Pivotal Studies Pave Way for Nonmetastatic CRPC Treatment

Richard JaeBong Lee, MD, PhD

When it comes to the treatment of patients with nonmetastatic castration-resistant prostate cancer (M0CRPC), 3 pivotal trials—SPARTAN, PROSPER, and most recently, ARAMIS—have demonstrated the safety and efficacy of second-generation targeted antiandrogens, said Richard (Rick) JaeBong Lee, MD, PhD.

Data from the phase III SPARTAN trial, which evaluated the use of apalutamide (Erleada) in adult patients with high-risk M0CRPC, showed that treatment with this agent led to a significant improvement in metastasis-free survival (MFS).¹ The median MFS was 40.5 months with apalutamide compared with 16.2 months with placebo (HR, 0.28; 95% CI, 0.23-0.35). These data led to the February 2018 FDA approval of the agent in this setting.

Next, enzalutamide (Xtandi) was granted an approval in July 2018 for this patient population, based on data from the phase III PROSPER trial, in which this agent also demonstrated significant improvement in median MFS compared with placebo, at 36.6 versus 14.7 months, respectively (HR, 0.29; 95% CI, 0.24-0.35).²

Darolutamide is the most recent agent to enter the landscape, boasting a median MFS of 40.4 versus 18.4 months with placebo plus androgen deprivation therapy (HR, 0.41; 95% CI, 0.34-0.50), according to data from the phase III ARAMIS trial, which were recently published in the New England Journal of Medicine.³ Based on these promising data, the FDA granted a priority review designation in April 2019 to a new drug application for darolutamide as a treatment for patients with M0CRPC.

“All 3 drugs improve metastasis-free survival. There are slight differences in terms of patient eligibility, and slight differences, perhaps, in terms of the hazard ratios for benefit, and there may be some differences in terms of the adverse event profiles,” said Lee. “Which one should we use?”

In an interview during the 2019 OncLive^® State of the Science Summit™ on Genitourinary Cancers, Lee, a medical oncologist at Massachusetts General Hospital and assistant professor of medicine at Harvard Medical School, discussed the differences between these agents and highlighted potential factors to consider in terms of selection.

OncLive: What does the treatment landscape look like for M0CRPC?

Lee: In this space, there are 3 trials that have really paved the way if we're thinking about treatments. These are all different, advanced antiandrogens or second-generation targeted antiandrogens. They include apalutamide and enzalutamide as well as darolutamide, which was presented at the 2019 Genitourinary Cancers Symposium and just published in the New England Journal of Medicine.

Each one of these 3 trials that have come out, the ARAMIS trial for darolutamide, the SPARTAN trial for apalutamide, and the PROSPER trial for enzalutamide, incorporated patients with M0CRPC. These are patients who have a prostate-specific antigen (PSA) doubling time that is less than 10 months, so that was an important part of the criteria. The 2 studies with apalutamide and darolutamide included patients who might have had nodal disease in the pelvis. These were all randomized trials, each randomized 2:1 and looked at MFS, as assessed by PSA, as well as a bone scan and CT scan of the chest abdomen and pelvis every 16 weeks. That is very similar across the trials.

Also, in each of the trials, the entry criteria included negative scans of those conventional imaging studies. One of the studies included at CT scan of the brain, but none of these included the more novel PET tracers that have become more commonplace in our assessments and are thought and proven to be more sensitive than our conventional imaging agents. That’s an important piece to [remember in terms of] inclusion criteria for all 3 studies.

Could you discuss darolutamide and the findings from the ARAMIS trial?

Patients were given darolutamide, at 600 mg twice daily or placebo. Patients were blinded to their PSA values and then they were followed for MFS, which is defined as the identification of metastasis or death, whichever came first. [Investigators saw] an improvement in MFS. I can't remember the exact numbers, but it was an over 20-month improvement compared with placebo and there was a HR for benefit of 0.41.

Some other endpoints that they described as well looked promising, but are probably too premature to discuss—such as overall survival. In looking at safety, the adverse events (AEs) described did not seem to be very different [from the other agents]. Patients who received darolutamide did not appear to have a statistically significant increase in AEs, such as fatigue, seizures, falls, and fractures, which have been some AEs of interest in other trials. I should note that this is not yet an FDA-approved therapy, so everything we're talking about is in the context of a drug where the paper has been published but is not yet approved for use.

What is the hope for this agent and where will it fit in the paradigm?

That is a tricky situation because there are already 2 effective drugs that are very similar in this space: apalutamide and enzalutamide. These have been established for, at least in terms of apalutamide, probably about 1 year prior to the publication of the darolutamide study. Enzalutamide has been used for metastatic CRPC, dating back to 2000 or so.

