John Otrompke

Newer immunotherapies being used in kidney cancer can help create a dramatic, durable response, but only in a small subset of patients, according to David F. McDermott, MD. Methods of expanding on progress seen in the field of immunotherapy, both in the case of kidney cancer and other tumor types, was the subject of McDermott&rsquo;s presentation at the PER&reg; European Congress on Immunotherapies in Cancer held in Barcelona.

Researchers have been exploring the PD-1/PD-L1 blockade for many years, as immunotherapy agents of this kind have seen successes in melanoma, lung cancer, and more. McDermott called single-agent therapy targeting the PD-1 pathway blockade the new standard of care for patients with renal cell carcinoma (RCC).

Nivolumab (Opdivo), a PD-1 checkpoint inhibitor, was approved by the FDA for use as a second-line therapy for metastatic RCC in 2015 following the results of the CheckMate-025 trial.

McDermott, assistant professor of Medicine at Dana-Farber/Harvard Cancer Center, pointed out that the trial, which compared nivolumab to the mTOR inhibitor everolimus (Afinitor), showed both statistically significant and clinically meaningful improvements in overall survival (OS).

The median OS for nivolumab was 25 months (95% CI, 21.8-not estimable) compared with 19.6 months (95% CI, 17.6-23.1) with everolimus (HR, 0.73; 98.5% CI, 0.57-0.93;

= .002). The objective response rate (ORR) with nivolumab was 25% versus 5% with everolimus (

&ldquo;This is probably one of the cleanest trials in the history of kidney cancer because not only did we see improvements in overall survival but we also saw improvements in safety and quality of life. And this story has been played out in multiple tumor types,&rdquo; McDermott said.

Many patients also experienced a durable benefit with this immunotherapy treatment. Long-term follow-up for patients treated with nivolumab in the phase I and II trials, in data presented by McDermott at ASCO this year, showed that about one-third of the patients were still alive at &ge;4 years.

However, McDermott also mentioned that a majority of patients were not retaining the bene t of the treatment or needed to stay on the drug for an extended period of time.

The development of biomarkers is one of the ways that researchers hope to find patients that may benefit most from these treatments and give those patients a more durable remission. Various approaches are being explored to improve predictive biomarkers, McDermott said, including CD-8 T cells and PD-L1 expression at the invasive margin, clonality of T cells in the tumor, mutational frequency, neo-epitope signature, in ammatory gene expression pattern, and tumor histology. Together, McDermott said, they may provide a richer model that will hopefully help researchers select the best treatments for these patients going forward.

PD-L1 does not work as a solitary predictor of outcome in kidney cancer, however, or as a means of selecting patients, especially since when looking at tumor biopsies for PD-L1 expression, one biopsy alone may not provide a good representative sample, McDermott said, which may explain why some PD-L1negative patients have a prolonged benefit. For example, in the nivolumab phase III trial, patients with negative PD-L1 expression had higher median OS compared with PD-L1&ndash;positive patients on nivolumab (27.4 vs 21.8 months, respectively).

A study of the difference in PD-L1 expression between the primary tumor and metastases sites in RCC showed a 20% discordance in expression between the tumors.

A needle biopsy of the primary tumor is therefore not suf cient for a representation of the patient&rsquo;s predicted outcome.

&ldquo;In the ideal setting, we believe that when you&rsquo;re deciding about immunotherapy for a patient&rsquo;s kidney cancer, you should probably biopsy the metastasis soon before you&rsquo;re starting treatment, and you should be considering an excisional biopsy,&rdquo; said McDermott.

Exploring combination therapies including immunotherapy agents is another way in which researchers are hoping to increase durable responses as additional therapies may help to overcome innate or acquired resistance.

A small trial explored combined VEGF blockade and PD-L1 checkpoint inhibition with bevacizumab (Avastin) and atezolizumab (Tecentriq), and the patients with RCC demonstrated a 40% ORR with partial responses in 4 of the 10 patients. Six patients were still on the combination therapy after 15 months.

