therapies could be an avenue for nontraditional 

 mutations as well, Chapman added. Though 90% of mutations are V600, some other mutations are targetable with newer drugs still in development.

Some of these other nontraditional mutations are divided into 2 groups: class II and class III, Chapman said. While class II mutations are similar to V600, they require dimerization of mutated 

. Clinical trials are looking at breaking these dimers, he explained.

Class III mutations require a different approach to treatment in that they need upstream activation by RAS. MEK inhibitors can be used to target them, but how to optimally administer one for this population remains unclear.

Chapman suggested that examining tumors that are wildtype for 

will reveal drivers in these tumors that will bridge the gap between current and novel treatments. Translocation and fusion proteins could eventually be identified as another target, he added. For example, Chapman cited one of his patients who had a ROS1 translocation and had a complete response to crizotinib (Xalkori). “These patients are not common, but you won’t find them unless you look, and the place to look, as I said, is probably the wild-type tumors,” he said.

Looking forward, Chapman said that targeted therapies may be used with deference to immunotherapy, but there are no long-term data directly comparing targeted therapy and immunotherapy. However, recent data on the long-term follow-up of patients on BRAF/MEK inhibitor combination therapy have led researchers to hypothesize that the potential of targeted therapies to facilitate steady OS may not be as distinct from immunotherapies as previously believed. Current research that is looking to combine the 2 therapies may abnegate the need to select a frontline therapy altogether, he concluded.

Long GV, Stroyakovskiy D, Gogas H, Levchenko E. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma.

2014;371:1877-1888. doi: 10.1056/NEJMoa1406037.

Long GV, Hauschild A, Santinami M, et al. Efficacy outcomes in the phase 3 COMBI-AD study of adjuvant dabrafenib (D) plus trametinib (T) vs placebo (PBO) in patients (pts) with stage III BRAF V600E/K—mutant melanoma. In: Proceedings of the 2017 World Congress of Melanoma; October 18-21, 2017; Brisbane, Australia. Presentation SMR09-1.

Das Thakur M, Stuart DD. The evolution of melanoma resistance reveals therapeutic opportunities. 

 2013;73(20):6106-6110. doi: 10.1158/0008-5472.CAN-13-1633.

With the advent of the combination of dabrafenib (Tafinlar) plus trametinib (Mekinist) in melanoma physicians are no longer using BRAF inhibitors alone, but rather in combination with MEK inhibitors due to the improved efficacy.

Updates in Targeted Combination Therapies for Melanoma

Preliminary findings from an ongoing study have demonstrated efficacy and quality-of-life benefits associated with robotic-assisted cystectomy in patients with muscle-invasive bladder cancer, pointing to a potential shift in current practice.

Results presented at the 2017 AUA Annual Meeting showed that, of the 150 patients in the RARC arm and 156 patients in the ORC arm, estimated blood loss was substantially lower in the robotic arm. Shorter length of hospital stay was also reported for patients who underwent RARC. Complications were reported to be similar in both groups, as well as the number of lymph nodes removed.

A mainstay in clinical practice has been open cystectomy in the management of muscle-invasive bladder cancer. Respective clinical trials are few and far between, and those that have been conducted have failed to randomize all aspects of the trial, explained William C. Huang, MD. Minimally invasive approaches, such as robotic-assisted surgery, have typically been used in cancers outside of the bladder cancer realm.

: Please provide an overview of your presentation.

How has the use of robotic surgery evolved in the treatment of patients with bladder cancer? 

Are there new trials looking at new surgical techniques or neoadjuvant approaches?  

Is there a certain patient population that is eligible for robotic surgery? 

How do you see the role of surgery evolving for patients with bladder cancer? 

What general advice would you like to provide community physicians with on how this field is changing?

 on Genitourinary Cancers, Huang, associate professor, Department of Urology, co-director, Robotics Program, Chief Urology Service, Tisch Hospital, NYU Langone Health, discussed the transition from open cystectomy to minimally invasive robotic-assisted surgery in the management of muscle-invasive bladder cancer.

