Which scenario would you prefer: “I’ve got high-risk prostate cancer. I sure hope it doesn’t come back after surgery or radiation! Fingers crossed! My doctor and I are really hoping for the best!” or,
“I’ve got high-risk prostate cancer that has a chance of coming back after initial treatment. So, my doctor is going after it relentlessly, like Inspector Javert hunting Jean Valjean in Les Mis.”
High-risk prostate cancer is formidable: it will spread if not treated and is more likely to recur after initial treatment. That’s why doctors like Rana McKay, M.D., medical oncologist and PCF-funded Young Investigator at the University of California San Diego (UCSD) are now throwing the proverbial kitchen sink at high-risk prostate cancer as soon as it is diagnosed.
This marks a huge shift in medical thinking. Advanced prostate cancer treatment in the past has been like a methodical series of “if: then” statements in math, like, “If A, then B,” or “C if and only if B.” If cancer spreads beyond the prostate, then the traditional next step has been androgen deprivation therapy (ADT), shutting down testosterone and other male hormones that drive prostate cancer’s growth. If the cancer becomes resistant to ADT, then other medications are added: chemotherapy and/or androgen-directed therapies (also called AR-signaling inhibitors).
Over the last few years, doctors have been compressing this time frame, giving these androgen-directed drugs at the time that ADT is initiated – based on studies such as STAMPEDE and LATITUDE, suggesting that the cancer, which evolves and mutates as it spreads, is more vulnerable to treatment sooner rather than later. Although these treatments can extend survival, they are not a cure.
What’s different about this new, full-on, kitchen-sink approach? First, a high-intensity burst of hormonal suppression (ADT plus an androgen-directed drug, such as enzalutamide or abiraterone) is finite, given as neoadjuvant therapy for a few months before surgery and for up to a year afterward. Then it’s over, and within a year, testosterone comes back.
Second: “We are going for a cure,” says McKay.
Early results of exciting clinical trials, with more on the way, are highly encouraging. One Phase II trial still in progress, led at UCSD by McKay in collaboration with PCF-funded investigator Mary-Ellen Taplin, M.D., of the Dana-Farber Cancer Institute, grew out of a 2014 PCF Challenge Award study, led by Taplin. The investigators tested two combinations of drugs given for six months before surgery: abiraterone and prednisone plus leuprolide (Lupron), vs. abiraterone and prednisone, Lupron, and apalutamide. After surgery, “men were randomized to continue therapy for one year, or simply to be monitored.” The initial results of this trial were presented at the American Society of Clinical Oncology meeting in 2020.
“We showed that about one out of five men who received intensive hormonal therapy up front demonstrated very residual amounts of tumor, or no tumor at all, in their prostatectomy specimen” when the surgically-removed tumor was thoroughly examined by a pathologist under the microscope. This “pathologic response,” seen in the surgically removed tissue, “hasn’t yet been proven in prostate cancer to be associated with long-term outcome,” notes McKay. “But in several other tumor types – breast, bladder, rectal cancer, and others – evidence demonstrates that the pathologic response is associated with overall survival.” In follow-up data from this and two other neoadjuvant studies, recently published in the Journal of Urology, McKay and colleagues showed that “of those patients who had no tumor or very little tumor left behind in their prostate, the rate of recurrence (the average follow-up time so far is 3.6 years) was significantly lower. In our cohort of 117 patients, only two patients who had a pathologic response and minimally residual disease had a recurrence, and no man died of prostate cancer. Our hope is that we will develop data to prove that a pathologic response is associated with long-term outcomes in prostate cancer.”
Up next: Part Two: In Some Responders, at Prostatectomy, Cancer’s Already Dead!