The study also found that there were increases in intratumoral CD8+ T cells post treatment with both drugs, as well as decreases in vascular gene signature and upregulation of immune effector gene signatures. Ongoing clinical trials are needed to continue to explore the additional effect of VEGF blockade on these patients.

&ldquo;When you talk about combinations, not every combination is a good one,&rdquo; McDermott cautioned. A phase I/II trial of pazopanib (Votrient) and pembrolizumab (Keytruda) for patients with metastatic RCC encountered considerable hepatotoxicity.

Not all combination treatments will perform as well as the combination of nivolumab and ipilimumab in melanoma.

When exploring combination therapies, it needs to be considered whether or not the agents together would perform better than separately in sequence, McDermott suggested, and whether or not the benefits outweigh the costs that come with additional treatments. A complete remission, for example, would outweigh all costs.

Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015;373(19):1803-1813.

McDermott DF, Motzer RJ, Atkins MB, et al. Long-term overall survival (OS) with nivolumab in previ- ously treated patients with advanced renal cell carcinoma (aRCC) from phase I and II studies. Pre- sented at: the 2016 ASCO Annual Meeting; June 3-7, 2016; Chicago, IL. Abstract 4507.

Callea M, Albiges L, Gupta M, et al. Di erential Expression of PD-L1 between Primary and Metastatic Sites in Clear-Cell Renal Cell Carcinoma. Cancer Immunol Res. 2015;3(10):1158-1164.

Wallin JJ, Bendell JC, Funke R, et al. Atezolizumab in combination with bevacizumab enhances anti- gen-speci c T-cell migration in metastatic renal cell carcinoma. Nat Commun. 2016;7:12624.

McDermott DF, Infante JR, Chowdhury S, et al. A Phase I/II study to assess the safety and e cacy of pazopanib (paz) and pembrolizumab (pembro) in patients (pts) with advanced renal cell carcinoma (aRCC). Presented at: the 2015 ESMO Annual Meeting; September 25-29, 2015; Vienna, Austria. Abstract 2622.

Articles

David F. McDermott, MD, discusses methods of expanding on progress seen in the field of immunotherapy, both in the case of kidney cancer and other tumor types at the PER&reg; European Congress on Immunotherapies in Cancer held in Barcelona.

Expanding the Reach of Immunotherapies for Kidney Cancer

The second revision of the 2016 guidelines on bladder cancer from the National Comprehensive Cancer Network (NCCN) contains substantial changes from past versions, including, for the first time, a reference to molecular profiling as a permissible consideration for treatment decision making. Research has identified tumor mutations in some 236 cancerrelated genes as potential subjects of study in clinical trials, although there are, as of yet, no FDA-approved mutation-specific targeted therapies in bladder cancer.

The NCCN&rsquo;s recommendation for molecular testing could make a considerable difference in increasing the amount of trials and targeted therapies in the long run for subtypes of patients with bladder cancer.

NCCN Guidelines Suggest Molecular Testing

&ldquo;The whole Principles of Imaging section6 pages worth outlining the appropriate use of imaging and varying modalities one would use across various stages of the disease&mdash;is brand new, as are many other supplemental sections,&rdquo; said Peter Clark, MD, professor of urologic surgery at Vanderbilt University Medical Center, and chair of the NCCN guidelines panel for bladder cancer. While some changes seem to have come quickly, acceptance of molecular profiling, by contrast, has been developing slowly.

The guidelines for metastatic disease now contain a footnote acknowledging that molecular imaging is an option. &ldquo;That&rsquo;s new, and from a medical oncology perspective, it represents a substantial change,&rdquo; explained Sumanta Kumar Pal, MD, assistant professor in genitourinary oncology and medical oncology at the City of Hope Comprehensive Cancer Center, in Duarte, California.