: My presentation today was about the use of robotic-assisted surgery for the management of muscle-invasive bladder cancer. The traditional operation, known as a radical cystectomy, is done in an open fashion to remove the bladder along with lymph nodes. The focus of my talk tonight centered on the performance of this procedure using the assistance of robotic technology in a minimally invasive approach. 

A lot of the application of robotic techniques in bladder surgery essentially evolved from the use of robotic surgery in prostate surgery. For instance, the lymphadenectomy was already being done for prostate cancer and we just extended that by using robotics [in bladder cancer]. Since the removal of the bladder requires removal of the prostate as well, for many experienced prostate surgeons, removing the bladder at the same time was just an extension of a technique that we were already familiar with, so it seemed like a natural evolution for robotic surgeons to move from robotic prostate surgery to robotic bladder surgery. 

For bladder cancer surgery specifically, there was one randomized trial that compared robotic cystectomy to open cystectomy. In a letter to the editor we wrote, Marc A. Bjurlin, DO, of NYU Langone Health, and I pointed out that even though they presented a randomized trial, the urinary diversions in the trial were all done in an open fashion. There is, however, an ongoing trial called the RAZOR trial, which is hoping to answer some of those questions.

These are patients who are going to require removal of their bladder for the management of muscle-invasive bladder cancer. In terms of selection criteria, almost any patient who is eligible for an open cystectomy is also a candidate for the robotic approach. Exceptions would be patients who have had a large number of previous surgeries before, or patients who have a contraindication for undergoing general anesthesia and/or inflating their abdomen with air. [Additional exceptions are] patients who are morbidly obese who cannot tolerate the positioning that we use, or those who have significant pulmonary issues.

The gold standard treatment for patients with muscle-invasive bladder cancer remains removal of the bladder, and that necessarily won't change with the use of robotics. What will happen as time goes on is more and more people will likely utilize the robotic approach because they are much more comfortable doing robotic surgery for other urologic cancers. I do see that there is going to be a greater uptick in the use of robotic-assisted bladder removals, or robotic cystectomies as time goes on. 

One of the things that has to be taken into consideration is the removal of the bladder itself. Whether it is done through an open incision or a robotic incision is not the main source of morbidity or complications from this type of surgery; it’s really the reconstruction that’s done afterwards.

The majority of robotic cystectomies these days are still done with an eventual conversion to an open urinary reconstruction. That is the great barrier to a widespread adoption of the robotic-assisted removal of the bladder. Unless we see a benefit in the reconstruction, I don't think a lot of people will necessarily make that jump to performing the urinary reconstruction robotically. If they're going to perform the open reconstruction anyway, they may ask themselves, “What is the point of doing the first part robotically if I'm going to convert to an open procedure for the second half of the operation?”

Parekh, Dipen. PNFLBA-18. A prospective, multicenter, randomized trial of open versus robotic radical cystectomy (RAZOR). 

2017;197(4S):e918. doi: 10.1016/j.juro.2017.03.044.

The ongoing randomized phase III RAZOR trial is comparing open radical cystectomy (ORC) with robotic-assisted radial cystectomy (RARC) in patients with stage T1-T4, N0-N1, M0 bladder cancer. The study has a noninferiority endpoint, as well as blood transfusion rate, estimated blood loss, length of stay, complications, lymph node yield, and margin status.

William C. Huang, MD, discusses the transition from open cystectomy to minimally invasive robotic-assisted surgery in the management of muscle-invasive bladder cancer.

Robotic Approaches Advancing Surgical Scope in Muscle-Invasive Bladder Cancer

Over the last few years, immunotherapy has taken center stage in the landscape of bladder cancer, with the approval of 5 PD-1/PD-L1 agents: atezolizumab (Tecentriq) and pembrolizumab (Keytruda)—both as first- and second-line therapies&mdash;and avelumab (Bavencio), durvalumab (Imfinzi), and nivolumab (Opdivo) in the second-line setting. Next steps in this field, experts have noted, are to study these agents in combination with other novel or existing therapies.

