Pivotal Trials Propel Progress in Prostate Cancer

Celestia Higano, MD, FACP

Several key abstracts presented at the 2019 ASCO Annual Meeting demonstrated practice-changing potential in the prostate cancer field, said Celestia S. Higano, MD, FACP.

For example, long-term data from the phase III GETUG-AFU 16 trial (NCT00423475) showed that adding short-term hormonotherapy to salvage radiotherapy after radical prostatectomy led to a significant improvement in metastasis-free survival (MFS) at 10 years versus salvage radiotherapy alone.¹

“I believe it can be a standard of care that we really didn't have before, but there are some patients who might not [currently] benefit from 6 months of androgen deprivation therapy (ADT),” said Higano. “It’s really something to consider, but at least now we understand that adding hormone therapy to salvage radiation can be important—at least in terms of MFS—just like the addition of ADT is important in primary therapy with radiation.”

Results from the phase III TITAN trial showed that the addition of apalutamide (Erleada) to ADT led to a significant improvement in radiographic progression-free survival (rPFS) and overall survival (OS) versus placebo/ADT.² Due to these data, apalutamide serves as a third drug— joining docetaxel and abiraterone acetate (Zytiga)—that can be utilized to extend life in this patient population, added Higano.

Conversely, in metastatic castration-resistant prostate cancer (mCRPC), the phase III ALLIANCE A031201 trial failed to show prolonged survival with the addition of abiraterone acetate to enzalutamide (Xtandi).3 Furthermore, treatment with the combination resulted in more adverse events (AEs) than with enzalutamide alone.

“People are still using this approach, and now there is evidence against this practice,” said Higano.

Lastly, the phase III EORTC 1333/PEACE III trial provided confirmatory insight into whether the addition of bone-protecting agents to anticancer drugs in mCRPC treatment is beneficial in mitigating fracture risk. It is known that the risk of fracture increases when radium-223 dichloride (Xofigo) is added to enzalutamide; however, mandatory continuous administration of bone protecting agents, when started ≥6 weeks prior to the first injection of radium-223 almost eliminated the risk of fracture.

Moreover, though there have not been any significant advances made with immunotherapy in the space for quite some time, research is ongoing, she added.

In an interview with OncLive, Higano, professor in the Medical Oncology Division, University of Washington School of Medicine, member in the Clinical Research Division, Fred Hutchinson Cancer Research Center, and medical oncologist, Seattle Cancer Care Alliance, shared insight on these key trials in prostate cancer.

OncLive: What were some of the key prostate cancer abstracts presented at the 2019 ASCO Annual Meeting?

Higano: These are abstracts that I believe could change practice or how clinicians are thinking about how they practice.

The first one was the GETUG-AFU 16 trial, which was presented by Nicolas Magńe, MD, PhD, of Jean Monnet Saint Etienne University, who had presented this trial a couple of years ago. At this meeting, he presented long-term follow-up in that trial and results showed very significant MFS. Now, what was that trial about? It [sought to answer a] very important clinical question that I personally had for a long time, which is, "If you're going to give someone salvage radiation after a radical prostatectomy, should you add hormone therapy?" For years, radiologists have been telling us, "No, you don't need to."

However, this trial examined whether or not adding short-term, meaning 6 months, of hormonal therapy added anything to radiation in terms of MFS. Even in the first report of this trial, there was a difference; now, with an additional 5 years, there continues to be a very significant difference in MFS. What is not as clear is whether this translates into an OS advantage. However, most patients would say that delaying metastasis in their disease trajectory is important. I believe the authors of the trial felt like this would change standard of care, and I believe that it can.

The TITAN trial was a phase III trial that reported the outcomes for [patients with] metastatic hormone-sensitive prostate cancer treated with either standard hormonotherapy or with hormonotherapy plus apalutamide. This is of great interest, but it’s also kind of confusing because now, with the results of this trial, we have a third drug that we can use to extend life in [these patients].

One of the important things in this trial is that it allowed a small number of patients who were going to be also treated with docetaxel to be treated; it was about 11% of patients. I don't believe it was terribly contaminating, but at the end of the day, we have 3 options. We have docetaxel, abiraterone, or apalutamide. We're also probably going to hear that we also now have a fourth one: enzalutamide. This is going to require us to look very deeply into what kind of comorbidities a patient has that could be negatively impacted by adding 1 of those therapies to ADT. Right now, there is no guidance as to which one of those to choose.

