Metastasis-Directed Therapy for Prostate Cancer a Clear Winner in Meta-Analysis

SAN FRANCISCO — Progression-free survival (PFS) in oligometastatic prostate cancer improved significantly with metastasis-directed therapy (MDT) in addition to systemic treatment, a meta-analysis of recent studies showed.

Median PFS increased from 14.9 months with standard of care (SOC) to 32 months with SOC plus MDT. The benefit held up across a range of key subgroups, including hormone-sensitive and resistant disease, stage, number of metastases, and prior androgen deprivation therapy (ADT). Radiographic (r) PFS, freedom from castration, and overall survival (OS) all improved with MDT.

Ongoing clinical studies will provide additional data to inform decisions about pursuing MDT, reported Chad Tang, MD, of the University of Texas MD Anderson Cancer Center in Houston, at the ASCO Genitourinary Cancers Symposium.

“Across the different endpoints, the pooled analysis of all published trials randomizing oligometastatic prostate cancer to MDT versus not, in addition to standard of care, systemic therapy or observation, reveal an improvement in progression-free survival and later endpoints, specifically radiographic progression-free survival, and castration resistance-free survival,” said Tang. “MDT improved OS … in a random-effects model. MDT benefit was maintained across subgroups.”

In response to a question from the audience, Tang said researchers found no interaction between treatment of the primary tumor and the efficacy of MDT.

“We know from multiple different analyses that when you have de novo disease, it’s usually more aggressive,” said Tang. “In terms of the benefit of MDT, we did not see a significant interaction, and the benefit of MDT in patients with de novo or metachronous disease was very similar.”

Responding to another question, Tang said that about 60% of the patients were on androgen receptor pathway inhibitors (ARPIs), and the benefit of MDT was similar in those on or off ARPI therapy.

Unresolved Issues

During an extended discussion about oligometastatic disease, a member of the audience asked whether different imaging modalities affect findings relative to the number of metastases, total tumor burden, and treatment decisions.

“As far as finding the ‘sweet spot’ of oligometastatic disease that you can treat, that’s really confined, I’m not sure,” said panelist Brandon Mahal, MD, of the University of Miami. “Those questions still have to be answered. I used to think that PSMA [prostate specific membrane antigen] was going to be the end all and would usher in a new era and the [radiation oncologists] would burn everything out, all five lesions, and the patients would live forever. That’s not the case.”

With respect to the benefit of MDT, the number of lesions does not seem to matter, said Nicholas James, MD, PhD, of the Institute of Cancer Research and the Royal Marsden Hospital in London. However, a linear relationship does exist, in that the magnitude of benefit declines gradually as the number of metastases increases.

“It doesn’t go to zero, it just drops,” he said. “You don’t stop seeing a failure-free survival benefit, in our analyses, until you get to 10 mets. So, to a degree, what number you pick as oligometastatic is arbitrary, to be quite honest.”

The line is blurring in terms of defining oligometastatic disease and the benefit from MDT, added Kenneth Gage, MD, of Moffitt Cancer Center in Tampa, Florida. That’s particularly true in light of the PEACE-1 trial, which showed a benefit of irradiating the prostate regardless of metastatic burden.

“I question how much [metastatic burden] matters,” said Gage. “I wonder how much more we should be considering radiation of the prostate throughout the metastatic spectrum.”

Key Findings

In his introductory remarks, Tang noted that data regarding the efficacy of MDT is limited to several small phase II trials. Hypotheses and speculation have surrounded discussions about specific patient subgroups who might benefit from MDT, but subgroup analyses have been limited. Additionally, data from randomized phase II trials have spanned several eras of prostate cancer imaging and treatment.

A global research collaboration contributed data from recent studies of MDT to form the basis for a meta-analysis of pooled information. Studies eligible for inclusion defined oligometastatic as fewer than five metastases and compared MDT plus SOC versus SOC alone. The primary endpoint was PFS, and additional endpoints were rPFS, castration resistance-free survival (CRFS), and OS.

The analysis comprised five randomized trials and a total of 472 patients with oligometastatic prostate cancer. Baseline characteristics were balanced between the SOC and SOC + MDT groups.

A trial-level analysis using a random-effects model showed that the addition of MDT to SOC reduced the PFS hazard by 55.6% (95% CI 0.349-0.565, P<0.001) overall. The magnitude of benefit ranged from 48% to 91% across the individual trials. A Cox regression analysis yielded a hazard ratio of 0.45 in favor of MDT (95% CI 0.35-0.58, P<0.001). A pre-specified subgroup analysis produced hazard ratios ranging from 0.24 to 0.53 in favor of MDT.

Cox regression analyses of the other endpoints showed a consistent benefit with the addition of MDT:

• rPFS: 21 vs 35 months, HR 0.59, 95% CI 0.46-0.76, P<0.0001
• CRFS: 63 vs 72 months, HR 0.58, 95% CI 0.37-0.91, P=0.020
• OS at 48 months: 75% vs 87%, HR 0.64, 95% CI 0.40-1.01, P=0.057

Five ongoing or planned trials will continue the evaluation of MDT in more than 3,600 patients. Four of the five define oligometastatic as fewer five or fewer metastases, and the other specifies three or fewer. All allow concurrent ADT, and primary endpoints across the trials are failure-free survival, CRFS (two trials), OS, and rPFS.

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