Additionally, kidney cancer has also seen an emergence of immunotherapy approaches, especially as combinations. For example, a breakthrough therapy designation was granted by the FDA in January 2018 to the combination of pembrolizumab and the VEGF/FGF inhibitor lenvatinib (Lenvima) for the treatment of patients with advanced and/or metastatic disease. Moreover, in December 2017, the FDA granted avelumab plus the VEGF inhibitor axitinib (Inlyta) a breakthrough therapy designation in treatment-naïve patients with advanced disease.

“There are many advances taking place in the management of genitourinary cancers,” said Arjun V. Balar, MD. “In bladder cancer and kidney cancer in particular, we’re seeing a wave of new therapies, such as how to use novel immunotherapies effectively. There are trials now that are addressing combination approaches that I believe will quickly lead to new standards of care, probably in the next 1 or 2 years. It's critical to follow along with these studies to maintain an updated standard of care.”

 What is the state of immunotherapy in GU cancers?

 on Genitourinary (GU) Cancers, Balar, assistant professor, Department of Medicine, director, Genitourinary Medical Oncology Program, NYU Langone’s Perlmutter Cancer Center, and chair of the meeting, discussed the landscape of current and future standards of care for immunotherapy in bladder and kidney cancer.

 on GU Cancers, we spoke about advances in the management of GU cancers and, specifically, my area of focus on the talk was a focus on patients who were treated with metastatic kidney and bladder cancers. In advanced bladder cancer, we have seen a wave of new therapies being approved. These include agents targeting the PD-1 pathway. We have 5 agents approved in the second-line setting, and we have 2 agents approved in the first-line setting. This has been a very active year in terms of drug development. I've covered all of the data that supported the approvals of these agents.

Can you expand on some of these new therapies?

Then, I turned my attention toward the management of kidney cancers, where we have also seen a great deal of activity in terms of new therapies. I reviewed the data with respect to immunotherapy in the second-line setting, as well as emerging agents that include combinations in the first-line setting. 

Immune checkpoint inhibitors, in particular PD-1 pathway inhibitors in bladder cancer, have led to rapid and durable responses in the second-line setting. What we have seen, as a summary of the phase II and phase III trials, is response rates between 15% and 20%. In the second-line setting, these responses have been durable. The longest-term follow-up shows that some of these responses are going into multiple years—2 and 3 years after starting treatment, which is quite promising.

Will we start looking at more combination regimens of immunotherapy plus targeted therapy in bladder cancer?

Even more [impressive] are the data that we're seeing in the first-line setting for patients with cisplatin-ineligible disease. Two agents are currently approved [in that setting]. The median survival for 1 of the agents has been reported at 15.9 months. This appears to be much better than what we would typically expect for this patient population, which is approximately 9 months when they are treated with carboplatin-based therapy. 

In bladder cancer, the next step is obviously to combine agents. One of the interesting things to look at is other immune checkpoints, such as CTLA-4. We are seeing ongoing studies that are looking at combining ipilimumab (Yervoy) with nivolumab. Also, another randomized phase III trial is testing durvalumab with tremelimumab, which is a CTLA-4 antibody and PD-L1 combination. It appears that this combination may actually lead to higher response rates, and hopefully these responses are durable.

Are these targeted plus immunotherapy regimens also going to translate to kidney cancer treatment?

What we are also seeing is a combination with IDO1 inhibitors, in particular [the PD-1 inhibitor] pembrolizumab plus epacadostat, which is an oral IDO1 inhibitor. Those drugs are now entering phase III trials, as well. 

In kidney cancer, combinations are absolutely the future. However, what is unique about kidney cancer is that not only is it an immune-responsive tumor, but this is a tumor where VEGF-targeted agents are already a standard of care. Phase I data of the combinations of axitinib plus pembrolizumab, axitinib plus avelumab, and pembrolizumab plus lenvatinib are demonstrating very promising response rates upwards of 70%.

What does this mean for the role of chemotherapy as time goes on?

