Immune checkpoint inhibitors are revolutionizing the treatment of some genitourinary cancers. However, not all cancers respond to the drugs, and some responses are short-lived. In an effort to improve response rates and durations for patients with genitourinary cancers, clinical trials of new immune checkpoint inhibitors, drugs that target different immune pathways, and novel drug combinations are now enrolling patients with bladder, kidney, and prostate cancers.
Immune checkpoint inhibitors enhance the ability of T cells to fight cancer by blocking proteins such as CTLA-4 (cytotoxic T lymphocyte antigen 4), PD-1 (programmed cell death protein 1), and PD-L1 (PD-1 ligand)—all of which prevent T cells from finding and destroying cancer cells. Several PD-1 and PD-L1 inhibitors have been approved by the U.S. Food and Drug Administration (FDA) for treating bladder and kidney cancers, but immune checkpoint inhibitors have been less successful against prostate cancer.
In a series of ongoing clinical trials, researchers at The University of Texas MD Anderson Cancer Center hope to learn more about how different types of cancer respond to immunotherapy and to increase the responses of genitourinary cancers to immunotherapeutic agents. “We’re combining immune checkpoint inhibitors approved as monotherapy for bladder and kidney cancers with other agents,” said Padmanee Sharma, M.D., Ph.D., a professor in the Departments of Genitourinary Medical Oncology and Immunology and the scientific director of MD Anderson’s Immunotherapy Platform. “And we’ve developed strategies that may help immune checkpoint agents work better against prostate cancer.”
In the past year, five immunotherapy drugs have been approved by the FDA for treating metastatic bladder cancer. These were the first drugs approved for the disease in 2 decades. “People in the field are excited about these approvals,” said Jianjun Gao, M.D., Ph.D., an assistant professor in the Department of Genitourinary Medical Oncology. “But when the dust settled and we looked at these five agents given individually, their response rates ranged from approximately 15% to 25%. We hope that combining some of these agents will improve the response rates.”
Dr. Gao is the principal investigator of a clinical trial (No. 2016-0033) that combines the PD-L1 inhibitor durvalumab, which is FDA approved as a second-line treatment for patients with metastatic bladder cancer, with the CTLA-4 inhibitor tremelimumab. In this trial, the drug combination is given as neoadjuvant therapy for patients who have muscle-invasive urothelial carcinoma and poor kidney function, hearing loss, neuropathy, or heart failure—all of which contraindicate standard cisplatin-based chemotherapy.
“As many as 40% of patients with urothelial carcinoma have muscle-invasive disease and need neoadjuvant therapy,” Dr. Gao said. “But many of these patients also have other medical conditions that prevent them from getting standard cisplatin-containing neoadjuvant chemotherapy, so there is an urgent need to develop some alternative therapy for these patients. Neither of the immunotherapy agents used in the trial is known to significantly affect hearing or kidney function.”
As part of the trial, Dr. Gao and his colleagues will compare pretreatment biopsy specimens with posttreatment samples collected after radical cystectomy.
“Many of these immunotherapy drugs induce immune changes in the tumor microenvironment,” Dr. Gao said. “We may learn more about the mechanisms of response or, for patients whose disease doesn’t respond, the mechanisms of resistance.”
Blood samples taken before and after the completion of neoadjuvant immunotherapy will also be analyzed. Researchers in the Immunotherapy Platform will look for immunological changes in the blood and tumor samples.
To date, only one immune checkpoint inhibitor has been approved for kidney cancer. The FDA approved the PD-1 inhibitor nivolumab for the treatment of metastatic renal cell carcinoma in patients whose disease progressed during treatment with antiangiogenic agents. The approval resulted from a multi-institutional phase III trial (CheckMate 025, No. 2012-0869) comparing nivolumab to everolimus, the standard of care for such patients. Dr. Sharma was the trial’s principal investigator at MD Anderson and the senior author of its report, which showed that the median overall survival of patients who received nivolumab was significantly longer than that of patients who received everolimus.
“Now that we’ve established immune checkpoint inhibition as a second-line treatment for metastatic kidney cancer, we’re testing strategies to combine immune checkpoint inhibitors with other treatments in the metastatic disease setting,” Dr. Sharma said. She is currently the principal investigator of two clinical trials using this approach for patients with kidney cancer.
One of these trials (No. 2013-0715) is enrolling patients with metastatic renal cell carcinoma who have not previously been treated with immune checkpoint or VEGF (vascular endothelial growth factor) inhibitors. The patients are randomly assigned to receive treatment with nivolumab only, nivolumab and the VEGF inhibitor bevacizumab, or nivolumab and the CTLA-4 inhibitor ipilimumab. After treatment, all patients will undergo biopsy of a metastatic lesion or surgery to remove metastatic disease or an affected kidney.
