Ongoing research offers new promise for patients with metastasized, castration-resistant prostate cancer.
Diagnosed when androgen depletion therapy does not stop the spread of prostate cancer, metastasized, castration-resistant prostate cancer (mCRPC) is historically difficult to treat. As a result, such a diagnosis has commonly been followed by patient mortality within nine months to three years. New regiments of hormonal and cytotoxic therapy have begun to improve survival, but there is still much to be done.
In the second half of 2020, a phase 3 study and a pre-clinical trial had positive findings with promise to advance the care of mCRPC.
Phase 3: CA184-043
CA184-043 was an international phase 3 trial aimed at testing an immune checkpoint inhibitor in men with prostate cancer. Having accrued patients with mCRPC from 2009 to 2012, CA184-043 reports on the very long follow-up data. As an inclusion criterion, men in the study were required to have failed docetaxel. At the time of the study, the median survival for these men was approximately one year, significantly shorter than the typical mCRPC patient.
Participants received the humanized monoclonal IgG1 antibody ipilimumab. Following treatment, researchers discovered significant and exciting outcomes. More than a decade after treatment, some of the men who took ipilimumab were still alive.
“When the trial was first analyzed, we saw that some patients from the ipilimumab group may be harmed by treatment — directly or indirectly — so that survival curves initially favored the control group,” says Karim Fizazi, MD, PhD, Professor of Oncology at University of Paris-Saclay and medical oncologist at Gustave Roussy in Villejuif, France. “Then after seven months, the curves crossed, followed by persistent separation of the curves beyond this point, favoring the ipilimumab group.”
According to Dr. Fizazi, this change in survival curves resulted in two to three times more long-term survivors among those administered ipilimumab. Additionally, some patients in the trial achieved long-term, complete remission after receiving ipilimumab treatment.
Despite the overarching positive outcome, all patients did not benefit. Some experienced early deterioration without long-term improvement. This likely indicates that within mCRPC patients, there are various populations with differing cancer biology. So while researchers are hopeful, this study does not have the final word on the efficacy of widespread use of ipilimumab for men with mCRPC.
“This trial provides clear demonstration that in some subgroups of prostate cancer, men benefit from immune checkpoint inhibitors. We now need to decipher who these men are,” Dr. Fizazi says. “Treating all comers with expensive — and sometimes toxic — drugs when less than 20% of patients derive benefit does not make sense. This is a perfect scenario where precision medicine is needed.”
Alongside ipilimumab, radiotherapy was utilized during CA184-043. The goal of simultaneous radiotherapy was to boost the patient’s immune system and increase the efficacy of ipilimumab. However, the trial did not address directly the role of radiation, so further studies will be necessary to determine whether similar positive outcomes will manifest without accompanying radiotherapy.
Repurposing Labetuzumab Govitecan
A particularly deadly subtype of prostate cancer, neuroendocrine prostate cancer (NEPC) generally arises in a late stage of mCRPC. For decades, the field has been focused on targeting the androgen receptor signaling axis as a critical driver of prostate cancer. However, it has become increasingly apparent that as much as 20% of mCRPC escapes a dependence on the androgen receptor and undergoes conversion to NEPC.
Men with NEPC often have genetic abnormalities in the genes RB1, TP53, PTEN and MYCN — though such an abnormality does not always result in NEPC. Regardless of the presence of a genetic abnormality, men with NEPC have a bleaker outlook than those with other cases of mCRPC.
Recently, two findings are helping to rectify this poor outcome. The first was discovering that carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is present on the surface of approximately 60% of NEPCs. Second was finding that labetuzumab govitecan, an antibody-drug conjugate developed for colorectal cancer, can induce significant tumor responses in NEPC models.
“NEPC is associated with a very poor prognosis, and there are no currently approved targeted treatments,” says John K. Lee, MD, PhD, Assistant Professor in the Human Biology and Clinical Research Divisions at Fred Hutchinson Cancer Research Center in Seattle, Washington. “If labetuzumab govitecan is successful in clinical trials, it would provide a targeted treatment option for patients with NEPC where one has previously not existed.”
Current treatment for NEPC includes cytotoxic chemotherapy. For some men, NEPC may be initially sensitive to this treatment. However, recurrence often occurs rapidly, coupled with a developed chemotherapy resistance. At this point, there is no effective alternative treatment available.
To determine the efficacy and viability of this treatment for men with NEPC, a clinical study is in the planning stages. Should labetuzumab govitecan be found safe and effective, new hope will be provided to men with NEPC. But researchers do not view this therapy as an end-all treatment. Just as NEPC developed due to evolution that rendered traditional therapies ineffective, the same will likely occur in the future, causing the need for yet another advanced treatment option.
“We fully anticipate that there is likely to be additional cancer evolution in response to treatments,” Dr. Lee says. “As prostate cancer is not just one disease, we also believe that NEPC may be made up of a few subtypes. Additional studies are needed to understand how these subtypes are different and how they can be effectively targeted as they evolve.”