This demonstrates that there may be synergy between these agents to generate a more effective antitumor immune response. Ultimately, I do believe that these agents will lead to new standards of care in the first-line setting. Ongoing randomized trials hope to demonstrate that this combinatorial approach will lead to durable responses and better overall survival. 

In bladder cancer, where we use chemotherapy often, I don't think chemotherapy is going to go away. In the first-line setting, approximately 5% or 10% of patients have cancer that is rapidly growing and highly symptomatic. We know for those patients, immunotherapy is not very effective. They are better treated with chemotherapy. Certainly, because we know that a significant proportion of patients will not respond to the immunotherapy, chemotherapy can still be an effective tool in the second-line setting. There is emerging evidence that certain forms of chemotherapy may combine well with immunotherapy, so we may also see combinatorial approaches. There are certainly phase III trials addressing that question, as well. 

Arjun V. Balar, MD, discusses the landscape of current and future standards of care for immunotherapy in bladder and kidney cancer.

Balar Addresses Advances in Bladder and Kidney Cancer

The use of MRI scans to detect and treat prostate cancer more effectively continues to be a growing area of investigation, according to Samir Taneja, MD.

Researchers are investigating how MRI scans can more precisely target and stage aggressive disease, as well as clinically insignificant cancers. Prior data published in the 

showed that MRI-guided biopsies were 3 times as likely to identify cancer compared with traditional biopsies. MRI detected 38% of high-grade cancers that had been missed with a biopsy.

: Can you provide an overview of your presentation?

 on Genitourinary Cancers, Taneja, director, Urologic Oncology, Genito-Urologic program leader, NYU Langone’s Perlmutter Cancer Center, discussed his research on MRI-guided prostate biopsies and other modalities in development.

: My research really has focused on the idea of using imaging to change the way we diagnose the disease, risk-assess prostate cancer, select treatments, and even the way we've started to treat it in order to reduce some of the side effects that men experience when they go through conventional therapy. We started thinking we could see the cancer before we biopsy it, very similar to the way a woman gets a mammogram before she gets a biopsy.

With the advent of the multiparametric MRI, which allows us to use different functional sequences to better assess the prostate and determine what’s cancer and what’s not, we're able to localize cancers accurately. NYU Langone is one of the early innovators in the area of prebiopsy MRI of the prostate. We think we can monitor the disease better than we used to be able to with fewer biopsies.

If you have an image in front of you, what are some characteristics to look for that determine how you are going to assess risk? 

Finally, we have used it to change the way we think about treatment. Whereas previously, we used to treat patients uniformly by removing the whole prostate or radiating the whole prostate. Now, we are trying to transition to a paradigm similar to a lumpectomy where we find the tumor, localize it, and then destroy it using some energy source—heat, freezing, or the like. We have very early data on the effectiveness of that, but it is the imaging that has empowered us to do it.

When we look at a prostate MRI, there are some basic functional sequences we look at. The first is what’s called the standard image, or the T2-weighted image. That's really an anatomic image that allows us to visualize the prostate at high resolution. We are looking for dark areas in the prostate that might represent cancer—essentially small, rounded areas or smudges through the cancer that look darker than the normal tissue.

The problem is that the sequence alone is very nonspecific; inflammation, scarring, and atrophy can cause a similar appearance to cancer on that T2-weighted image. We improve the accuracy and we reduce the false positive rate by adding functional sequences—one of which is called the diffusion-weighted image. Diffusion-weighted imaging is basically a method of measuring water movement in the tissue. Normal tissues allow passive movement of water molecules, but cancer, because it tends to be densely packed and higher pressure, restricts the movement of water. Restricted diffusion or restricted movement of water is another indicator of cancer. Now, if we see an area that’s dark on a T2-weighted image and there is a region of restricted diffusion, that increases our suspicion that there could be cancer.

Then, we look at perfusion images. We give gadolinium contrast to the patient and measure the rate at which the contrast accumulates in the area of suspicion and the rate at which it flows out. Cancers tend to accumulate contrast faster than normal tissues and lose contrast, or wash out, faster than normal tissues. By measuring that every 5 seconds and creating a curve, one can add additional information about suspicion.