The researchers will evaluate adverse events and objective responses (complete and partial responses) in the three treatment arms, and correlative studies will evaluate pre- and post-treatment samples for biomarkers of clinical response or resistance. Dr. Gao, a co-investigator of the trial, said, “This trial combining agents that target different pathways will evaluate both clinical outcomes and immunological data, which is similar in concept to our trial of neoadjuvant therapy in patients with bladder cancer.”
A preliminary analysis of 60 evaluable patients in the trial showed that all three treatment regimens were generally well tolerated and showed promising clinical activity. Drs. Gao and Sharma and their colleagues presented the preliminary findings at the 2017 annual meeting of the American Association for Cancer Research.
The other ongoing trial (No. 2013-0539) of treatment with an immune checkpoint inhibitor is enrolling patients with renal cell carcinoma and at least one metastatic lesion that is amenable to cryoablation. Patients are randomly assigned to receive tremelimumab only or cryoablation of one metastatic lesion followed by tremelimumab. All patients then undergo biopsy of a metastatic lesion or surgery to remove metastatic disease or an affected kidney.
Patients are allowed to continue receiving tremelimumab until the occurrence of disease progression or intolerable toxic effects. Dr. Sharma, the trial’s principal investigator, along with her colleagues will evaluate the clinical outcomes of patients in the trial’s two treatment arms.
“So far, single-agent immune checkpoint inhibitors have had lower response rates in patients with prostate cancer than in patients with other cancers,” said Sumit Subudhi, M.D., Ph.D., an assistant professor in the Department of Genitourinary Medical Oncology. “We’re working to understand why that is the case.”
Toward that goal, Drs. Subudhi, Gao, and Sharma and their colleagues have explored the microenvironments of primary prostate cancers and metastases from prostate cancers. Their findings led to clinical trials using three approaches to immune checkpoint inhibition: selecting patients according to their response to hormonal therapies, targeting both the CTLA-4 and PD-1/PD-L1 pathways, and focusing on macrophages rather than just T cells.
Immunotherapy and hormonal therapy
The backbone of therapeutic strategies for metastatic prostate cancer is hormonal agents that either reduce the production of testosterone or prevent testosterone from binding to the androgen receptor. In a recent trial (No. 2009-0378) of concurrent ipilimumab and a hormonal therapy that inhibits testicular production of testosterone, 10 of 24 patients with metastatic prostate cancer reached the trial’s endpoint of undetectable serum levels of prostate-specific antigen (PSA). However, the trial was stopped early because 12 patients experienced grade 3 toxic effects. Since that trial began, researchers have learned more about avoiding and managing the toxic effects of such drug combinations, and a new clinical trial of ipilimumab with different hormonal agents is under way.
In the DynaMO trial (No. 2014-0386), whose principal investigator is Ana Aparicio, M.D., an associate professor in the Department of Genitourinary Medical Oncology, patients with metastatic castration-resistant prostate cancer initially receive maximal hormonal blockade. This regimen comprises apalutamide (ARN-509), an experimental androgen receptor antagonist, plus abiraterone, an inhibitor of the androgen synthesis enzyme CYP17A1.
After 8 weeks of treatment, initial response is measured by a composite of changes in serum markers (e.g., PSA level and circulating tumor cell [CTC] count), radiographic findings, and clinical symptoms. A satisfactory response is defined as a PSA level decrease of 50% or more and a favorable CTC count with no clinical or radiographic indications of disease progression.
Patients with satisfactory responses are randomly assigned to have ipilimumab added to apalutamide and abiraterone or to continue the regimen without ipilimumab. Dr. Subudhi noted that about 95% of patients whose responses are not classified as satisfactory still derive some benefit from the regimen. Therefore, patients without satisfactory responses continue to receive apalutamide and abiraterone with the addition of standard chemotherapy drugs (cabazitaxel plus carboplatin).
The trial’s primary outcome measures are overall survival and the toxicity profile of each drug combination.
“We know from previous studies that approximately 70% of patients will have satisfactory responses to maximal hormonal blockade,” Dr. Subudhi said. “And we hypothesize that the patients in this study who receive immune checkpoint inhibition will have the best overall survival.”
