Adding apalutamide to androgen deprivation therapy prolongs survival in patients with metastatic hormone-sensitive prostate cancer

Results from the randomized, phase III TITAN trial demonstrate that the addition of apalutamide to standard androgen deprivation therapy results in a significantly longer radiographic progression-free and overall survival in men with metastatic hormone-sensitive prostate cancer. In addition, combining apalutamide with androgen deprivation therapy was also associated with a significant delay in the time to cytotoxic chemotherapy. Importantly, the treatment was well tolerated and did not lead to a detriment in quality of life for patients.

Background

Metastatic hormone-sensitive prostate cancer (mHSPC) has a relatively poor prognosis, with a median overall survival (OS) of less than 5 years. Until recently, the standard of care for patients with mHSPC consisted of continuous androgen deprivation therapy (ADT) alone. However, over the past years, several large clinical trials have changed this treatment paradigm by demonstrating superior outcomes in these patients when ADT was combined with docetaxel, abiraterone acetate, or enzalutamide (CHAARTED, STAMPEDE, LATITUDE, ARCHES, ENZAMET). Similar to abiraterone acetate and enzalutamide, apalutamide binds to the androgen receptor (AR), thereby preventing its activation by testosterone and other androgens. The rationale behind the development of these androgen-receptor targeting agents is that direct inhibition of the AR provides a more complete reduction of androgen signaling than ADT alone, leading to improved clinical outcomes. The targeted investigational treatment analysis of the novel anti-androgen (TITAN) study was conducted to evaluate apalutamide versus placebo in a broad population of mHSPC patients who receive continuous ADT.

Trial set-up and results

The double-blind, randomized phase III TITAN trial randomly assigned 1,052 castration-sensitive prostate cancer patients with at least one distant metastatic lesion on bone scan to apalutamide (240 mg daily) plus ADT, or placebo + ADT. The co-primary endpoints of the study were radiographic progression-free survival (rPFS) and OS, while secondary objectives included the time to cytotoxic chemotherapy, time to pain progression, time to chronic opioid use and the time to the first skeletal related events (SREs). In addition to this, time to PSA progression and second progression free survival (PFS2) were exploratory endpoints in the trial. The study was designed to include a broad spectrum of patients. As a result, participants had both low (38%) and high-volume (62%) metastatic disease, and while some had been newly diagnosed with prostate cancer, others had previously received docetaxel (11%) or definitive local therapy (8%).

At the time of the presented analysis, the median follow-up was 22.9 months in the apalutamide + ADT arm and 22.4 months for patients randomized to placebo + ADT. At that time, two thirds (66%) of patients in the experimental arm were still on treatment as compared to 46% in the placebo arm. While the median rPFS was not yet reached for apalutamide + ADT, patients on placebo + ADT had a median rPFS of 22.1 months. This translated into a 52% reduction in the risk of radiographic progression or death with apalutamide + ADT (HR 0.48 [95% CI 0.39-0.60]; p<0.0001). At 24 months, 68% of patients on apalutamide were still free of radiographic progression as compared to 48% with placebo + ADT. This significant rPFS benefit was seen in all investigated subgroups, irrespective of metastatic disease burden, age, prior docetaxel use and the presence of visceral metastases. TITAN also met its second co-primary endpoint by demonstrating a significant OS improvement from the addition of apalutamide to ADT (median not reached in both arms; HR 0.67 [95% CI 0.51-0.89]; p=0.0053). At two years, this translated into an 8% absolute OS benefit in favor of apalutamide + ADT compared to placebo + ADT (82% vs 74%).

No difference was observed between both treatment arms in terms of time to chronic opioid use (HR 0.77 [95% CI 0.54-1.11]), or time to first SRE (HR 0.80 [95% CI 0.56-1.15]). However, the apalutamide + ADT combination did result in a significant delay in the time to cytotoxic chemotherapy (HR 0.39 [95% CI 0.27-0.56]; p<0.0001). Also the time to PSA progression was significantly better with apalutamide + ADT than with placebo + ADT (median not reached vs 12.91 months; HR 0.26 [95% CI 0.21-0.32]; p<0.0001) as was the PFS2 (medians not reached; HR 0.66 [95% CI 0.50-0.87]; p=0.0026).

Preserved quality of life

Both arms of the TITAN study had similar overall rates of grade 3/4 adverse events (42.2% vs 40.8%, respectively). Both arms also had similar rates of clinically important events, such as fatigue (19.7% vs 16.7%), falls (7.4% vs 7.0%), and fractures (6.3% vs 4.6%), even though the treatment exposure was longer with apalutamide plus ADT than with placebo plus ADT (median 20.5 and 18.3 months, respectively). Adverse events leading to treatment discontinuation occurred in 8% of patients on apalutamide + ADT vs 5.3% in the placebo + ADT arm. Rash accounted for most of this discrepancy, affecting 27% vs 9% of patients, respectively. Likewise, although hypothyroidism affected 8% vs 2% of patients in the respective arms, nearly all cases were grade 1, meaning that they were asymptomatic and required no intervention. The quality of life of patients was essentially preserved throughout the TITAN study, with no significant change from baseline or between treatment groups.

Conclusion

In summary, the TITAN trial once again demonstrates that the addition of a highly potent androgen-receptor targeting agent to standard ADT improves survival and delays the disease progression in mHSPC patients. These benefits were seen in patients with both high- and low-volume disease and irrespective of prior docetaxel use and did not come at the cost of additional toxicity.

Reference

Chi K, Bjartell A, Ha Chung B, 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). Presented at ASCO 2019; Abstract 5006.