Another trial that is very important, despite its negative results, was the ALLIANCE A031201 trial. This looked at an older question of whether adding abiraterone to enzalutamide in mCRPC would be beneficial. There was a lot of reason to think that this might make sense, but at the end of the day, the trial was completely negative; there was no advantage to adding abiraterone to enzalutamide. Therefore, it should not be done.

The final trial is very important for practice [when] treating patients with metastatic castration-resistant prostate cancer in terms of whether or not we use bone-health agents. Bone-health trials date back to 2002, showing a benefit in terms of preventing skeletal-related events. Nonetheless, over the years, there has always been a group of skeptics who don't believe the data, because it doesn't make the prostate-specific antigen (PSA) go down and it doesn't increase survival. If it doesn't do any of those things, people are not always willing to use these drugs in addition to the anticancer drugs. They say, "Well, this drug is good enough; it's treating the cancer, and the PSA is going down."

There was an ongoing study that was amended in the context of the information we had about radium-223 and abiraterone together and the increased incidence of fractures. Soon after that was reported, the EORTC 1333/PEACE III trial, which is sort of the sister trial looking at enzalutamide with or without the addition of radium-223, said "Whoa, we better think about [the safety] this." Their solution, which I believe was an excellent one, was to mandate a bone-health agent for all patients in whom there were no contraindications across the board.

This was an interim safety report that showed very convincingly—at least in my mind—that the addition of bone-health agents does make a significant difference. As a matter of fact, the curves that Bertrand F. Tombal, MD, PhD, of Université Catholique de Louvain, showed that in the 2 arms, there were no fractures after bone-health agents were added. That’s a very important message. Somewhere between 40% and 50% of clinicians are not using bone-health agents, so we have a lot of room to improve.

What research is being done with immunotherapy in prostate cancer?

There's a lot going on in terms of immunotherapy. It has now been almost 10 years since sipuleucel-T (Provenge) was approved by the FDA. Nothing has been approved since that in terms of a vaccine. Therefore, we have a lot of work to do.

By now, people have an understanding that prostate cancer is not quite as liable to respond to the immune system; we have to figure out ways of jazzing up the whole presentation of prostate cancer to immunity. There are many small, phase I/II trials that are ongoing with immunotherapy. We're doing one [at our institution] where we give a cocktail composed of a vaccine, and then a PD-1 inhibitor. This is just 1 of many trials and many of them do include PD-1 inhibitors, and with or without PARP inhibitors. There are all kinds of combinations going on, but right now there's nothing that's sticking out there to say, "This is what we should do."

Where should future research be focused?

It's going to be very busy; that’s the first thing. There will be ongoing research in immunotherapy, and hopefully, we can break through and make a little bit more progress than we have. But then, we are going to have the other side, where we're trying to figure out how to use all of these new drugs in the context of the successes that we've had. Beyond that, we want to answer the question of, “What biomarkers do we have that might identify one drug as a better option for a patient versus another drug?” Bringing that all together, what about combining immunotherapies with all of our successful therapies that we have so far? It’s going to be a lot of work for a lot of people.

References

1. Carrie C, Magńe N, Burban-Provost P, et al. Interest of short hormonotherapy (HT) associated with radiotherapy (RT) as salvage treatment for metastatic free survival (MFS) after radical prostatectomy (RP): update at 9 years of the GETUG-AFU 16 phase III randomized trial (NCT00423475). J Clin Oncol. 2019;37(suppl 15, abstr 5001). doi: 10.1200/JCO.2019.37.15_suppl.5001.
2. Chi KN, Agarwal N, Bjartell A, et al. First results from TITAN: a phase III double-blind randomized study of apalutamide (APA) versus placebo (PBO) in patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) receiving androgen deprivation therapy (ADT). J Clin Oncol. 2019;37(suppl 15, abstr 5006). doi: 10.1200/JCO.2019.37.15_suppl.5006.
3. Morris MJ, Heller G, Bryce AH, et al. Alliance A031201: a phase III trial of enzalutamide (ENZ) versus enzalutamide, abiraterone, and prednisone (ENZ/APP) for metastatic castration resistant prostate cancer (mCRPC). J Clin Oncol. 2019;37(suppl 15, abstr 5008). doi: 10.1200/JCO.2019.37.15_suppl.5008.
4. Tombal BF, Loriot Y, Saad F, et al. Decreased fracture rate by mandating bone-protecting agents in EORTC 1333/PEACE III trial comparing enzalutamide and Ra223 versus enzalutamide alone: an interim safety analysis. J Clin Oncol. 2019;37(suppl 15, abstr 5007). doi: 10.1200/JCO.2019.37.15_suppl.5007.