Packing a PUNCH in Prostate Cancer: Chemo & ADT & Surgery

CHICAGO — "Not everyone is going to accept these results as being something convincing enough to change their practice," said James Eastham, MD, of Memorial Sloan Kettering Cancer Center, New York City, while sitting outside the press room here at the American Urological Association (AUA) 2019 Annual Meeting.

Eastham is the lead investigator of the PUNCH (Preoperative Use of Neoadjuvant Chemotherapy) trial, which pitted standard surgery against experimental neoadjuvant chemohormonal therapy (CHT) plus surgery for the treatment men with high-risk, clinically localized prostate cancer (stage T1 to T3aNxM0).

Results from this trial, presented for the first time here at the meeting, show that the experimental approach yielded some positive outcomes compared to surgery alone, but the trial did not meet its primary endpoint.

Specifically, there was no difference in 3-year biochemical progression-free survival (bPFS) among 391 men who received neoadjuvant CHT and surgery vs 397 men who underwent surgery alone (hazard ratio, 0.87 vs 0.82; P = .13)

Nonetheless, Eastham believes that secondary outcomes — including overall survival (OS) — are worth discussing with men with high-risk localized prostate cancer.

"I think [urologists] should have a conversation with their patients about the benefits of this approach," he told Medscape Medical News in an exclusive interview.

Such patients are those with Gleason scores of 8–10 who have a high probability (>40% on a nonogram) of biochemical recurrence within 5 years after radical prostatectomy (which was the PUNCH population).

"Patients, rather than going to surgery immediately, should consider a neoadjuvant approach first," added Eastham. The neoadjuvant CHT approach consisted of androgen deprivation therapy (ADT) plus docetaxel. This should now be a standard of care in this setting, Eastham suggested.

However, another prostate cancer expert dismissed the trial — and the treatment approach used for this group of patients — as not being proven to be helpful.

The basic idea behind PUNCH is a good one, suggested Eric A. Klein, MD, Glickman Urological and Kidney Institute, Cleveland Clinic, Ohio, who was approached for comment at the meeting.

More aggressive cancers need more aggressive treatments. Dr Eric A. Klein

"More aggressive cancers need more aggressive treatments," he told Medscape Medical News.

"We have known for a long time that we could cure men with early-stage [localized] prostate cancer with single-modality therapy," he continued. But that has not been completely true for high-risk localized disease, he added.

As a result, the world of prostate cancer research has performed a string of trials that tested more aggressive strategies in this setting.

None have succeeded. The new results do not alter that, said Klein.

"Does this [PUNCH trial] change the standard of care?," he asked. "Absolutely not."

"They didn't meet their primary endpoint," he concluded.

Overall Survival Considered

The failure of PUNCH to meet its primary endpoint is an involved tale. Part of the complexity stems from the fact that about 40% of men received salvage radiotherapy, ADT, or both prior to meeting the study's definition of biochemical failure. During the course of the long study, "there was a change in clinical practice to initiate salvage therapy earlier," said Eastham.

He also pointed out that "there is a statistically significant improvement in bPFS over the course of the study," referring to the entire study period (P = .02), not just the 3-year bPFS, which was the primary outcome. Median follow-up was just over 5 years in the study.

Eastham also championed the OS findings. In his oral presentation, he told the AUA audience that "although the confidence interval covers 1, there is strong evidence for a survival benefit stemming from neoadjuvant CHT."

This was a reference to the OS data, which were not statistically significant (P = .06).

Treatment	3-Year OS (%)	5-Year OS (%)	8-Year OS (%)
Surgery alone	96	91	82
Surgery plus CHT	98	94	87

The survival benefit "happened earlier than we thought," Eastham said. The question then becomes, "Is it worth it?" He was questioning whether the toxicity of the treatment is worth the possibility of modest benefit later.

Cleveland Clinic's Klein was not impressed. He pointed out that at 8 years, there were data on only eight men in the surgery-alone arm and 11 men in the neoadjuvant arm. The confidence intervals were also "fairly wide," he added.

"This doesn't move the bar, this does not change the standard of care," Klein told Medscape Medical News.

Eastham presented the AUA audience with a different conclusion: "These data support neoadjuvant chemohormonal therapy plus radical prostatectomy as a standard option for at least delaying bPFS in men with clinically high-risk prostate cancer."

The study was funded by the Canadian Cancer Trials Group, SWOG, and Sanofi-Aventis.

American Urological Association (AUA) 2019 Annual Meeting: Abstract LBA12. Presented May 5, 2019.

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