Targeting the PD-1 and CTLA-4 pathways
One reason PD-1 and PD-L1 inhibitors have been ineffective against prostate cancer in previous trials is that prostate cancer cells and the surrounding immune cells normally do not express high levels of either protein. However, Dr. Subudhi said, “We’ve learned that PD-1 and PD-L1 are upregulated in the prostate tumor microenvironment as a resistance mechanism to treatment with certain agents.” For example, treatment with ipilimumab alone can upregulate PD-1 and PD-L1 expression in the prostate cancer microenvironment (see figures). This finding provided the rationale for combining checkpoint inhibitors to target both the CTLA-4 and PD-1/PD-L1 pathways in two new clinical trials for prostate cancer patients.
“Our mouse studies indicated that combinations such as nivolumab plus ipilimumab or durvalumab plus tremelimumab can be successful in a subset of patients with prostate cancer,” Dr. Subudhi said. “So we’re hoping that these trials will have a higher proportion of patients with durable responses than we’ve seen in trials of monotherapy with such agents.”
The first trial (No. 2016-0848) is a phase II study in which patients with metastatic castration-resistant prostate cancer receive up to four doses of nivolumab plus ipilimumab followed by nivolumab monotherapy until disease progression or unacceptable toxic effects occur. The trial’s primary outcome measures are objective response rate according to Response Evaluation Criteria in Solid Tumors and progression-free survival. Dr. Sharma, the trial’s principal investigator, expects preliminary results to be available in late 2018.
The second trial (No. 2016-0769) is a pilot study in which patients receive up to four doses of durvalumab and tremelimumab for 4 months followed by durvalumab monotherapy for 9 months. The trial’s primary outcome measure is toxic effects, and the secondary outcome measure is progression-free survival as measured by PSA level changes.
Also, the researchers are performing serial bone biopsies on every patient in the pilot trial to understand how the drugs affect the bone microenvironment. “When prostate cancer metastasizes, 80% of the metastases go to the bone. And our recent data suggest that the bone immune microenvironment is vastly different from what we see in the prostate,” Dr. Subudhi said. These biopsies may provide valuable information that could not be obtained in previous studies because many trials exclude patients who have only bone metastases.
Dr. Subudhi thinks that combining immune checkpoint inhibitors with drugs that target macrophages may benefit patients with prostate cancer. One such drug is daratumumab, which depletes CD38-expressing immune cells (including macrophages) and cancer cells and is approved by the FDA for treating multiple myeloma.
“There are good macrophages and bad macrophages,” Dr. Subudhi said. “And our studies indicate that prostate cancers have a lot of these bad macrophages.”
Dr. Subudhi is the principal investigator of a pilot trial of daratumumab in patients with prostate cancer (No. 2017-0103). Eligible for the trial are patients with high-risk (at least one biopsy core with a Gleason score of 8 or higher) localized adenocarcinoma of the prostate; patients with small cell, transitional cell, or neuroendocrine carcinomas are excluded. Patients in the trial also must be candidates for radical prostatectomy plus pelvic lymph node dissection. All patients receive weekly daratumumab for 4 weeks before surgery.
Dr. Subudhi said that the trial’s protocol is being amended to add a drug that inhibits CSF1R (macrophage colony-stimulating factor 1 receptor), which is expressed on tumor-associated macrophages in prostate cancer.
The trial’s outcome measures include toxic effects and pathological complete response, defined as an absence of residual tumor in the surgical specimen. Although Dr. Subudhi expects targeting macrophages to benefit some patients, future studies of daratumumab and similar drugs in patients with prostate cancer will likely include immune checkpoint inhibitors. “We may need a combination of therapies that target macrophages and therapies that target T cells,” Dr. Subudhi said.
Moving the field forward
By combining immune checkpoint inhibitors that have different targets and by combining immune checkpoint inhibitors with other treatments for patients with genitourinary cancers, Drs. Gao, Sharma, and Subudhi hope to improve response rates and the duration of responses.
“Physicians and patients should be aware that there are ongoing trials of immunotherapy for patients with genitourinary cancers,” Dr. Sharma said. “And we expect to move the field forward so that we will have effective immunotherapy strategies for patients with these malignancies.”
For more information, contact Dr. Jianjun Gao at 713-563-4195 or firstname.lastname@example.org, Dr. Padmanee Sharma at 713-792-2830 or email@example.com, or Dr. Sumit Subudhi at 713-792-2830 or firstname.lastname@example.org. To learn more about clinical trials for patients with genitourinary cancers, visit www.clinicaltrials.org and search by trial number or cancer type.
Gao J, Ward JF, Pettaway CA, et al. VISTA is an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer. Nat Med. 2017;23:551–555.
OncoLog, January 2018, Volume 63, Issue 1