Q&A: Prostate cancer expert Julie Graff, M.D., explains how a new treatment option fills a void for men with resurgent tumors.

When prostate cancer isn’t cured by surgery or radiation, the next line of defense is androgen deprivation therapy: lowering androgen hormone levels or stopping them from getting into prostate cancer cells. But these cancers inevitably develop resistance that enables them to progress, and at that point treatment options dwindle.

Photo: Julie Graff, M.D., meets with patient and clinical trial participant David Seidl and his wife Linda. (Michael Moody)In February, the U.S. Food and Drug Administration gave its first approval for a drug to treat men with prostate cancers that have become resistant to hormone therapy but have not yet spread. Apalutamide, brand named Erleada, significantly improved metastasis-free survival, a composite endpoint measuring the length of time before tumors metastasize to other parts of the body or until death occurs.

OHSU and the VA Portland Health Care System enrolled more subjects than any other clinical trial site in the country in the practice-changing study establishing the benefit of apalutamide for this population of prostate cancer patients. Cancer Translated talked with OHSU Knight Cancer Institute oncologist Julie Graff, M.D., a co-author of the New England Journal of Medicine paper presenting the clinical trial results. Graff is interim chief in hematology/oncology at the Veterans Affairs Portland Health Care System and an associate professor in the OHSU School of Medicine.

Cancer Translated: How big is the problem this clinical trial took on?

Julie Graff: About a third to a fourth of the time when we try to cure a man’s prostate cancer, it comes back. PSA levels, which we use to track cancer growth, start to rise. We have this large population of men who fit this category: PSA rising but no detectable metastases. We give them hormone suppression therapy and usually that brings the PSA down, but after a few years that doesn’t work anymore.

CT: That’s inevitable?

JG: If you live long enough, it’s pretty uniform. And we were not sure what to do with these guys who have castration-resistant prostate cancer but no metastases because all of the most recent drug approvals were for people with metastases. So what we’ve been doing is using first-generation androgen receptor antagonists or estrogen patches just to try to get that PSA down again. None of them are that effective. This study and another looked at using second-generation androgen receptor antagonists to find out if we can delay the appearance of metastases.

CT: The median metastasis-free survival for patients taking apalutamide was about 40 months compared with 16 months for patients taking a placebo. But what about overall survival?

JG: It’s too early to know. It will probably be years until that can be known. But this drug appears to delay symptomatic disease from prostate cancer, such as bone pain, so that’s a clinically meaningful endpoint. We looked at quality of life, because second-generation androgen receptor blockers have side effects. We looked to see if we were diminishing the quality of life of patients and we did not see that. Men in the placebo arm of the study and those receiving apalutamide had the same quality of life and it didn’t really change.

“We now have options that can delay metastases. And the treatment might have long-lasting effects.”

‾‾‾‾‾‾‾‾‾‾‾‾‾‾‾‾‾‾‾‾‾‾‾‾‾‾‾‾‾‾

CT: Second-progression–free survival was significantly longer in the apalutamide group than the placebo group. What is that measuring?

JG: Men who developed metastases, they were offered the drug abiraterone, or they could receive whatever their doctor prescribed. If they progressed on that, we counted that as the time to second progression. It was delayed in men who were on apalutamide.

CT: What are the key takeaways from this clinical trial?

JG: We now have options that can delay metastases, which is where you get cancer-related symptoms. And the treatment might have long-lasting effects, such that it might improve overall survival, but we don’t know that yet. Patients who received this treatment didn’t have a decreased quality of life, they maintained their quality of life. We should mention toxicities. There were more fractures with this drug. I’d want to make sure that patients are aware that that’s an issue – that they should be looking at their bone health, taking calcium and vitamin D and doing what they can to prevent fractures. Other side effects include rashes and hypothyroidism, which is treatable but it does happen.

CT: Apalutamide is a second-generation version of antiandrogen drugs that have been used for decades. And at least one critic has questioned why the clinical trial compared apalutamide with placebo and not with a first-generation anti-androgen such as bicalutamide.

JG: In this trial, more than 70 percent of the patients had already progressed on a first-generation antiandrogen. It’s common to prescribe high-dose bicalutamide, ketoconazole, and estrogen patches in these patients.

CT: Was there clinical trial evidence to support the use of bicalutamide and those other agents?

JG: There were studies showing that these agents can bring down the PSA, but nothing to show whether it could improve survival.

CT: How were you able to succeed at enrolling more subjects than any other U.S. clinical trial site? Oregon isn’t exactly the most densely populated state…

JG: For one thing, we didn’t have any competing studies, and I offered enrollment to everyone eligible. I heard, too, that we were seeing people more often than they are sometimes seen in the community. So we were detecting PSA rises that might otherwise be missed. I don’t know that urologists would see prostate cancer patients as frequently as in academic medicine, where patients get sent to oncology a bit sooner. We always see patients with prostate cancer receiving androgen deprivation therapy every three months to watch their PSA, document bone density and talk about bone health.

CT: Do you have other trials underway now for men with prostate cancer?

JG: There are more than a dozen clinical trials for men with prostate cancer at OHSU. For instance, we have a trial of the combination of cabazitaxel and enzalutamide; we’re looking to see if combining treatments can achieve better outcomes than either agent alone for men whose disease is progressing despite androgen suppression therapy. Another is testing how a new immunotherapy drug called pembrolizumab affects prostate cancer. The Knight Cancer Institute clinical trials website explains all of the studies enrolling men with prostate cancer.

CT: In a clinical trial, the effectiveness of the treatment being tested is unknown. What are the advantages for patients who volunteer?

JG: Patients should consider enrolling because it might benefit them but also it will help us learn more about the disease for the benefit of future patients. And it does give you options you wouldn’t otherwise have. Being in this trial gave a large number of men access to a drug that turned out to work. [Patients were randomly assigned, in a 2:1 ratio, to receive apalutamide or placebo, and if cancer spread patients were eligible to receive treatment with sponsor-provided abiraterone plus prednisone.] I hope that patients who participated are proud that they contributed to helping us learn. We still have a lot of clinical trials that need to be filled.

∞

Further reading:

Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer by Matthew R. Smith, Fred Saad, Simon Chowdhury, Stéphane Oudard, Boris A. Hadaschik, Julie N. Graff, David Olmos, Paul N. Mainwaring, Ji Youl Lee, Hiroji Uemura, Angela Lopez-Gitlitz, Géralyn C. Trudel, for the SPARTAN Investigators. New England Journal of Medicine (April 12, 2018)

FDA approves new treatment for a certain type of prostate cancer using novel clinical trial endpoint. U.S. Food and Drug Administration news release  (February 14, 2018)