Pertuzamab is a new targeted anti-cancer drug that blocks the human epidermal growth factor (HER) receptor family. It belongs to the class of drugs called monoclonal antibodies (MAbs). According to Dr. David Agus, a researcher involved in a Phase II study reported in this week’s Journal of Clinical Oncology, pertuzumab “shows promise” in extending the lives of patients with recurrent prostate cancer. Pertuzumab did not shrink tumors, though, nor lower PSA’s in any of the 41 “heavily pre-treated” patients enrolled in this trial. And in sixty percent it carried diarrhea as a side effect.

A handful of patients obtained months of stable disease. Comparing patients in this study with records of other patients who, like them, had already used up hormone blockade and taxane chemotherapy, Agus and his colleagues determined that for those who respond to it, pertuzumab extends survival. Full story … read more.

Meanwhile after a similar trial in the UK for men with hormone refractory prostate cancer the researchers declared pertuzumab a failure.

Int he UK trial results were as follows:

Sixty-eight castrate, chemotherapy-naive men with HRPC were
enrolled. A total of 35 patients were treated at 420 mg; no PSA
declines >= 50% were observed at the interim analysis and recruitment
was stopped. A total of 33 patients were then treated at 1,050 mg,
and no PSA declines >= 50% were observed at the interim analysis.
Pertuzumab was well tolerated.

CONCLUSION: Pertuzumab has no clinically significant single-agent
activity in castrate patients with HRPC at either of the tested dose
levels. This may reflect the continued presence of significant levels
of intraprostatic androgen driving androgen receptor signaling.

That study appeared in Journal of Clinical Oncology, January 20. Medscape reported it under the headline Pertuzumab Ineffective
in Hormone-Refractory Prostate Cancer.

Interestingly, the UK researchers conclude that the lack of objective response “may reflect the continued presence of significant levels of intraprostatic androgen driving androgen receptor signaling.” If pertuzumab works at all on PCa, why would it be expected to block androgen? Might it be that pertuzumab may normalize prostate cancer cells sufficiently to resensitize them to androgen? The UK lead author, Dr. Johann Sebastian de Bono, points out that HER2 inhibition might cause tumor cells to revert to androgen dependence. If so, giving a HER kinase inhibitor together with an antiandrogen may prove more useful.

Dr. Agus says: “Ultimately, we hope drugs like pertuzumab will help us reach the point where cancer can be viewed as a lifetime disease to be managed much like AIDS is looked at now. This would be major shift from the current paradigm for cancer treatment, and is a promising area of research.”

Presumably, this will only come about if drugs like pertuzumab can be shown to be effective in giving at least stable disease for patients with early recurrence of prostate cancer. At present it’s hard to demonstrate any effect on biochemical recurrence unless a drug lowers PSA.

Unlike relatively cheap, readily available drugs which some studies suggest may slow biochemical progression in recurrent prostate cancer – from vitamin D3, NSAIDs and statins to pomegranate juice – MAbs are high-cost drugs. Maybe what’s needed is one of more MAbs in combination with chemotherapy or forms of radiation and with genetic pre-testing to select likely responsive patients. As both studies show, however, if the endpoint is >= 50% PSA drop, it won’t be easy to demonstrate efficacy against early recurrence (where commonly PSA rise is the sole sign of disease). Some prostate cancer researchers have been making noise to get other endpoints recognized. Dr. Petrylak has made a pitch for PSA drop alone (Prostate Cancer Research May Speed up With Use of PSA Surrogate Endpoints). But that wouldn’t help in the present case.

David B. Solit and Neal Rosen from Memorial Sloan-Kettering Cancer Center write in an editorial on the UK trial (Targeting HER2 in Prostate Cancer: Where to Next?):

The take-home lesson is that there remains little evidence for a significant role for HER2 or EGFR as the primary driver of prostate cancers. Given the lack of efficacy seen with these agents, the use of HER kinase inhibitors in multidrug combinations in prostate cancer patients should be based on strong hypotheses and preclinical data. To maximize the likelihood for success, the studies should be informed by molecular profiling and mutational analyses of the tumor. It took large, expensive clinical trials conducted for many years to show that lung tumors with RAS mutation were unlikely to respond to EGFR inhibition. This ought to have been recognized as a likely outcome 10 years before these studies were initiated. Unfortunately, this situation continues to be repeated in other disease sites, with other agents. Studies of targeted agents in prostate cancer and other tumors continue to proceed without patient stratification or association of outcome with common mutations in RAS, BRAF, and PTEN that might affect drug efficacy. We recognize that such studies are particularly challenging in prostate cancer, given its long natural history (which makes archival tissue collected at diagnosis of limited value) combined with a lack of accessible tissue for biopsy at the time of recurrence. Therefore, to accelerate the identification of more effective therapies for prostate cancer, efforts must be made to develop novel minimally invasive technologies that will allow for genetic stratification of patients in future clinical trials in this disease.