Once we see that, the radiologist then assigns a score that assesses their suspicion level. We call that the PI-RADS score, which is now a nationally standardized 5-point scale created by the American College of Radiology that allows us to assess risk. A PI-RAD V classification would be almost definitely cancer. A PI-RAD I would be a normal MRI.

What other approaches are you using to appropriately diagnose patients?

Staging is a little different. There, the radiologist is looking for whether or not the cancer extends outside of the prostate. MRI has some limitations in detecting small amounts of disease outside the prostate, but it can be used for that purpose, too. 

There are 3 kinds of men who come to us for diagnosis. One would be a man who has never had a biopsy but has an elevated prostate-specific antigen (PSA). Another would be a man who has had previous biopsies, but there is still concern because his PSA is going up. The third would be somebody who has been diagnosed with cancer on a standard biopsy, but it’s not clear whether he needs treatment or not.

In each of those applications, MRI can enhance our ability to detect the cancer and determine what the right course of action would be. The middle is where we can make the most impact because these are men who have been subjected to multiple procedures without a clear answer of what’s going on. We have learned that if we do an MRI, we can separate the men who need biopsies from the ones who don't. A normal MRI or low-suspicion MRI would predict a very low likelihood of a high-grade cancer, whereas a high-suspicion MRI allows us to target the right area and make the diagnosis.

A year and a half ago, my collaborator at NYU Langone, Dr Andrew B. Rosenkrantz, chaired a committee of the American Neurologic Association and Society of Abdominal Radiology. I chaired the urology side, and we created a consensus statement that has been adopted by both organizations, which advises urologists that they should consider MRI as standard in that setting as long as good quality MRI is available.

The application in the first scenario, in which a man who has never had a biopsy before just comes in with an elevated PSA, is a little more controversial. As a community, we have not adopted the use of MRI uniformly in those men. However, at NYU Langone, since 2012, nearly every man who comes to us receives an MRI. Our data clearly show that when we use MRI in those men, it allows us to find more high-grade cancers and to predict who is more likely to have low-grade disease, which perhaps we wouldn't want to find because we're not going to treat it anyway.

The example would be: someone comes to us at an older age and it’s not clear that treatment is going to benefit them. If they have a high PSA and the MRI shows no suspicion, we usually advise them it’s probably okay to [watch and wait]. In someone with a marginal PSA elevation but it’s not clear, we can use the MRI to help us. In most men, we still feel they need a biopsy; we do a better biopsy in that situation with the MRI.

In the coming years, there will be data from large global studies that will confirm that is a good paradigm for people to consider so that we are not missing cancers, and we can reduce biopsies.

What imaging technique might you use to determine if disease has spread? 

In the third setting, MRI has a different purpose for the man who is on surveillance. It allows us to identify the men upfront who have high-grade disease so we can treat them as well as the ones who are truly at low risk, so we're able to do fewer biopsies and follow-up. By using MRI as a substitute, we are learning that we can minimize invasive procedures and still be able to carefully monitor when somebody needs treatment. 

We are still very interested in determining whether or not something in the MRI gives us a sense of which cancers are at risk for spreading and which are not. There can be quantitative metrics of diffusion you can measure to try and help with that. The future of that area will be combining the MRI signal with genetic findings in the tissue we sample, so that if that you can create somewhat of a radiomic signature, you might be able to predict who is at risk from the image.

Where we are making advances that are more tangible to the patient is in the area of molecular imaging—PET. When we fuse PET with MRI or fuse it with CT, we can localize PET signaling to areas that would help us to identify oligometastatic disease. That might help us to identify the extent of metastatic disease at much lower PSA levels. The typical setting in which we would use this is in somebody who has a rising PSA after they've been treated. We've removed or radiated the prostate, but now they come back with a rising PSA and we don't know where that disease is coming from.

There are a number of different PET ligands that have been investigated. Recently, the FDA approved FACBC (anti-1-amino-3-[18F]fluorocyclobutane-1- carboxylic acid; Axumin). We've been using that at NYU. Some of the newer ligands—choline, as an example, or something called prostate-specific membrane antigen (PSMA)&mdash;are PET scans which seem to have tremendous specificity for prostate. PSMA in particular is able to detect oligometastatic or widely metastatic disease at very low PSA levels.

