Dr. Emmanuel Antonarakis is an Associate Professor of Oncology and Urology at the Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center.
Prostatepedia spoke with him recently about his clinical trial combining Provenge (sipuleucel-T) with Xofigo (radium-223).
What is the thinking behind your clinical trial?
Dr. Emmanuel Antonarakis: There is a lot of interest in combining immune therapies with other drugs to make immunotherapy work better.
The FDA approved Provenge (sipuleucel-T) in 2010. We’ve been using that drug for the last seven years. We’ve seen that patient survival improves by approximately three to four months on Provenge (sipuleucel-T) compared to a placebo.
However, we don’t typically see PSA levels dropping, tumors shrinking, or symptoms improving. While we recognize that Provenge (sipuleucel-T) is an immunotherapy that does have some activity in prostate cancer, the effects are fairly marginal.
We, and others, have been trying to increase its effectiveness by combining it with other medications. In this particular trial, we’re combining Provenge (sipuleucel-T) with a radiopharmaceutical drug called Xofigo (radium-223).
Why? We think radiation therapy can boost immunotherapy for several reasons.
One reason is that in patients who receive external beam radiotherapy, or conventional radiotherapy, healing tumor cells can release proteins called antigens from inside the cancer. Those antigens released into the circulation by radiotherapy can stimulate the immune cells that recognize and fight prostate cancer.
The second reason is that there is some preliminary evidence that these liquid radiotherapies—or radiopharmaceutical drugs that are injected into the veins, bind to the bone and then give off radiation particles at the bone—might also increase the number of antigens.
An antigen is a substance foreign to the body that elicits an immune response. These antigens are released as part of the cancer cell into the circulation and are then recognized by a stimulated immune system.
The hypothesis is that if you combine Xofigo (radium-223) with Provenge (sipuleucel-T), you would see higher immune responses against the tumor than if you used Provenge (sipuleucel-T) by itself.
What should patients expect?
Dr. Antonarakis: We’re selecting hormone-resistant prostate cancer patients with one or more bone metastases. In other words, their cancer has progressed after standard hormone therapy, but they don’t have any bone pain. Bone metastases have to be present, you have to have hormone-resistant disease, but you can’t have bone pain.
Patients will be randomized to one of two groups. Group 1 will receive Provenge (sipuleucel-T) by itself, according to the FDA dose schedule of three doses two weeks apart.
Group 2 will receive a combination of Xofigo (radium-223) plus Provenge (sipuleucel-T). The Xofigo (radium-223) will be given first according to the FDA dose schedule of intravenous injection every four weeks for six doses.
After the second out of six doses of Xofigo (radium-223), they will then receive the Provenge (sipuleucel-T).
After Provenge (sipuleucel-T), they will receive the third through sixth doses of Xofigo (radium-223). In other words, we give Provenge (sipuleucel-T) in between the second and third Xofigo (radium-223) doses.
Why in the middle?
Dr. Antonarakis: We are guessing when the immune system will be most stimulated by the Xofigo (radium-223). We hypothesize—and this is only a guess—that it will take at least two doses of Xofigo (radium-223) to release enough tumor antigens into the circulation to simulate the antitumor immune cells. We wanted to continue to give at least four additional doses of Xofigo (radium-223) after the immune system has been stimulated to see if we can maintain a prolonged immune stimulation period.
In a perfect world, we would have multiple different sequences, but that would require a much larger trial with at least four different study arms. We thought that was too complicated.
You said you were looking for patients with one or two bone metastases. Are you excluding those with more?
Dr. Antonarakis: Patients have to have a minimum of one bone metastasis, but there is no maximum. If a patient has a hundred bone metastases, he is eligible.
Patients cannot have liver or lung metastases larger than one centimeter in diameter.
Xofigo (radium-223) does not get into the liver or the lung. It only targets the bone. And we have never seen liver or lung metastases shrink with Provenge (sipuleucel-T) by itself. We wanted to exclude patients who wouldn’t benefit from Xofigo (radium-223), so we decided to exclude liver or lung metastases more than one centimeter.
We also exclude patients with lymph node metastases more than three centimeters. We allow small liver or lung metastases less than one centimeter and modest lymph node metastases less than three centimeters.
Is the trial being conducted only in Baltimore, Maryland?
Dr. Antonarakis: The trial is being conducted at four sites across the United States: John Hopkins University in Baltimore, Maryland is the lead site. The other sites are Tulane University in Louisiana; Duke University in North Carolina; and Cedars-Sinai Cancer Center in Los Angeles, California.