Prior to this there was no consensus regarding whether molecular testing is appropriate, and it had not been referred to in the guidelines. &ldquo;This particular statement acknowledges the fact that bladder cancer is a very heterogeneous disease, and we might be able to exploit multiple targets,&rdquo; explained Pal, who also serves on the NCCN panel. However, there are no targeted therapies that are currently approved for use for advanced bladder cancer, Pal said, so they cannot be included in the guidelines.

&ldquo;As it stands right this second, we really don&rsquo;t have any of these targeted agents which exist in other diseases, like lung, breast, and kidney cancer, specifically approved in bladder cancer. There is a school of thought that would say for certain patients, if standard therapies started to not workfor example, if the patient developed metastatic bladder cancer&mdash;if you&rsquo;re looking at what to do next, a consideration would be perhaps molecular profiling, and perhaps an off-label use of another agent that targets that pathway,&rdquo; Clark explained.

Experimental Options for Patients With Advanced Disease

&ldquo;What we&rsquo;re really trying to do with molecular testing is to exploit the genetics of patients with advanced bladder cancer,&rdquo; noted Pal. In a recent

in support of molecular testing, Pal, the lead author, noted that researchers have found that 93% of patients with advanced bladder cancer have clinically relevant mutations that make them viable for studies of potential targeted agents.

Researchers studied 295 cases of relapsed/metastatic urothelial carcinoma to test for frequent genomic alterations, and found 75 individual genes. The most clinically relevant alterations found included

&ldquo;We need to start steering patients toward clinical trials to explore therapies,&rdquo; he added. &ldquo;Right now the dilemma is that individuals in the community do not order these tests, so the change in the guidelines gives physicians in the community the opportunity to order profiling in a way that may facilitate patient care,&rdquo; he said. While molecular profiling may prove important to progress in developing a cure for bladder cancer, as it has in other fields, several concerns have led the NCCN committee to be cautious.

&ldquo;The single biggest unknown is whether or not its use actually impacts survival,&rdquo; explained Clark, who added that the cost of the tests is also a factor. &ldquo;It can be expensive, and I don&rsquo;t know to what degree insurance covers it; patients may end up having to pay for it themselves,&rdquo; he noted.

Clinical trials are underway exploring if these mutations can be targeted for a more beneficial treatment for subsets of patients with advanced bladder cancers.

A phase I study of BGJ398, a selective pan-FGFR inhibitor, for example, found antitumor activity in patients with

The trial included 5 patients with urothelial carcinoma with

activating mutations, and of these patients, 4 demonstrated a reduction in tumor size of 27% to 48%.

BGJ398 is now being explored in a pilot study for patients with nonmuscle invasive urothelial carcinoma (NCT02657486), as well as in a phase II trial for patients with tumors, both solid and hematologic malignancies, with

alterations (NCT02160041). For patients with

mutations, afatinib (Gilotrif), an irreversible inhibitor that targets the ErbB family, has shown activity in patients with metastatic urothelial carcinoma.

alterations achieved progression-free survival of at least 5 months (range, 5.0-10.3) compared with 15 patients without an alteration (

<.001). The median time to progression in these patients was 6.6 months versus 1.4 months for patients without an alteration.

Afatinib was approved by the FDA in July 2013 as a first-line treatment for patients with nonsmall cell lung cancer with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations. An ongoing phase II open-label study is exploring afatinib for patients with metastatic urothelial carcinoma following progression on a platinum-based chemotherapy (NCT02780687).

The issue is, however, that none of these treatments have yet been approved for use in bladder cancer by the FDA and are still a long way off from consideration. &ldquo;I am not in any way trying to advocate the use of nonFDA-approved agents in bladder cancer,&rdquo; Clark stated. Yet these new agents can target specific oncogenic pathways that already approved treatments cannot.

A Historical Interest in Molecular Profiling

Notwithstanding the fact that it has been slow to adopt principles calling for molecular testing in bladder cancer patients, the NCCN has a history of interest in molecular testing. In 2011, the NCCN published a white paper on the effectiveness of molecular testing, in light of an FDA guidance issued that same year.

