Houston researchers are reporting promising results combining immunotherapies in advanced prostate cancer, the second success with the cutting-edge treatment in less than a week against a nasty form of the disease that has defied previous interventions.
At a cancer conference Thursday, MD Anderson Cancer Center scientists said preliminary data from a new study shows the use of two drugs that release immune system brakes benefited some patients whose tumor had spread to another region and no longer responded to standard of care. Currently, there is no treatment for such patients.
“This provides a foundation to test this strategy in larger clinical trials,” said Dr. Padmanee Sharma, a professor of genitourinary medical oncology and immunology at MD Anderson and the study’s primary investigator. “We now appear to have a way to bring immunotherapy to prostate cancer and maybe get durable responses.”
Sharma said the biggest challenge going forward is the side effects caused by the drug combination. A significant percentage of patients had to drop out, most because of diarrhea or colitis. Such side effects are not uncommon in patients with other types of cancer who receive two immunotherapy drugs, considered the treatment’s next frontier.
The trial is the first in prostate cancer using combinations of the approach that won MD Anderson immunologist Jim Allison the 2018 Nobel Prize in Medicine. His identification of a brake that reins in the immune system and development of a drug to unleash it to attack cancer realized the potential of immunotherapy, now transforming cancer treatment. It has produced cures in a wide range of cancers, including some patients whose forms of the disease were considered death sentences, such as lung cancer and melanoma.
But prostate cancer trials using a single drug that releases an immune system brake, a class known as checkpoint inhibitors, had all flopped. It appeared that prostate cancer might be one of a number of “immunologically cold” tumors that don’t respond to the drugs, which work best when there’s a natural immune response blocked by the brake. In immunologically cold tumors, there is little to no immune response in the first place.
That was also thought to be the case with recurrent glioblastoma, the most aggressive form of brain cancer. But a study published Monday showed that giving an immunotherapy drug before surgery doubled survival, compared to only giving it after the procedure. The benefit was also double life expectancy statistics for the disease after it has returned following initial treatment.
Prostate cancer is effectively treated or doesn’t require treatment in most of the roughly 165,00 American men diagnosed annually with the disease. But about 30,000 die every year, after the cancer spreads to other parts of the body. At that point, hormonal therapy and chemotherapy can buy time but won’t cure the disease.
Sharma’s trial enrolled 90 metastatic patients at MD Anderson and six other sites, 45 of whose tumors had progressed after hormonal therapy failed and 45 whose tumors had progressed after chemotherapy and hormonal therapy failed. Both groups got Yervoy, the checkpoint inhibitor developed by Allison, and Opdivo, a checkpoint inhibitor that targets a second brake, every three weeks for 12 weeks; those able to tolerate the combination continued to get Opdivo once a month.
Sharma reported one-year data on 62 of those patients at a genitourinary cancer symposium in San Francisco. In the group that had only received hormonal therapy, drugs that lower testosterone, tumors shrank in 25 percent of patients; in the group that got chemotherapy and hormonal therapy, tumors shrank in 10 percent.
Four of the patients — two in each group — had no detectable cancer at least a year after beginning the two checkpoint inhibitor drugs.
Among those is Steve Johnson, a Florida man diagnosed four years ago, when doctors discovered metastatic prostate cancer was the cause of a hairline fracture in his hip. He’d been told he didn’t have long to live when he heard about Sharma’s trial.
Twenty one months after starting the combination therapy, Johnson describes himself as “a new man.”
“It saved my life,” said Johnson, who owns a construction business and comes to MD Anderson for the therapy. “I was almost dead, walking on two canes, lethargic and in pain, before the trial. I got better immediately and now I’m back to a normal life, able to work every day and again do the things I used to be able to do.”
Johnson said he can’t wait to ring the bell, the signal the cancer battle has been won, after three more months on Opdivo. He says MD Anderson staffers tell him he’s the poster child for the combination therapy.
The basis for the trial was previous research analyzing tumor samples — conducted by Sharma and Allison, her research partner and husband — that found Yervoy triggered an immune response that was shut down by the brake that Opdivo targets. Cancers frequently exploit immune system brakes to continue growing.
That work, published in Nature Medicine in 2017, prompted the authors to hypothesize that combination therapy would induce an immune response and then protect it from deactivation.
Sharma said follow-up trials will be designed to find ways to limit toxicity — such as lowering doses, giving fewer doses or spreading out the doses.
Thirty-three percent of patients in the first group and 36 percent in the second group dropped out of the trial due to side effects, which included fatigue, skin rashes, nausea and hypothyroidism in addition to diarrhea and colitis. Though such side effects are usually easily managed once treatment is stopped, four patients died from therapy-related adverse events.
Sharma said some patients continued to benefit from the treatment even after they dropped out. That’s because immunotherapy can initiate an immune response that doesn’t require continued treatment. That’s a big difference from chemotherapy, whose effect stops soon after the last treatment.
“This is a first step, just like the initial ones those that showed checkpoint inhibitors benefit some melanoma and lung cancer patients,” said Sharma. “It provides a lot of optimism immunotherapy can take its place alongside other standard of care therapies for prostate cancer once we understand how to best give these combinations.”