New nonmetastatic PCa agents address unmet need

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Are new antiandrogens the gold standard for treatment of nonmetastatic castration-resistant prostate cancer (nmCRPC)? Three novel androgen receptor inhibitors provide an embarrassment of riches when it comes to treatment options for nmCRPC patients, but there are still questions to be answered-including the extent of these drugs’ clinical benefit.

The approvals of apalutamide (Erleada) in February 2018, enzalutamide (XTANDI) in July 2018, and darolutamide (Nubeqa) in July 2019 for the nmCRPC indication were the first moves away from a “watch-and-wait” approach for managing patients with nmCRPC.

Prior to the availability of these antiandrogens for nmCRPC, “It was a dealer’s choice approach of what to do, with no clear guidelines,” said Leonard G. Gomella, MD, professor and chair of urology at Thomas Jefferson University and senior director for clinical affairs at the Sidney Kimmel Cancer Center, Philadelphia.

“We didn’t really have a good option for treatment, which meant physicians waited for something bad to happen. We’d wait for patients’ PSA to shoot up; we’d image them; and the minute we saw signs of metastasis, we would begin metastatic castration-resistant prostate cancer treatment.”

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One-third of patients with nmCRPC develop metastases within 2 years.

Now, phase III clinical trials including the SPARTAN study, a trial of apalutamide; PROSPER, a study of enzalutamide; and ARAMIS, a study of darolutamide, are changing the landscape for nmCRPC by presenting options for prolonging metastasis-free survival-the endpoint that formed the basis for FDA approval of these three agents for nmCRPC.

“These drugs fulfill an unmet need for treatment of nonmetastatic castration-resistant prostate cancer,” Dr. Gomella said.

The use of metastasis-free survival as a study endpoint has drawn questions. “There’s no proven clinical benefit associated with an improvement in metastasis-free survival per se,” said Philip Kantoff, MD, chairman of medicine at Memorial Sloan Kettering Cancer Center, New York. “The clinical benefits for this subset of patients should be measured in delayed symptoms referable to their cancer or an improvement in overall survival.”

And while data from recent studies are very encouraging, “We don’t have the long-term data to say definitively that prolonged metastasis-free survival significantly increases overall survival,” Dr. Gomella said.

As a result, there is still a need to exercise caution in using these drugs in the context of treating nmCRPC patients, Dr. Kantoff said.

“You’re treating patients who are asymptomatic, sometimes elderly, with drugs that have side effects. They’re going to feel less well than they did before they were treated with the hope that it eventually leads to clinical benefit,” Dr. Kantoff said.

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Early results from clinical studies show little difference among the drugs. While apalutamide and enzalutamide have a different chemical structure than darolutamide, each of these androgen inhibitors demonstrates similar rates of metastasis-free survival after 24 months as well as reduction in PSA. The populations studied-both in terms of size and patient characteristics (eg, patient age and PSA doubling time)-also are highly comparable.

But the drugs are not without side effects. While the improvements in metastasis-free survival rates are similar, studies show patients who take apalutamide and enzalutamide may suffer from profound fatigue and increased incidence of falls and fractures. Enzalutamide also has been linked to increased risk of seizures. Meanwhile, darolutamide appears to lack the central nervous system side effects associated with apalutamide and enzalutamide and results in less fatigue, but may prompt feelings of weakness, diarrhea, hot flashes, anemia, and decreased appetite.

How can physicians choose the right drug for their patients? “That’s a challenging question-one that hasn’t been fully addressed,” said Tomasz M. Beer, MD, professor of medicine, division of hematology/medical oncology, and Grover C. Bagby Chair of Prostate Cancer Research for the Oregon Health & Science University School of Medicine, Portland. Typically, these decisions are based on a physician’s experience with the drug and the patient’s health profile, Dr. Beer said.

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“For somebody with a history of seizures, somebody with a risk of falls, someone on a blood thinner-those people are not good candidates for apalutamide or enzalutamide, but darolutamide might be a better choice,” said Adam S. Kibel, MD, Elliott Carr Cutler professor of surgery in urology at Harvard Medical School and chief of urology, Brigham and Women’s Hospital and Dana-Farber/Brigham and Women’s Cancer Center, Boston.