The organization has also compiled a list of available assays, according to oncologist Paul Engstrom, MD, professor of medicine at Temple University Medical Center in Philadelphia, and the lead author on the 2011 white paper.

&ldquo;It certainly has an effect on what treatment might be utilized in that patient, and in some cases the profile may identify patients with a poor prognosis that need more intensive therapy. The position of NCCN is that molecular testing of tumors can be a valuable way of defining mutations that might contribute to precision treatments that effect only a small part of the metabolism of the tumor, and cause remissions with less toxicity,&rdquo; said Engstrom, who is currently on the NCCN committee that sets guidelines for colon, rectal, and anal cancer.

The hope of the increased support by the NCCN for molecular profiling is that it may increase the accessibility and frequency of genetic testing. With more cancer-specific genetic information available, patients can be pointed toward clinical trials that could benefit from increased recruitment numbers. Further trials could also lead to more targeted agents for the treatment of patients with advanced bladder cancer eventually being accepted by the FDA and incorporated into future guidelines.

One of the other major additions to version 2 of the 2016 NCCN guidelines was the inclusion of atezolizumab (Tecentriq), which also speaks to the importance of molecular analysis, according to Pal. Molecular profiling can also be used to detect mutational load and molecular subtypes of tumors, which may help in predicting a patient&rsquo;s sensitivity to immunotherapy approaches, such as PD-1/PD-L1 inhibition.

Atezolizumab, a PD-L1 inhibitor, was approved in May as a second- line treatment for patients with advanced bladder disease based on results of the phase II IMvigor 210 trial.

The drug showed an overall response rate of 14.8% in patients with locally advanced or metastatic urothelial carcinoma regardless of PD-L1 expression, which rose to 26% for patients with PD-L1 expression &ge;5%.

&ldquo;Immunological drugs like atezolizumab are not offered in a mutation-specific context, but it is important to keep in mind that response rates imply that less than a quarter of the patients will respond to therapy. Most responses are partial, yet there is the potential for a complete response, and I think that lends itself to the importance of molecular testing,&rdquo; he said.

&ldquo;There is a lot of research taking place trying to look at the role for immune therapy, given the newfound role for atezolizumab for second-line treatment, and trying to make those links between particular genetic mutations,&rdquo; said Clark, who noted that meetings will soon take place among the members of the NCCN panel to discuss the 2017 guideline revisions. &ldquo;For example, we need to figure out what to do with nonmuscle invasive bladder cancer that has become refractory to treatment.&rdquo;

NCCN. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines&reg;), Bladder Cancer Version 2.2016. https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf. Published June 23, 2016. Accessed September 29, 2016.

Pal S, Agarwal N, Boorjian S, et al. National Comprehensive Cancer Network Recommendations on Molecular Profiling of Advanced Bladder Cancer. [Published online July 25, 2016]

Ross JS, Wang K, Khaira D, et al. Comprehensive genomic profiling of 295 cases of clinically advanced urothelial carcinoma of the urinary bladder reveals a high frequency of clinically relevant genomic alterations.

Sequist LV, Cassier P, Varga A, et al. Phase I study of BGJ398, a selective pan-FGFR inhibitor in genetically preselected advanced solid tumors. Presented at: 2014 AACR Annual Meeting; April 5-9, 2014; San Diego, CA.

Choudhury NJ, Campanile A, Antic T, et al. Afatinib Activity in Platinum-Refractory Metastatic Urothelial Carcinoma in Patients With ERBB Alterations.

Engstrom P, Bloom M, Demetri G, et al. NCCN Molecular Testing White Paper: Effectiveness, Efficiency, and Reimbursement.

Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial.

The recommendation for molecular testing made in the&nbsp;second revision of the 2016 guidelines on bladder cancer&nbsp;from the National Comprehensive Cancer Network (NCCN)&nbsp;could&nbsp;make a considerable difference in increasing the amount of trials&nbsp;and targeted therapies in the long run for subtypes of patients&nbsp;with bladder cancer.

