Questions About Metastasis-Free Survival in Prostate Cancer

Nick Mulcahy

January 08, 2019

Last year, a new measure for prostate cancer was used in the regulatory process for the first time. The endpoint of metastasis-free survival (MFS) was used by the Food and Drug Administration (FDA) to approve a new anti-androgen, apalutamide (Erleada, Janssen), and to extend the approval of enzalutamide (Xtandi, Astellas/Pfizer), so that they could be used in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC).

Now, two oncologists re-examine MFS, which is a novel surrogate marker, and raise concerns about its "relevance and applicability" in an essay recently published in the Journal of Clinical Oncology.

Ravi Parikh, MD, of the University of Pennsylvania in Philadelphia, and Vinay Prasad, MD, of the Oregon Health and Science University in Beaverton, remind readers that the ultimate goal of any surrogate marker is "to accelerate bringing efficacious drugs to market — not to justify approvals of drugs with questionable long-term effectiveness."

At the same time, the essayists concede that MFS has "the merit of biologic plausibility" and, notably, in the past, a "demonstrated association with overall survival" in localized, mostly high-risk prostate cancer.

They also say that use of MFS in the approvals of apalutamide and enzalutamide in nmCRPC was "well-considered."

However, the pair also argue that this setting is undergoing great change and that the pivotal trials of apalutamide and enzalutamide that led to these new approvals have yet to show an improvement in survival.

"We are not sure, in today's age, whether preventing a metastasis translates to improved survival or quality of life. We hope that it will, as it would represent a major step in prostate cancer treatment," said Parikh in an email to Medscape Medical News.

A prostate cancer expert approached for comment suggests that the essay shortchanges the significance of the marker and the new drugs. Christopher Sweeney, MBBS, a medical oncologist at Dana Farber Cancer Institute in  Boston, Massachusetts, believes that the new endpoint of MFS is clinically meaningful.

Demonstrating improved overall survival among patients with nmCRPC requires long-term follow-up, he pointed out. In both the SPARTAN (apalutamide) and PROSPER (enzalutamide) trials, there was a trend in favor of improving overall survival. Also, in both trials, there was a delay in onset of pain and no decline in quality of life, added Sweeney.

"These drugs didn’t get approved just on the delay of the radiographic event," Sweeney told Medscape Medical News. The FDA also required a favorable risk-benefit profile, he pointed out.

As a clinician who treats men with prostate cancer, Sweeney believes that delaying radiographic progression of metastatic events is impressive but not overwhelmingly so: "I would give it a B. It's not like markedly improved overall survival."

These results with MFS in nmCRPC do not reach the high bar set by results from earlier trials in the metastatic CRPC setting — the CHAARTED or STAMPEDE studies — where the survival benefit among men with metastatic disease is "clear cut."

"This is edging in the right direction — it’s not the be all and end all," he said about improvement in MFS.

Sweeney provided examples of unlikely and likely patients for the new anti-androgens. "An 85-year old with a slowly rising PSA probably never needs to see these drugs. But a 55-year old with PSA rising should definitely consider it," he said. "It depends on the patients in front of you and the total clinical picture."

Changing Technology

In their new essay, Parikh and Prasad point out that whether or not a patient actually has nonmetastatic disease — and therefore can be evaluated for MFS — depends on available technology.

"MFS may become outdated in the era of advanced nuclear imaging," the essayists write. Newer, powerful technologies such as prostate-specific membrane antigen-based and sodium fluoride-based nuclear imaging detect "more asymptomatic (and possibly clinically trivial) metastases earlier in the disease course, modifying the MFS outcome," they say.

This concern about the shifting detection of disease has also been stated by other genitourinary cancer specialists, including urologists.

Last year at the Genitourinary Cancer Symposium, Monty Pal, MD, of City of Hope Comprehensive Cancer Center in Duarte, California, asserted that the nmCRPC population may be "shrinking."

The current imaging standards of CT and conventional bone scanning, which, for example, were used in the SPARTAN trial, detect the spread of disease later, allowing for a larger pool of nmCRPC, Pal observed. Newer imaging is more in sync with the rapid rise of PSA, potentially detecting metastatic disease in conjunction with that blood testing, he suggested.

The essayists also say that "MFS ignores other important prognostic variables, such as site of metastasis." They cite other research (Eur Urol. 2015;68:325-334) that indicates not all metastases are equal: "For the 17% of patients with metastatic prostate cancer who present with visceral metastases, the median OS is nearly 40% lower than for patients with bone-only metastases."

In its pivotal phase III trial, enzalutamide "did not seem to prevent visceral metastases" in nmCRPC, write Parikh and Prasad. It’s "unclear" whether other surrogates, such as PSA doubling time or site of metastasis, might be "stronger surrogates" for overall survival than development of first metastasis, they say.

Another clinical concern, write the essayists, is that apalutamide and enzalutamide were approved for use in nmCRPC "without knowledge of long-term risks to bone and sexual health."

But Dana Farber Institute's Sweeney says this is largely mistaken worry.

Candidates for apalutamide and enzalutamide have had biochemical progression after definitive treatment and have already been on hormones and castrate for a long-time. "A patient’s sexuality does not change once they go on these [new] drugs," said Sweeney.

"It’s gone," he said about such patients’ sex drive, due to castration.

In terms of bone health, "the important thing for these men is the cancer-related fractures, which need to be prevented," Sweeney said.

Delaying the appearance of the cancer "overcomes" the potential for osteoporotic fractures, he believes. Any osteoporosis — if it is there — is already well set in from the previous hormones, he said.

"I don’t think these drugs have as big a risk [of osteoporotic events] as a drug like abiraterone [Zytiga]" because of different mechanisms of action, he said.

Priyah and Prasad are also concerned about the potential for higher and unnecessary drug spending if apalutamide and enzalutamide are overused in men with prostate cancer.

In terms of evaluating cost, Sweeney believes that health technology assessments are needed because they provide a larger view on total cost. "What is the cost saving of not having a symptomatic bone event because you delayed it, or the cost saving of not needing radiotherapy for bone pain or not needing or delaying chemotherapy," he asked.

The cost to society is "not just the cost of the drugs," he argued.

Parikh has financial ties to Merck and Prasad is a paid Medscape contributor. Sweeney has financial ties to the makers of both apalutamide (Janssen) and enzalutamide (Astellas/Pfizer) in addition to multiple other pharmaceutical companies.

J Clin Oncol. Published December 11, 2018. Full text

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