However, it’s not FDA approved. We don't have it at NYU, so when we want to get PSMA-PET, we have to seek out protocols that are open for the patient. That is the future. At NYU, what we do have is one of the few PET/MRI facilities in the region. This is a scanner that simultaneously obtains MRI and PET. That increases the specificity because if we see an area in the bone that lights up on PET but also has a restricted diffusion signal on MRI, we can be pretty confident that that’s an area of prostate cancer.

PET/MRI may have wider applications than recurrent disease. We may use it in high-risk patients when we're deciding what treatment to offer them. We may even use it for better staging our patients with metastatic disease if we believe that there are new paradigms for oligometastatic disease.

Albertsen PC, Marks LS. MRI before prostate biopsy—yes or no? 

2013; 190(6):1978-1980. doi: 10.1016/j.juro.2013.08.050.

Samir Taneja, MD, discusses his research on MRI-guided prostate biopsies and other modalities in development.

Expert Highlights Significance of MRI-Guided Prostate Biopsies 

Implantable cardiac devices are providing a more nuanced understanding of how technology can extend care to the patient’s front door, according to Jean-Bernard Durand, MD.

According to data from The University of Texas MD Anderson Cancer Center, survivors of cancer are more likely to die of heart disease than their cancer, and should be carefully monitored for heart problems both during and after cancer treatment. Approximately 3% to 50% of patients have heart failure during chemotherapy, depending on the systemic drug used.

“When caring for cancer survivors, it’s important to recognize their vulnerability to atrial fibrillation and heart failure caused by previous chemotherapy, and to be vigilant for these heart problems,” said Durand, associate professor in the department of cardiology at MD Anderson. Chemotherapy and radiation therapy can increase the risk for cardiovascular problems such as severe hypertension, cardiomyopathy, ischemia, atrial fibrillation, and congestive heart failure, he added.

Though the symptoms of systemic drugs vary, cytotoxic chemotherapeutic drugs weaken the heart muscle. Taxanes can cause abnormal heart rhythms during treatment in some patients, and angiogenesis inhibitors can cause increases in blood pressure, risk for blood clots, and heart failure.

 What are the specifics of this technology?

With implantable cardiac devices like the CardioMEMS and Reveal LINQ systems, Durand hopes to eliminate the need to discontinue cancer treatment in order to prevent heart failure. In an interview with 

, he discussed the new medium and how patients may be able to continue their treatment regimen.

 There is a relatively common problem we all have in our practice, and that is when we have patients who see us from all over the city, all over the state, and all over the country, how do we communicate with these patients and monitor them? Historically, we have always managed this by patients coming to our clinic and having a face-to-face encounter with them. Then we make our decisions about therapies, diagnostics, and diagnosis.

Now, with all these new technologies that have come along, we have some new tools that we can use, specifically using web-based technology where we can not only monitor patients remotely but also diagnosis. What is happening in parallel to these new technologies is that governmental agencies are now recognizing the importance of being able to communicate through web-based technology with patients who cannot get to our offices.

Think about the patient who lives very far away and then has to get into the city to see our doctors. How do we communicate with those individuals? We now have this web-based technology. Web-based technology is the ability to monitor and track patients with different diagnoses, in particular for cardiovascular disease. We now can use noninvasive, FDA-approved technology that we can implant within the patient’s body, and we can monitor them anywhere they are around the world and anywhere the provider is around the world.

That information is transmitted through cellular technologies, so as long as there is a cell tower around them, they can transmit information either to our computer or our smartphone anywhere in the world. The importance of how that relates to oncology is, we already know there are many oncology drugs that have side effects, in particular that affect the heart. Typically, we require these patients to come into our clinic.