Molecular Profiling on the Uptake for Increased Targeted Therapies in Bladder Cancer

A set of guidelines for treating patients with relapsed and refractory multiple myeloma published by the International Myeloma Working Group (IMWG) guides general oncologists in making treatment decisions. As treatment options have grown both more promising and complex in the last two years, with the approval of at least 4 new drugs in 2015 alone, and with patients surviving, on average, for 10 years following diagnosis, decisions over which treatment to use have grown more complicated.

The IMWG recommendations published in February in

however, may not aid researchers in identifying ideal treatment paths for those with relapsed and refractory disease until more genomic data has been gathered.

To that end, physicians can look to results from the CoMMpass trial, a genomic study of 1,000 individuals with multiple myeloma being conducted by Baylor University and the Translational Genomics Research Institute (TGen) (NCT01454297), with interim results expected to be presented at the annual meeting of the American Society of Hematology (ASH) this December in San Diego.

Effective New Options Make Treatment Complex

&ldquo;For induction, we have a pretty good algorithm; we&rsquo;re moving toward triplet therapy with a proteosome inhibitor and immune-modulatory drug (IMiD),&rdquo; said Philip McCarthy, MD, professor of oncology and internal medicine at the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo.

&ldquo;But for relapsed patients, we have to look at whether they are eligible or ineligible for an autologous stem cell transplant, because they could potentially get a second transplant, which makes it a little more complicated,&rdquo; added McCarthy, a co-author of the February recommendations.

&ldquo;The recommendations are a bit of a laundry list for the poor community oncologist who treats 40 different cancers. Those with myeloma may be less than 5% of his case mix, and he has so many choices that we try to help guide him,&rdquo; said Joseph Mikhael, MD, professor of medicine at the Mayo Clinic in Phoenix.

"For example, we do have evidence some of these drugs work better in those with high-risk disease. And drugs like monoclonal antibodies have really minimal side effects, and so are more feasible to combine together with other drugs. Or perhaps the patient lives two-and-a-half hours away, and it&rsquo;s hard to give them carfilzomib twice a week intravenously, when we have a different drug we could offer them,&rdquo; added Mikhael, who co-authored another set of guidelines from IMWG last December on the use of stem cell transplants in myeloma patients with relapsed or refractory disease.

Recent Papers Meta-Analyze Clinical Trials

The mere existence of many alternatives does not mean that oncologists cannot simply repeat the treatment that produced the first remission; the guidelines suggest that &ldquo;in patients who experience a high-quality, prolonged response with minimal toxicity to initial therapy, re-treatment can be considered if they have obtained at least a 6 to 9 months&rsquo; treatment-free interval.&rdquo;

Thereafter, the guidelines get somewhat more complicated. The paper analyzes reports of clinical trials and discusses a multitude of options and a dizzying array of combinations of old drugs, including thalidomide, cyclophosphamide, and prednisone, as well as newer agents, like pomalidomide, and other treatments.

The article also discusses allogenic and autologous stem cell transplants (ASCT), recommending an autologous transplant for patients who have not had an ASCT in the first-line setting before, or who had a durable response to a prior ASCT.

The authors also recommend &ldquo;allogeneic stem cell transplantation be discussed in eligible patients with poor prognostic features, preferably in the context of a clinical trial.&rdquo; According to the December report of the stem cell consensus conference, only 3% to 5% of patients who relapse following an autologous transplant go on to receive an allogenic transplant; the February recommendations suggest this may be due to graft-versus-host disease or other forms of treatment-related mortality.

Two other recent articles also performed a meta-analysis and a review of the literature for treating relapsed myeloma patients.

Anticipating CoMMpass Trial Interim Results

Researchers have not yet determined what distinguishes the fraction of myeloma patients who survive for 20 years. However, an important clinical trial, &ldquo;Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile&rdquo; (CoMMpass), is investigating the role of genomics.

&ldquo;The expected survival in this cohort is in the range of a decade, and we expect 20% to 30% of patients to live two decades,&rdquo; said Jonathan Keats, PhD, director of bioinformatics at the Translational Genomics Research Institute (TGen) in Phoenix, which is collaborating on the study.

