ARASENS Trial Demonstrates Significant Survival Benefits With Triplet Therapy in mHSPC

The addition of darolutamide (Nubeqa) to androgen deprivation therapy (ADT) and docetaxel led to improved overall survival (OS) and prolonged the time to metastatic castration-resistant prostate cancer (mCRPC) vs placebo plus ADT and docetaxel in patients with metastatic hormone-sensitive prostate cancer (mHSPC), according to post-hoc findings from the phase 3 ARASENS trial (NCT02799602).

The analysis, which was performed to understand patient experiences post-progression, demonstrated that the median time to mCRPC was not reached (NR) in the triplet arm vs 19.1 months in the placebo group. Median OS was also NR vs 48.9 months in the triplet and placebo arms, respectively.

Notably post-progression survival was improved only in the placebo arm in patients who received ARPI therapy vs non-ARPI therapy, with median values of 23.0 months and 13.5 months, respectively. Minimal differences in post-progression survival were seen between first subsequent treatments in the darolutamide arm.

“The patients who received the triplet combination had major benefit because they [remain longer] in mHSPC, which is associated with good quality of life, and usually no pain, or at least no pain progression,” explained Marc-Oliver Grimm, MD, lead study author and professor and chairman of the Department of Urology at the Jena University Hospital in Germany.

In an interview with OncLive^®, Grimm emphasized that for younger patients the triplet combination could be beneficial because it was shown to extend the time to mCRPC, a stage in which patients may experience worse quality of life and pain.

OncLive: What was the rationale and design behind the ARASENS trial?

Grimm:The ARASENS trial was conducted in patients with mHSPC, and it compared a triplet of darolutamide, ADT, and docetaxel with docetaxel and ADT plus placebo. [Results from this trial] showed significant improvement or reduction in the risk of death by 32.5% overall, with relatively long follow-up and mature data.

What was the rationale for this post-hoc analysis?

We wanted to know what happened to the patients after progression, and we analyzed the post-progression treatments they received, which were mainly either chemotherapy or an ARPI. This was quite different in the two treatment arms. In the patients who received the triplet combination, there was no difference [in post-progression survival] between treatment with an ARPI or non-ARPI treatment. These patients—after they received darolutamide and docetaxel—progressed relatively rapidly [on subsequent therapy]. However, these patients had a very long time in the mHSPC setting, which may be a major advantage. The median time to mCRPC was NR [with the triplet], whereas in the placebo arm, the median time to mCRPC was 19.1 months, which is associated with worse quality of life and usually also with pain at progression. The patients in the triplet arm had a major benefit because they stayed in the mHSPC stage [for a longer amount of time].

Regarding the post-progression therapy in the placebo group, these patients did benefit from ARPI treatment with abiraterone acetate [Zytiga] or enzalutamide [Xtandi] compared with non-ARPI treatment, mainly with docetaxel or cabazitaxel [Jevtana]. The median OS starting from the time when patients reached the mCRPC stage was 23.0 months [with an ARPI] compared with 13.5 months [with non-ARPI therapy].

What are some of the implications of these findings?

For young patients, the triplet combination is a very good choice. We could decide between an ARPI plus ADT compared with an ARPI, chemotherapy, and ADT. However, if patients progress, they will receive chemotherapy anyway. It’s a decision between early chemotherapy and late chemotherapy.

The other implication is that we need better treatments for those patients who have received chemotherapy and an ARPI. We need new treatment modalities, because we have seen that in the triplet arm, patients die relatively rapidly if they progress and have already received an ARPI and chemotherapy.

Are there any next steps that are planned for research using the ARASENS dataset?

There’s still biomarker material available, [which] may help to identify patients who benefit most from the triplet combination. We also expect new data from other studies with darolutamide, in which darolutamide is compared with ADT alone. We expect this data by the end of this year.

What other unmet needs exist for this patient population? Are there any ongoing research efforts that aim to address these needs?

We have to recognize that one ARPI treatment and one chemotherapy [agent] appear to be the main life-prolonging treatment we have available, so we need better treatments. If these patients progress after having both classes of drugs, radioligand therapy may be a [better] option. PARP inhibitors may be an option in those who are biomarker positive. We are also waiting for new hormonal agents, which may be a good choice in the future, but we have to wait for the studies to read out.

Reference

Grimm MO, Smith MR, Hussain MHA, et al. Post-progression survival of patients with metastatic hormone-sensitive prostate cancer (mHSPC) who received darolutamide or placebo: post hoc analysis of ARASENS. J Clin Oncol. 2024;42(suppl 16):5083. doi:10.1200/JCO.2024.42.16_suppl.5083