In 1996, while investigating taxanes’ effects on prostate cancer cells in a laboratory setting, Petrylak discovered that docetaxel (Taxotere) combined with estramustine (Emcyt) demonstrated activity that he and his colleagues wanted to examine further. They designed a phase I trial with the combination, but when they approached the drugs’ manufacturers, the response was, “We have good news and bad news.” The good news was that the companies would happily supply their drugs; the bad news was they would not fund the trial.
So, naturally, the team came up with their own funding and ran their own trial (docetaxel was not yet approved). “I remember, very well, treating the first patient who didn’t respond, and I said to myself, ‘We put all this effort into this and look what happened here,’ and then the next 5 or 6 patients responded,” Petrylak recalls.
At the next Southwest Oncology Group (SWOG) meeting, they presented their results and, with support from E. David Crawford, MD, moved forward with a phase III trial, SWOG 9916. The trial accrued patients and was 1 of the studies that led to docetaxel’s approval for treating patients with castration-resistant prostate cancer (CRPC). To this day, docetaxel is a standard-of-care treatment for patients with CRPC in the first-line setting.
That trial taught Petrylak an important lesson that he carries as his philosophy: Never quit, and always remember to stay positive, because you never know what’s around the corner. “If something doesn’t seem to fit, or it doesn’t seem to be working, keep on plug-ging, keep on going at it, because you just don’t know what’s going to happen,” he says. “I’ve seen so many things that looked bleak and dim [but], in the end, turned out well.”
Since then, Petrylak has led other secondary trials for combination treatments with docetaxel, including serving as the principal investigator on the SPARC trial that investigated satraplatin in patients with CRPC. “Unfortunately, that drug did not show a survival benefit, but I think if we did the trial now and selected patients who had DNA repair mutations, I think we would have had a positive trial,” Petrylak says. This trial showed him how the field had evolved to look at more biologically targeted therapies against different markers.
New Approaches in Bladder Cancer
Reflecting on his field, Petrylak says that the ability to conduct trials for bladder cancer has greatly improved. “If you talked to someone about doing a bladder cancer trial with a pharmaceutical company 4 or 5 years ago, they would run in the other direction,” he says. Now, many clinical trials are investigating treatments for bladder cancer because researchers have observed the effectiveness of novel agents such as PD-1 and PD-L1 inhibitors.
According to Petrylak, 3 main areas hold the newest developments for treating bladder cancer: checkpoint inhibitors, potential interactions between antiangiogenic agents and chemotherapy, and newer antibody–drug conjugates that are showing activity. He has been involved in the trials for atezolizumab (Tecentriq) and pembrolizumab (Keytruda) as treatments for bladder cancer. He presented data at 2017 European Society for Medical Oncology Congress from the RANGE study, which is investigating ramucirumab (Cyramza) and docetaxel combined, compared with docetaxel alone, in patients who had prior therapy for metastatic bladder cancer.
Recently, he and his colleagues have been working with an anti–Nectin-4 antibody and an anti-SLITRK6 antibody, which are linked to chemotherapeutic agents, and are already seeing responses in patients who failed prior checkpoint therapy. He says integrating all these therapies will be a very interesting area, and he looks forward to working in it.
What’s ahead for Petrylak? He hopes to continue to develop drugs. “That’s what I have a passion for, that’s what I really enjoy,” he says. “We’ve come a long way in both [bladder and prostate] tumors, and there’s a lot of room for improvement still.”
For prostate cancer, Petrylak sees research and treatment moving toward the era of personalized medicine, particularly with PARP inhibitors showing efficacy in patients with DNA repair mutations. There is also promise in identifying variants of the androgen receptor that may predict whether a patient will respond to the newer generation of hormonal agents. “I think both fields will start using a more personalized approach as we identify markers for each of those tumors,” Petrylak says.