&ldquo;Our goal is to identify genetic biomarkers that predict response to specific therapies. We&rsquo;re looking at genes of significance numbering around 20 right now. With a year of follow-up data for this cohort we hope to be able to identify which treatment regimens are most effective given a certain genetic phenotype at baseline,&rdquo; Keats added.

The trial organizers intend to correlate molecular profiles and genomic tests on bone marrow aspirates from 1,000 patients at baseline with primary and secondary outcomes at 1- and 5-years follow-up, and survival at 8 years. Each of the arms will receive an immunomodulatory agent, a proteosome inhibitor, or both, and physicians can also add additional therapies, and/or transplants. Interim results from the study are expected to be announced at ASH later this year.

New Genomic Analysis for Relapsed Patients

&ldquo;Seventy percent of patients do poorly, but 30% do fine. In one case we&rsquo;ve conclusively showed what sets the two groups of patients apart. Tumor protein 53 has been implicated in myeloma, but the hypothesis has been that if the patient has two hits, they&rsquo;re at high risk. We&rsquo;ve shown that the biology of a tumor suppressor does matter, if they do not fit the two-hit hypothesis, in other words, if they have just one hit. Clinically, we just test for one hit,&rdquo; explained Keats.

Experts say that genetic analysis should be part of the standard of care for myeloma patients, and when a patient relapses, the genetic expression of the cancer should be re-analyzed.

Some scientists have determined that 15% of myeloma patients have a high-risk gene signature, so oncologists should initially do a cytogenetic analysis looking at chromosome abnormalities, and fluorescence in situ hybridization (FISH). It&rsquo;s still not done everywhere, but it should be, and it&rsquo;s getting better,&rdquo; said McCarthy.

&ldquo;And when patients relapse, they definitely need to be FISHed again at a minimum, because of clonal infidelity. You can see changes that pop up that were not there on the original diagnostic sample. If you look at the new ones, the old ones may be gone. It&rsquo;s not just one cancer all the time,&rdquo; he added.

Laubach J, Garderet L, Mahindra A, et al. Management of relapsed multiple myeloma: recommendations of the International Myeloma Working Group.

Giralt S, Garderet L, Durie B, et al. American Society of Blood and Marrow Transplantation, European Society of Blood and Marrow Transplantation, Blood and Marrow Transplant Clinical Trials Network, and International Myeloma Working Group Consensus Conference on Salvage Hematopoietic Cell Transplantation in Patients with Relapsed Multiple Myeloma.

Liu L, Zhao N, Xu W, et al. Pooled analysis of the reports of carfilzomib, panobinostat, and elotuzumab combinations in patients with refractory/relapsed multiple myeloma.

Zou Y, Ma X, Yu H, et al. Carfilzomib/pomalidomide single-agent or in combination with other agents for the management of relapsed/refractory multiple myeloma: a meta-analysis of 37 trials. [Published online July 21, 2016]

<p>A set of guidelines for treating patients with relapsed and refractory multiple myeloma published by the International Myeloma Working Group may not aid&nbsp;researchers in identifying ideal treatment paths for those with relapsed and refractory disease until more genomic data has been gathered.</p>


Insight into Drug Therapy and Stem Cell Transplant Options for Relapsed Myeloma Patients

Approximately four years after the FDA approval of two powerful new oral androgen-targeting agents for metastatic castration-resistant prostate cancer (mCRPC), an analysis raised issues complicating treatment with the two drugs, as well as what oncologists don&rsquo;t yet know.

serves to heighten clinical awareness of the potential for both under-treatment and over-treatment with abiraterone acetate, as well as potential drug-drug interactions with both abiraterone acetate and enzalutamide.

The paper also takes a position on a discrepancy between the labeling approvals by the FDA and EMA. While regulatory agencies of both regions suggest that clinicians should avoid using enzalutamide along with strong CYP3A inducers such as oxycodone or methodone, the FDA suggests that an elevated dose of the cancer drug may be feasible when such co-administration cannot be avoided. In the article the authors hypothetically adopt the FDA&rsquo;s position.