Therefore, there's a lot of clinical experience with both of those drugs. Whether or not [darolutamide] is an improvement is very difficult to know. There are many hazards to doing cross-trial comparisons, so I would caution against doing that. It would be reasonable to say that all 3 of these drugs improved MFS. There might be slight differences in terms of effectiveness between them that we cannot yet compare because there has been no head-to-head study, and there may be some differences in AE profiles. Perhaps that may be the trigger that might help the clinician and the patient decide between these 3 agents when they are all considered for a patient with M0CRPC.

Clinicians are going to be drawn to perhaps looking at the differing HRs for benefit as well as the differing AE profiles, and that might help with the decision making. Certainly, there are other aspects that we could consider, such as the financial toxicity of these therapies. But by and large, this category of drugs seems to be similarly priced with a similar sort of impact for patients. Therefore, I don't think that [financial toxicity is] necessarily what's going to drive selection of the agent. However, I do believe that [apalutamide and enzalutamide] have a head start in terms of already established use in practice.

What are the important takeaways from the SPARTAN trial?

SPARTAN was the trial that looked at apalutamide compared with placebo. Again, it was a very similar set-up to what I described for darolutamide. This also included patients who had N1 disease, so some patients had [regional nodal spread]. In this case, there was an improvement in MFS that was about 24 months.

Perhaps a distinguishing feature of the SPARTAN study was that patients were offered at the time of progression to receive abiraterone acetate (Zytiga) and prednisone; [these were] patients who either had placebo or apalutamide. In this study, they also looked at another exploratory endpoint called progression-free survival 2 (PFS2), that was defined as the time from randomization to actually having progression on the second-line therapy. What they saw, which I believe is of interest here, is that patients randomized to apalutamide still had a benefit in terms of PFS2 compared with patients who received placebo and then went on to a second therapy, which is, for most patients, abiraterone.

The reason this is interesting is that some have criticized that perhaps these drugs that we are giving in this space, which didn't have any FDA-approved therapies, may not necessarily impact overall survival (OS) or the overall care for these patients. However, what we're seeing here is that by sustaining PFS2, by sustaining a difference between how the patients were originally randomized to apalutamide, is that the benefit from the apalutamide may still be seen in the patients even when they're given subsequent therapies.

Said differently, the patients who received placebo don't necessarily have a catch-up in terms of their clinical benefit once they're given an effective therapy after having received the placebo. That’s important. As a field where there are many therapies now that have proven to improve OS, and in other diseases as well, concepts like PFS2 are of particular interest to us—perhaps as another way to define how these different drugs may be distinct from each other.

What is important to note from the PROSPER trial?

The PROSPER study was looking at enzalutamide. Very similarly, an improvement in MFS was observed. I believe in this study, patients were not permitted to enroll if they had nodal metastasis, so there is a slight difference in that case compared with the other studies. Patients who had a seizure history were also not permitted to enroll on the study, whereas I believe they were permitted in the darolutamide study. Therefore, there is a slight difference in terms of eligibility criteria. In this [study], there was an improvement in MFS with enzalutamide that I believe was still greater than 20 months. Again, there were other secondary endpoints that were evaluated that seemed to favor enzalutamide versus placebo. In this case, looking at the AEs of interest, there was some increase in fatigue and cardiovascular events, but there didn't seem to be any change or difference in terms of seizure risk. However, these AEs are what we would have expected, based on our own experience using enzalutamide in M1 CRPC.

What is your take-home message to your colleagues treating these patients?

I would say that we now have these 3 trials that all look very effective. Two of those drugs that were described, apalutamide and enzalutamide, are FDA-approved for this population, whereas darolutamide awaits a decision. Is there a difference between these 3?

We can go all the way back to chemistry and understand that darolutamide has more distinctive features structurally compared with apalutamide and enzalutamide. Perhaps it's that structural difference that might speak to why the AE profiles are slightly different. Whether or not that translates into a clinical difference among these 3 agents, for the patient sitting with you in the clinic room, is completely unknown to me. Whether or not that pricing is going to drive the use of these drugs differently is completely unknown to me. MFS is improved with each of them. and we all just need to think carefully and tailor the treatment to the patient sitting with us.

References

1. Small EJ, Chowdhury S, Hadaschik BA, et al. SPARTAN, a phase 3 double-blind, randomized study of apalutamide (APA) versus placebo (PBO) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC). J Clin Oncol. 2018;36(suppl 6, abstr 161). doi: 10.1200/JCO.2018.36.6_suppl.161.
2. Hussain M, Fizazi K, Saad F, et al. PROSPER: a phase 3 randomized, double-blind, placebo (PBO)-controlled study of enzalutamide (ENZA) in men with nonmetastatic castration-resistant prostate cancer (M0 CRPC). J Clin Oncol. 2018;36(suppl 6, abstr 3). doi: 10.1200/JCO.2018.36.6_suppl.3.
3. Fizazi K, Shore N, Tammela TL, et al. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Eng J Med. 2019; 380(13):1235-1246. Doi: 10.056/NEJMoa1815671.