Saad Highlights Striking Survival Benefit With Apalutamide in nmCRPC

Fred Saad, MD, FRCS

The addition of apalutamide to androgen deprivation therapy (ADT), significantly improved overall survival (OS) and metastasis-free survival (MFS) in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC), according to final results from the phase 3 SPARTAN trial.

With a follow-up of 52.0 months, 428 OS events had occurred. Median OS was significantly longer with apalutamide plus ADT versus placebo plus ADT, at 73.9 months versus 59.9 months (HR, 0.78; 95% CI, 0.64-0.96; P = .0161). When adjusted for crossover effects, apalutamide increased median OS by 21.1 months versus placebo (73.9 months vs 52.8 months). Apalutamide also extended median second progression (PFS2) by 14.4 months compared with placebo (55.6 months vs 41.2 months; HR, 0.55; 95% CI, 0.46-0.66; P <.0001).

“In a nutshell, the results were striking. Patients who started on the placebo arm developed metastasis in 16 months and patients who started on apalutamide developed metastasis in 40 months. There was a 2-year improvement in MFS,” said lead study author Fred Saad, MD, FRCS. “Additionally, there was an improvement in the time the of PFS2 in patients who started on apalutamide compared with those who started on placebo, by over 50%.”

In an exclusive interview with OncLive during the meeting, Saad, the Raymond Garneau Chair in Prostate Cancer; a professor, chief of Urology, and director of Genitourinary Oncology at the University of Montreal Hospital Center; and the director of Prostate Cancer Research at Montreal Cancer Institute, discussed the final results from the pivotal phase 3 SPARTAN trial in nmCRPC.

OncLive: Could you provide background on the SPARTAN trial? What previous data have been seen with this drug in prostate cancer?

Saad: SPARTAN is one of the first phase 3 studies to tackle the issue of nonmetastatic castration-resistant disease. We enrolled patients who were at high risk of [developing] metastatic [disease], and high risk was defined as a prostate-specific antigen (PSA) doubling time of less than 10 months. Patients were nonmetastatic, based on conventional imaging.

Patients were randomized 2:1 between apalutamide and placebo, which was the standard of care of just continuing ADT with nothing else, until patients became metastatic. The primary end point of the trial was MFS. We captured metastasis on imaging that was scheduled on regular intervals. The SPARTAN trial is very unique because we followed patients until second progression, so PFS2. This was quite unique; it was the first study I’ve been involved in, after 30 years of studies, that made an effort to capture PFS2. We tried to understand what patients received as subsequent therapy and we followed them until they progressed again. The main question we wanted to answer was, “Does starting in the nonmetastatic state make a difference, or should we wait until [a patient developed metastatic disease] before we start the subsequent therapy?”

Another unique quality of this trial was that patients were offered abiraterone at the time of progression. Patients were not left in limbo; they were offered an active agent that was also being used as the standard of care in the metastatic setting.

In a nutshell, the results were strikingly positive. Patients who started on the placebo arm developed metastasis at 16 months and patients who started on apalutamide developed metastasis at 40 months; this translated to a 2-year improvement in MFS, and this continued to carry over in the PFS2, where there was an over 50% improvement to time to PFS2 in patients who started on apalutamide compared with those who started on placebo.

Apalutamide received regulatory approval based on earlier results from this trial. Since its approval, how has apalutamide impacted clinical practice?

Clearly, the results regarding MFS were beyond what we expected when we started the clinical trial. It completely changed because it was the first agent approved for treating patients with nmCRPC in the high-risk category.

We now had something to offer our patients who were at high risk of metastases. We were very concerned of being in a state of limbo between having something to offer or doing nothing until their disease became metastatic. Patients found that strikingly unnerving that we would do nothing until their disease became metastatic. It didn’t make any sense, but we couldn’t do anything until we proved that we had something useful. To this end, this agent completely changed what we were able to offer our patients.