Common Drug-Drug Interactions May Be Manageable

&ldquo;Prostate cancer patients tend to be in their sixth, seventh and eighth decades of life, so some of them are on many medications,&rdquo; said Robert Dreicer, MD, professor of medicine and urology at the University of Virginia, who commented on the paper in an interview with

. &ldquo;But I don&rsquo;t look at this as a deal breaker. Most of the time the interactions can be managed without having to stop the other drugs.&rdquo;

Abiraterone acetate and enzalutamide are thought to work by blocking secondary processes for prostate cancer growth. The primary treatment for patients with prostate cancer is to block the production of testosterone (the hormone that initially drives the tumor), but all patients will ultimately develop mCRPC.

&ldquo;As to how cancer cells become resistant to the lack of testosterone, there are many hypotheses,&rdquo; said Jorge Garcia, MD, department of Hematology and Oncology, Cleveland Clinic.

&ldquo;The first source of growth for the tumor is the androgen receptor, an antenna activated by the male hormone testosterone, but in the absence of that hormone, how can you still have growth through that antenna? Another pathway is the adrenal gland, which produces early androgens that can mimic testosterone and therefore activate the receptor,&rdquo; explained Garcia, who is the principal investigator in an ongoing clinical trial of enzalutamide following radical prostatectomy (NCT01927627).

While oncologists have used androgen-targeting agents before, the two newer agents are more powerful, and unlike the previous intravenous drugs, are available in oral form. However, both drugs effect the CYP system of enzymes, and are metabolized in the liver.

&ldquo;Many drugs do that, so if the drugs are competing for the same breakdown pathway, the drug may be metabolized more slowly,&rdquo; explained Dreicer.

In conducting their review of available literature, researchers Benoist et al conducted a search of the PubMed and EMBASE databases for full-text articles in English describing studies done in humans and published no later than February 22, 2016 for a total of 22 papers. Benoist and colleagues also included registration data from the regulatory agencies and data from clinicaltrials.gov.

Other commonly-used drugs which may have interactions with abiraterone acetate and enzalutamide include the commonly prescribed cholesterol agent gemfibrocil, rifampicin (prescribed for tuberculosis), the cough suppressant dextromethorphan, the diabetes drug pioglitazone, and, potentially, acid-reducing agents for GERD.

According to a drug interaction study carried out by Gibbons and colleagues, gemfibrozil, a CYP2C8 inhibitor, increased the exposure of enzalutamide 2.2-fold. Itraconazole increased the exposure 1.3-fold, and rifampicin decreased the exposure by 66%.

Therefore, the dosage of enzalutamide should be reduced to 80 mg per day when used in combination with CYP2C8-inhibiting drugs, according to the reviewers.

While an older prostate cancer drug, ketoconazole, also has an inhibitory effect on abiraterone acetate, it is not commonly used in patients on the newer agent, so the effect is clinically irrelevant, the paper said.

Additionally, not only should care be taken when co-administering enzalutamide with anti-seizure medication, but enzalutamide has also been associated with seizures even in patients without a known seizure disorder, Gibbons et al wrote in the article. The authors noted that regulators had requested a post-marketing safety trial to assess the risk.

&ldquo;Enzalutamide crosses the brain-blood barrier and competes with chloride channels in GABA receptors. Seizure activity was seen in the AFFIRM trial in 0.9% of patients on enzalutamide and 0.1% of patients, 1 to be exact, in the PREVAIL trial. However, the neurocognitive dysfunction from enzalutamide is far more important than seizure activity (just by incidence),&rdquo; explained Garcia in an email interview.

Dosing According to Bioavailability Factors

Not only are drug interactions a potential issue for abiraterone acetate and enzalutamide, but research shows that several factors beyond co-administration may affect the drugs&rsquo; activity, opening up the possibility for a wide variety of dosing strategies that have not yet been sufficiently researched, according to the review.

