In several clinical trials, including this one, an intense blast of neoadjuvant androgen deprivation therapy (ADT) and androgen-directed treatment (medications such as abiraterone and enzalutamide) has shown promising results in some men – but not all men. Why is this?
PCF-funded investigator Rana McKay, M.D., medical oncologist at the University of California-San Diego (UCSD), in collaboration with PCF-funded investigator Mary-Ellen Taplin, M.D,. of Dana-Farber, and colleagues have found an explanation: Men who have not responded (who had a significant amount of tumor remaining after neoadjuvant treatment) in these clinical trials have certain genetic differences in their prostate cancer – loss of PTEN (a tumor suppressor gene, which is knocked out in as many as 20 percent of men with localized prostate cancer) or alterations in ERG (an oncogene that fuses with another gene, called TMPRSS2, in as many as half of all men with prostate cancer).
“Very few of the men who responded had PTEN loss,” says McKay, “and ERG positivity was also associated with lack of response.” But these men also seem to have something else that might render AR-blocking drugs unhelpful: lower AR expression, compared to other men. Basically, if a tumor does not seem to have a lot of androgen receptor activity, then a medicine that targets these receptors won’t have much to work with.
This information is not discouraging, McKay hastens to add: it’s helpful! It has taught the scientists that “the responders have a certain tumor profile, and non-responders have a certain profile. Similarly, responders had mutations in a gene called SPOP” (which is mutated in about 10 percent of primary prostate tumors).
Knowing this, McKay adds, could be an opportunity: a springboard for additional or different therapy – perhaps neoadjuvant chemotherapy, for example. Remember: you’re still ahead of the game here. You don’t have metastatic cancer, and many scientists believe that high-risk cancer, when it’s localized, is still vulnerable enough to be cured, if it’s hit hard with multiple weapons.
“This is an opportunity for us to develop and design a personalized treatment strategy for these men,” says McKay. “It would be awesome if we could use somebody’s own genomics to help design the best treatment for him – similar to what’s being done in the breast cancer I-SPY trials, neoadjuvant studies with multiple treatment arms, some determined by biomarkers (specific genetic alterations that show up in a blood or tissue test).
Some men with high-risk prostate cancer might respond better to a PARP-inhibiting drug, such as olaparib and rucaparib. This is the focus of another study that will be starting soon, McKay says. “In men who have germline (inherited) alterations, such as a BRCA1 or BRCA2 mutation, we hypothesize that giving a PARP inhibitor in a neoadjuvant setting before prostatectomy might significantly improve pathologic response. We are finalizing the protocol for NEPTUNE, a biomarker-focused neoadjuvant trial testing PARP inhibitors in localized prostate cancer.”
“It is really exciting to be part of this paradigm shift,” says McKay. “We have the opportunity to improve outcomes for men with high-risk localized disease, and we’re in the midst of trying to prove that through well-organized, thoughtful clinical trials.
“At the end of the day, the question is, how can we help our patients live longer and live better? That’s really the big driver. The good thing about localized disease is that we can try to cure more men of prostate cancer – not just extend life for metastatic disease, but can we develop a pathway so they don’t ever develop metastatic disease, and so they can be cured? That’s what we’re aiming to do.” And, bonus: after the big blast of intense hormonal treatment, most men get their testosterone back. “Most patients actually recovered their testosterone fully within the first year of discontinuation of treatment.”
The groundwork for these studies was laid by PCF funding over the last six years. “PCF has been a champion in revolutionizing the science and helping advance the science,” says McKay. “PCF has been a huge catalyst in all of this.”
You can read the previous installments of this series here: