Early Intensification With Apalutamide Is Key in Metastatic Castration-Sensitive Prostate Cancer

Neeraj Agarwal, MD

New findings from the phase III TITAN trial suggest that early intensification with apalutamide (Erleada) may positively affect the disease trajectory for patients with metastatic castration-sensitive prostate cancer (mCSPC) who receive subsequent therapy with chemotherapy or novel hormonal agents, said Neeraj Agarwal, MD.

Interim overall survival (OS) results from the study demonstrated a 33% reduction in the risk of death with apalutamide plus androgen deprivation therapy (ADT) compared with ADT plus placebo (HR, 0.67; 95% CI, 0.51-0.89; P = .0053).¹ Additionally, apalutamide/ADT led to a 52% reduction in the risk of radiographic progression or death versus the placebo arm.

In September 2019, the FDA approved apalutamide for the treatment of patients with mCSPC, based on the interim data from the TITAN trial.

At the 2020 Genitourinary Cancers Symposium, a posthoc analysis of TITAN showed that the risk of second progression or death (PFS2) was significantly prolonged for patients who received apalutamide/ADT versus ADT/placebo (HR, 0.66; 95% CI, 0.50-0.87; P = .0026).²

Importantly, the advantage was observed regardless of whether patients received a taxane (HR, 0.634, 95% CI, 0.456-0.881; P = .0062) or treatment with enzalutamide (Xtandi) or abiraterone acetate (Zytiga; HR, 0.684; 95% CI, 0.482-0.971; P = .0326) as their first subsequent therapy.

In an interview with OncLive, Agarwal, director of the Genitourinary Oncology Program, Oncology Division, professor of medicine, physician, and investigator at Huntsman Cancer Institute, discussed the implications of the PFS2 data from the TITAN trial in mCSPC.

OncLive: Could you highlight the initial findings from the TITAN trial?

Agarwal: The TITAN study was a large, randomized, phase III placebo-controlled trial of patients with newly diagnosed mCSPC. More than 1000 patients were randomized to ADT plus placebo versus ADT plus apalutamide. The dual primary endpoints were radiographic progression-free survival (rPFS) and OS.

At the time of the first interim analysis, both primary endpoints were met after a median follow-up of 24 months. The OS was significantly improved with a 33% reduction in the risk [of progression or death]. rPFS was also improved, with a 52% risk reduction in radiographic progression or death.

Based on these exciting data, apalutamide was approved by the FDA for the treatment of patients with mCSPC.

How did the addition of apalutamide to ADT affect PFS2?

PFS2 is calculated from the first day of therapy to disease progression or death on subsequent therapy. It is not about how patients did on the first therapy or how patients did on the second therapy; it basically encompasses both the first and second therapies.

PFS2 tells us how early intensification or initial therapy affects subsequent therapies.

In the TITAN study, PFS2 in patients who received subsequent therapies, such as chemotherapy or novel hormonal therapy, with enzalutamide or abiraterone, was significantly improved in patients who had received earlier apalutamide versus those patients who did not. Remarkably, the improvement was seen regardless of what subsequent therapy the patient received.

These data [suggest] that early intensification [with apalutamide] is key. The strategy of treating patients with upfront apalutamide continues to positively affect their entire disease trajectory as evidenced by improved outcomes with subsequent therapies regardless of what those subsequent therapies are.

Are there any remaining questions with apalutamide from the trial?

The study population in the PFS2 analysis included patients who had already experienced disease progression or had to discontinue treatment. The median PFS of this patient population was around 11 months compared with the general patient population in the TITAN trial. The median PFS with apalutamide in the overall population was 21 months. These were early progressors who had experienced more rapid disease progression. Those patients were the ones who received subsequent therapies and were, in turn, included in this analysis.

The question remains: Why didn't [these early progressors] experience benefit and why did they experience a shorter PFS on apalutamide compared with the overall patient population in the TITAN trial? Could we have done something better? Can we do something better down the line? Should we continue doing everything the same?

[We have to] elucidate the molecular biology of disease in these patients, find new targets which are driving disease progression, and find novel drugs against these targets to combine with apalutamide. That would be the next step.

Were there any new safety signals with apalutamide in the trial?

We have not seen any new safety signal with apalutamide. It continues to be a very well-tolerated drug.

[At the 2019 ESMO Congress], I presented the quality-of-life (QOL) data [from the trial]. Patients who received apalutamide did not report any worsening QOL compared with patients who received placebo. While these patients were experiencing significant improvement in their survival outcomes, their QOL was not being diminished. That is what we need from these novel therapies: improved survival while maintaining QOL.

References

1. Chi KN, Agarwal N, Bjartell A, et al. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med. 2019;381(1):13-24. doi: 10.1056/NEJMoa1903307
2. Agarwal N, Chowdhury S, Bjartell A, et al. Time to second progression (PFS2) in patients (pts) from TITAN with metastatic castration-sensitive prostate cancer (mCSPC) by first subsequent therapy (hormonal vs. taxane). J Clin Oncol. 2020;38(suppl_6; abstr 82). doi: 10.1200/JCO.2020.38.6_suppl.82