Dr. Saad discusses pivotal ARASENS trial for metastatic hormone-sensitive prostate cancer

Favorable outcomes of the phase 3 ARASENS trial were presented at the 2022 ASCO Genitourinary Cancers Symposium last month, receiving praise from urologists worldwide.1 Urology Times® interviewed co-author Fred Saad, MD, FRCS, on the importance of this trial and the potential of triplet therapy as the future standard of care for metastatic hormone-sensitive prostate cancer. Saad is a professor and chief of urology, director of GU oncology, and Raymond Garneau Chair in prostate cancer at the University of Montreal Hospital Center (CHUM), as well as the director of prostate cancer research at the Montreal Cancer Institute/CRCHUM in Quebec.

Please discuss the background for this study.

The background behind ARASENs was the [clear] need to improve on available therapy in patients with metastatic hormone-sensitive prostate cancer. This remains the most lethal state of prostate cancer when it's diagnosed. We know that hormonal therapy, or [androgen deprivation therapy (ADT)], is very effective, but we've learned that by combining ADT [with] either chemotherapy or new-generation hormonal therapies, like apalutamide [Erleada], enzalutamide [Xtandi], or abiraterone [Zythiga] is very effective [in improving outcomes]. We know that prostate cancer is heterogeneous. There are clones that are hormonally dependent and will respond to an optimal approach for hormonal therapy, but we've got cells that are hormone independent [and] will need chemotherapy. So, the idea behind ARASENS was to [ask], "Is the triplet approach better than the doublet?" Triplet [refers to] ADT plus docetaxel plus darolutamide [Nubeqa], which is a very powerful new-generation hormonal therapy. [Doublet refers to] the control arm of ADT plus docetaxel, which, we've known for a long time, improves overall survival. And so, patients were randomized 1 to 1 in this study to try to answer that question: [Would] an aggressive triplet approach upfront rather than sequential lead to better overall survival? [This was] our bar for making a difference in patients’ lives and in the clinic.

What were the notable findings of this study? Were any of them surprising to you or your co-authors?

The most notable finding [was] the primary end point, which was overall survival. We had a 32% reduction in the risk of death in patients who got the triplet therapy of ADT, docetaxel, and darolutamide, compared to getting ADT and docetaxel alone. So, this was very significant because we're showing that triplet is better than doublet in terms of overall survival. Other very important findings [were] that whether or not patients were diagnosed with de novo metastatic disease or progressed from non-metastatic to metastatic hormone-sensitive disease, they benefited to the similar degrees. Whether or not they had visceral metastases, multiple metastases, or only lymph node metastases, they seemed to benefit. We [also] delayed symptomatic skeletal events, which patients suffer the most from. Of note, quality of life was maintained, regardless of the fact we used a triplet approach compared to a doublet. In terms of adverse events, by adding darolutamide to chemotherapy, we did not see an added toxicity profile. This was very reassuring that you can combine these drugs safely in patients who are obviously candidates for chemotherapy. That is the premise of the study—these patients were felt [by urologists] to need chemotherapy and were felt to be able to tolerate chemotherapy. And so, I think it introduces a new standard of care for patients with metastatic hormone-sensitive prostate cancer, where we clearly need to do better than what we're doing today, since the sequence of therapy seems to be less effective than hitting them hard upfront.

How will these findings guide your management of this population of patients in the future?

[For] any patient that I feel could be safely treated with chemotherapy, this will have to be an option I will be discussing with the patient. Clearly, nothing is for everybody, but somebody who is healthy enough to get chemotherapy should be considered for this form of therapy. We'll always think of the worst patients, the ones with the highest volume disease, the most aggressive disease, but I would venture to say even patients with less aggressive metastatic hormone-sensitive prostate cancer may clearly benefit because all [of] these patients will fail [other] therapy in a relatively short amount of time. So, if they have a good life expectancy, this is something I would consider. Sometimes we hear of people saying, "The hormonal approach of ADT plus a novel hormonal therapy is the standard of care already." What I would say is the thought of giving 6 cycles of docetaxel early may prevent us [from] dealing with a much more complicated disease when they start developing resistance to the hormonal approach. We know that they almost all [of] these patients will harbor some form of hormone-independent prostate cancer early on.

What makes ARASENS such a pivotal trial in the treatment of metastatic hormone-sensitive prostate cancer?

It was clearly designed to be a trial that was pragmatic in the sense [that it addressed] the issue of whether triplet therapy is better than doublet therapy. The primary end point was overall survival. When patients progressed, they went on to subsequent therapy very early. We were not blinded to PSA [and] we didn't insist on waiting for radiographic progression-free survival, so it's pivotal in the sense that it was designed to answer a clear question and patients really did get access to the best standard of care for the control arm since we didn't disallow patients to go on to subsequent therapy before they had radiographic progression, which is what goes on in the real world. So, I think it really is a study that needs to be looked at attentively. I think we need to change the mindset that chemotherapy is a bad thing. It is a very good thing when given appropriately and when patients are more likely to get long-term benefit.

What the take-home message for the practicing urologist?

The take-home message for the practicing urologist is quite simple. We now have evidence that we can do better in lethal prostate cancer. Patients with metastatic hormone-sensitive prostate cancer are almost all going to die of prostate cancer. And so, we now have an opportunity to do something more effective early [that will] allow patients to live longer, and definitely better in terms of long-term quality of life by avoiding the issues of treating resistant disease. So, we now have a way to do even better than what we've been doing for metastatic hormone-sensitive prostate cancer.

Is there anything else your audience should know about this topic or its findings?

The only other thing is that we need to keep an open mind. I think [clinicians] and patients have a negative view of chemotherapy, and I think we need to look at this data and view chemotherapy as an opportunity rather than a failure in treating patients with prostate cancer.

Reference

1. Smith MR, Hussain MHA, Saad F, et al. Overall survival with darolutamide versus placebo in combination with androgen-deprivation therapy and docetaxel for metastatic hormone-sensitive prostate cancer in the phase 3 ARASENS trial. Paper presented at: 2022 ASCO Genitourinary Cancers Symposium; February 17-19, 2022; San Francisco, California. Abstract #13