We still had people wondering whether delaying metastases was something that was really worth doing; they wanted to see overall survival (OS). OS is an extremely high bar when you are following patients very closely and are starting therapy in the metastatic state, much earlier than in the real world. Personally, I was cautiously optimistic because patients were treated very well; so many therapies were available in the placebo arm to catch up in terms of OS.

The data presented at the 2020 ASCO Virtual Scientific Program were truly striking. Even though patients received effective subsequent therapy very early in the placebo arm, we saw over a 14-month improvement in OS in patients who start apalutamide up front, rather than just waiting for metastasis to develop before starting very effective therapy. That is 3-4 times as long as the survival advantages that were seen when we start patients in the mCRPC state compared with starting them on placebo.

We went from a 4-month improvement when waiting for metastases, to a 14-month improvement when starting in the nmCRPC setting, which is probably very low-volume metastatic disease in reality. The importance of early therapy make a lot more sense now and I hope that all this controversy of whether or not to treatment the nonmetastatic state is diminished.

What characteristics of apalutamide sets the agent apart from other androgen receptor inhibitors available in this space?

Apalutamide is certainly in line with the other pure androgen receptor–targeted therapies. The agent really differs from the androgen synthesis inhibitors like abiraterone; it is not acting on the production of androgen, but on the blockage of the androgen receptor, such as enzalutamide (Xtandi) and darolutamide (Nubeqa). Thus, they are very similar in terms of efficacy. Interestingly, we saw less fatigue with apalutamide.

We conducted a clean quality of life (QoL) analysis and it was very reassuring. In the asymptomatic state, when a patient has nonmetastatic disease, we gave a drug that would potentially have adverse events. However, patients remained with very stable QoL and showed no signs of deterioration. If anything, we saw a trend deterioration in QoL in the placebo arm.

Ultimately, all 3 drugs are very efficacious and well tolerated. It’s great that we now have multiple options for treating an entity that was once considered an orphan entity in terms of treatment options.

Did you learn anything else in terms of the safety profile of this agent with the longer follow-up data?

We already had a good idea of how well it was tolerated, along with potential issues that could arise. For example, a slightly higher [rate of] fatigue [was observed] with apalutamide than with ADT alone. However, this was expected; it’s a class effect of these agents. Some patients did develop a rash, although it was very tolerable in the vast majority. A percentage of patients developed low-grade hypothyroidism, although this was also very easy to manage and was not found to be too bothersome for most patients. This was something that we actually looked for.

We don’t know whether the other agents have this issue with hypothyroidism. This was an elderly population with a median age of 74. Patients were followed on apalutamide three times as long as they were on the placebo arm. Thus, we have three times the opportunity to capture negative adverse events (AEs). The bottom line is to ask whether these AEs negatively affected the QoL of our patients and the answer was no.

Is anything left unanswered from this study that you hope to address with future research?

Every time we answer a question, multiple questions arise. This leads to good research. The vast majority of patients respond very well to apalutamide. However, one of the unanswered questions is, “What should we do for patients who don’t respond well?” Over 90% of patients respond to this agent, but what is happening in the group of patients who do not respond? How should we treat those patients?

We are going to be presenting some data on PSA kinetics, on combining PSA with genomic profiles. We are trying to figure out whether there are better ways to find early signals where we may have to intensify therapy over apalutamide alone. Although this agent may work for a majority of the patients, there is a minority that we are still trying to figure out. Impressive OS data have been reported with apalutamide in the metastatic hormone-sensitive state. This being said, I believe a case is building for combination therapy.

I’m leading a trial that is examining the combination of abiraterone plus apalutamide up front to see whether we can do better than abiraterone alone. Hopefully, we will be able to report these results in the coming months.

Reference

Saad F, Small EJ, Chowdhury S, et al. Final survival results from SPARTAN, a phase III study of apalutamide versus placebo in patients with nonmetastatic castration-resistant prostate cancer. J Clin Oncol. 2020;38(suppl 15):5516. doi:10.1200/JCO.2020.38.15_suppl.5516