Now with the implantation of this technology, we can monitor these patients remotely. We can look on our smartphone at a dashboard, for example, at their blood pressure or their heart rate, and whether their heart rate is fast or slow and what type of rhythm it is. Based on what we see on our smartphone or computer, we can call the patients and either adjust their medicines or start new medications without them ever coming into our offices provided they’re stable.

Patients who are sick need to have a face-to-face encounter, but now we have the ability to monitor these patients and make decisions in real time, anywhere around the world, so that they don't have to get into a cab, onto a train, find transportation to get here, and wait many hours to be seen. It is cutting down on our time to make real-time decisions.

Is this technology already being implemented in practice?

How else does that relate to oncology clinical trials? What about drugs that have a predisposition? Now, we can monitor them and we can detect exactly what their burden of cardiovascular disease is. Throughout the course of their clinical trials, and as these trials are completed, we have objective data that we can give the FDA about the cardiovascular side effects of these clinical trials in oncology. 

It is already being used at The University of Texas MD Anderson Cancer Center. We use it real time; it is part of our practice. We have found it very helpful for particular types of drugs that we know can cause rhythm disturbances. For patients with cancer, the goal is to successfully get them through their treatment with minimum toxicities. When these toxicities show up, our go-to move is to stop a life-saving drug.

For example, [there are cardiotoxicities with] ibrutinib (Imbruvica), which is approved for chronic lymphocytic leukemia and certain lymphomas. Now we have the capabilities to identify these problems, treat them, and prevent patients from stopping their crucial life-saving oncology drugs. That is where I see the biggest advantage in practice. Data show that if you discontinue drugs such as ibrutinib for just 8 days, that impacts how long patients live. We really need to do a better job of making sure patients get on their cancer therapy, but also stay on them so they can maximize their outcomes. 

This is likely something that can be useful during natural disasters when patients cannot come in for treatment, specifically when there was a hurricane in 2017 in Houston, where MD Anderson is based.

How does this get implanted? Is it during a surgery, or is it very noninvasive?

Are there any next steps or refinements that you’re still taking with this technology? Where do you see it going for the future?

No doubt about it. That is an example where, because cell towers were for the most part functional and because we didn’t have wind, we had water, they were functional. Many patients could not get into the medical center, and that allowed me to pull up their information on my smartphone to see how they were doing. When there were events, I was able to call these patients anywhere in the United States and make my adjustments in real time, without interfering with their cancer therapy. 

  It is done as an outpatient procedure. The technology now is moving more into the cardiovascular space so that we do things as fast as we can, as minimally as we can, and the technology is as small as it can be. Most of these devices can be placed through a vein into the heart or placed under the skin. The procedure [where the device] is placed under the skin takes less than 5 minutes with local sedation. The procedure where we have to go into a vein, for the most part, takes less than 30 minutes with conscious sedation. You don’t go on a respirator and can leave 2 hours after the procedure. 

We are now at a place where governmental agencies are realizing these problems of having access to healthcare, and they have requested that we start to develop current procedural terminology codes so that physicians and oncologists have the ability to communicate with their patients through whatever method and are able to identify ways to communicate with patients.

Where is this going for the future? We need better clinical trials. We can define problems much earlier; this is about pattern recognition. As we start to work from a dashboard and manage patients, we will start to recognize important patterns that can affect how a patient feels and their risk for having an event. Conversely, patients will learn things they never recognized about their weight, their rhythm, symptoms that they have, and identify these things much earlier, so they can warn their healthcare providers and a decision can be made earlier. The learning curve is going to be very important in the future, both for the provider and the patient.

How would another practice implement this technology?

The most important thing for the future is patient engagement. We already know from many clinical trials and studies that the more the patient is engaged, the better their outcomes are. It is a win-win for the patient and a win-win for the healthcare provider, but also for a system through which patients have access to their doctors without physically having to get to their clinics all the time. 

They can communicate with their local cardiologist. Usually, this is done with an electrophysiologist, the field within cardiology. They are electricians, if you will, and they are already very savvy about the use of web-based technology, cellular technologies, and using dashboards to be able to identify diagnostic problems, as well as to treat. 