Due to a wide variation in the bioavailability of abiraterone, &ldquo;hypothetically, a subgroup of patients will be undertreated at the normal dose of 1000 mg once daily,&rdquo; researchers noted.

On the other hand, according to several studies cited by the article, the bioavailability of the drug was between 2 and 17 times greater in patients who took the drug after a meal, compared with those who took the drug without food, although regulators recommend that abiraterone acetate be taken in fasting conditions. These findings merit further research, according to the article.

Yet again, the authors noted that oncologists have sometimes used a drastically reduced dose of abiraterone in patients with severe hepatic impairment. In one such study, patients with severe liver impairment received a greatly reduced dose (125 mg) compared with the healthy volunteers (2000 mg), the article noted. Other research showed that the half-life of the drug only increased by a little over three hours, even in patients with severe renal impairment.

Notwithstanding the dosing and drug interaction issues, these two agents have provided a much-needed line of treatment options for patients with advanced disease. Yet neither drug is a cure.

&ldquo;These drugs are pretty amazing; they&rsquo;ve really revolutionized the way we treat prostate cancer,&rdquo; said David Jarrard, MD, professor of urology at the University of Wisconsin Carbone Cancer Center. &ldquo;Both are well-described and have been studied in tens of thousands of patients. The interactions can be managed just by keeping an eye on the patient&rsquo;s liver function tests to make sure patients don&rsquo;t get in trouble.&rdquo;

Neither age, testosterone levels, nor BMI have been shown to affect abiraterone exposure, and the drug appears to have the same pharmacokinetics in Asians as in Caucasians.

But research is lacking for other biomarkers, the article said, noting that &ldquo;[n]o formal studies have been conducted to assess the influence of age, weight, height, or genetic polymorphisms on drug exposure and treatment response.&rdquo;

&ldquo;The biggest questions right now are, &lsquo;What is the appropriate sequence and what is the right phenotype?&rsquo;&rdquo; explained Garcia.

For example, in a 2014 study of 62 men with prostate cancer patients, researchers showed that a mutation in the androgen-receptor isoform encoded by splice variant seven, which lacks the ligand-binding domain that enzalutamide and abiraterone target, plays an important role in the effect of both drugs.

&ldquo;They proved that if patients have that variant, the likelihood of benefit from either drug is close to zero,&rdquo; noted Garcia.

&ldquo;Both drugs are in a myriad of clinical trials, particularly in combination with other novel agents such as sipuleucel, radium 223, and likely upcoming studies with PARP inhibitors,&rdquo; added Dreicer.

Benoist G, Hendriks R, Mulders P, et al. Pharmacokinetic Aspects of the Two Novel Oral Drugs Used for Metastatic Castration-Resistant Prostate Cancer: Abiraterone Acetate and Enzalutamide. [Published online April 22, 2016.]

Gibbons JA, de Vries M, Krauwinkel W, et al. Pharmacokinetic drug interaction studies with enzalutamide.

European Medicines Agency. European Public Assessment Report (EPAR): Zytiga (abiraterone acetate). London: European Medicines Agency; 2016.

Antonarakis ES, Lu C, Wang H, et al. AR-V7 and Resistance to Enzalutamide and Abiraterone in Prostate Cancer.

<p>Approximately four years after the FDA approval of two powerful new oral androgen-targeting agents for metastatic castration-resistant prostate cancer, an analysis&nbsp;heightened&nbsp;clinical awareness of the&nbsp;potential for both under-treatment and over-treatment with abiraterone acetate, as well as potential drug-drug interactions with both abiraterone acetate and enzalutamide.</p>


John Otrompke | Authors

Articles

Expanding the Reach of Immunotherapies for Kidney Cancer

Molecular Profiling on the Uptake for Increased Targeted Therapies in Bladder Cancer

Insight into Drug Therapy and Stem Cell Transplant Options for Relapsed Myeloma Patients

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