Patients’ individual preference, too, is a factor. “Many patients have a robust response to these drugs,” Dr. Beer said. “Some patients are unable to tolerate the side effects, and they discontinue treatment.”

Cost is also an issue. “There are situations where patients have to pay $1,000 a month to be on a drug, and there are patients who can’t afford it,” Dr. Kantoff said.

Researchers are exploring the “biology of resistance,” looking at biomarkers-such as androgen receptor variant-7 (AR-V7)-to help guide treatment. For example, AR-V7 can help predict resistance to hormonal therapies. But the incidence of AR-V7 mutations in patients with nmCRPC is low, Dr. Kantoff said. Additionally, some physicians are reluctant to use biomarkers to guide treatment.

“We are finding biomarkers of resistance; we are understanding better what the resistance mechanisms are. But there’s a little bit of a gap between our knowledge and translating that to clinical utility or benefit,” Dr. Kantoff said. As a result, “Most physicians have not used biomarkers to make a decision regarding, ‘Should I use this drug or something else?’ ”

Given the similarities among the drugs and the lack of definitive information on which treatment is best for specific patient profiles, Dr. Kibel said clinicians will need to be selective. “Each provider is going to have to pick their drug of choice and gain experience with it,” he said.

The advent of antiandrogens to prolong metastasis-free survival is exciting, presenting options for treatment of a disease that formerly left physicians’ hands tied.

“One of the important points to remember is that the patients in these studies had a rapid PSA doubling time of less than 10 months. That meant these patients were doomed to rapidly develop metastatic disease,” Dr. Gomella said. “These drugs delay progression of metastases and slow PSA doubling time.”

But even with these advancements, there are still many questions to be answered about treatment of nmCRPC. 

For example, the proper drug sequencing for prostate cancer that is progressing from hormone-sensitive nonmetastatic prostate cancer to nmCRPC “is an open book,” Dr. Gomella said. “In general, we believe certain patients may initially benefit from a next-generation androgen sequence inhibitor before they get chemotherapy. Others may benefit from upfront chemotherapy, depending on how much disease burden they have.”

There’s also the question of how to best assist patients who find the side effects of the drugs difficult to bear. “Is there some way to add something-like an immunotherapeutic-for patients who have a difficult response? That’s an area that requires further exploration,” Dr. Beer said.

Additionally, it’s not clear how often patients should undergo diagnostic imaging tests or the impact that next-generation imaging scans will have on detection of nmCRPC and treatment.

“The clinical trials all looked at progression of disease based on a standard bone scan, CT scan, and MRI. When we start to use next-generation imaging scans such as PSMA scans, are we going to decree that patients are progressing toward metastasis earlier? If so, how will this impact the use of these drugs?” Dr. Gomella said. 

Further, advancements in technology may change physicians’ perceptions of the state of disease in nmCRPC patients. 

“I think the biggest question we have to ask is, “What is M0 CRPC?” Dr. Kibel said. “We believe all of these patients have some form of metastatic disease. As new imaging agents do a better job of identifying metastatic disease, will we find that patients who were designated ‘M0 CRPC’ actually have micrometastatic disease that we just couldn’t pick up? Will the M0 designation go away?”

These are questions that will continue to be explored by researchers as well as groups such as the AUA, which has amended guidelines around nmCRPC based on recent advancements. 

Dr. Kantoff has stock/other ownership interests in Context Therapeutics, Druggability Technologies, Placon, Seer, and Tarveda Therapeutics; and has a consulting or advisory role with Bavarian Nordic, BIND Biosciences, Context Therapeutics, Druggability Technologies, GE Healthcare, Genentech/Roche, Janssen, Merck, Metamark Genetics, New England Research Institutes, OncoCell MDx, Progenity, Sanofi, Seer, Tarveda Therapeutics, and Thermo Fisher Scientific. Dr. Gomella is a consultant/adviser to Astellas, Janssen, MDx Health, Merck, Bayer, and Strand Laboratories. Dr. Beer has stock/other ownership interests in Salarius Pharmaceuticals and has a consulting or advisory role with Abbvie, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Clovis Oncology, GlaxoSmithKline, Janssen Biotech, Merck, and Pfizer. Dr. Kibel has received honoraria from Blue Earth Diagnostics, InSightec, Janssen, Merck, Pfizer, and Profound. 

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