Delsigne, Jill. Implantable devices monitor for cardiac events in cancer survivors and patients on chemotherapy.

Jean-Bernard Durand, MD, discusses implantable cardiac devices and how patients may be able to continue their treatment regimen.

Remote Monitoring of Cardiovascular Symptoms in Patients With Cancer

Results from the multicenter phase I/II SCOOP trial exploring the combination of the stemness inhibitor napabucasin (BBI608) and the PD-1 inhibitor pembrolizumab (Keytruda) demonstrated an acceptable safety profile in patients with metastatic colorectal cancer (mCRC).

Phase I, which was presented during the 2018 Gastrointestinal (GI) Cancers Symposium, was designed to determine the recommended phase II dose. The phase II portion will explore the efficacy of the combination.

In the phase I portion, investigators established 480 mg twice daily of napabucasin as the recommended phase II dose along with 200 mg every 3 weeks of pembrolizumab. Investigators also conducted biomarker research using paired samples from repeated tumor biopsies and blood collections.

Five patients were enrolled at the level 1 dose (240 mg twice daily), and 3 patients at level 2 (480 mg twice daily). All patients had microsatellite stable (MSS) mCRC, 7 of whom were included in the safety analyses. Two patients at level 1 were excluded from the dose-limiting toxicity (DLT) analysis because of disease progression.

Enrollment criteria for the trial included ECOG performance status of 0 or 1, histologically-confirmed colon or rectal adenocarcinoma, and verification of the KRAS codon 12 and 13 status by RAS gene testing.

Regarding safety, absence of DLTs and grade 3 treatment-related adverse events (TRAEs) were reported in both levels. Grade 1/2 TRAEs included diarrhea (57%), hyperthyroidism (14%), hypothyroidism (14%), and fever (14%). One patient at the level 2 dose displayed a tumor shrinkage over a 12-week span for lung and lymph node metastases with substantial decline of carcinoembryonic antigen levels.

 Can you please provide some background on napabucasin?

during the GI Symposium, lead investigator Akihito Kawazoe, MD, of the Department of Gastroenterology and Gastrointestinal Oncology at the National Cancer Center Hospital East in Kashiwa, Japan, discussed the study of napabucasin plus pembrolizumab in mCRC.

 We know that pembrolizumab showed an objective response rate (ORR) of 40% in microsatellite instability-high (MSI-H) CRC. On the other hand, it showed an ORR of 0% in patients with MSS CRC. It has been reported that WNT/β-catenin signaling has been involved in the elimination of lymphocyte infiltration and resistance to anti—PD-1. CRC is a tumor in which we need better catenin signaling activation. Preclinical models show that napabucasin in combination with anti–PD-1 shows antitumor activity. Thus, we initiated a phase I/II study of napabucasin in combination with pembrolizumab for CRC.

What impact could this study have on clinical practice for mCRC?

What do you predict to be the next steps of this combination?

The study has 2 cohorts. Cohort A is MSI-H CRC, and the target number is 10. Cohort B is MSS CRC, with a target number of 40. 

The safety profile is tolerable and expected with no DLTs. We decided to recommend a phase II dose of napabucasin at 480 mg per day with pembrolizumab at a fixed dose. One patient on 480 mg per day of napabucasin showed remarkable shrinkage. Also, a biomarker analysis showed that [there was] CD8 infiltration inside the tumor; this was observed by immunohistochemistry and flow cytometry.

There are unmet medical needs for MSS CRC in the development of immunotherapy. We will have those promising results in this study, so that we can [hopefully] change the [state of] immunotherapy in MSS CRC by this combination of napabucasin and pembrolizumab. 

We can show the promising result in this phase I/II trial, so then [we can begin] the phase III trial for MSS CRC of this combination in the future.

Kawazoe A, Kuboki Y, Komatsu Y, et al. Multicenter phase I/II trial of BBI608 and pembrolizumab combination in patients with metastatic colorectal cancer (SCOOP Study): EPOC1503. 

Akihito Kawazoe, MD, discusses the study of napabucasin plus pembrolizumab in mCRC.

Caroline Seymour