Darolutamide Plus ADT and Docetaxel for Metastatic Hormone-Sensitive Prostate Cancer

In an interview with Oncology Learning Network, Neal Shore, MD, medical director, Carolina Urologic Research Center, Myrtle Beach, SC, discusses the recent FDA approval of darolutamide plus androgen deprivation therapy (ADT) with docetaxel for the treatment of metastatic hormone-sensitive prostate cancer. This approval was based on results from the phase 3 ARASENS trial which demonstrated a survival benefit with the addition of darolutamide in this patient population.

Darolutamide was approved by the FDA for the treatment of patients with metastatic hormone-sensitive prostate cancer on August 5, 2022. This oral, androgen receptor inhibitor had previously been FDA-approved to treat non-metastatic castration-resistant prostate cancer.

Oncology Learning Network (OLN): What is darolutamide?

Dr Shore: Darolutamide is an androgen receptor blocking agent that was initially approved in the large phase 3 global ARAMIS trial in the non-metastatic castration-resistant prostate cancer population. Because the trial met its primary end point of overall survival and metastasis free survival, which was a composite end point of progression and survival, darolutamide got its initial approval.

What is interesting about this drug is that, in preclinical models, it does not cross the blood brain barrier. In all of the studies, inclusive of ARAMIS and their early phase 2 studies, as well as in ARASENS, patients with a history of seizure or on seizure prevention medication, or a history of a cerebrovascular event were not precluded from participating, unlike other with androgen receptor blocker therapies.

OLN: What data led to the study of darolutamide as a treatment option for patients with metastatic hormone-sensitive prostate cancer?

Dr Shore: There were 2 very important studies that were done for patients who had metastatic castration-sensitive prostate cancer, both low- and high-volume disease. If you accept the definition, and it is a bit arbitrary, that 4 or more bone lesions whereby at least 1 is in the appendicular skeleton, as well as in the axial skeleton, is considered high volume metastatic castration-sensitive prostate cancer. High volume would also be patients with visceral metastases, disease in the liver or lungs. No visceral metastases, or lymph node-only disease, or 3 or less bone lesions, that would be low volume.

The CHAARTED trial, as well as a corollary trial in the STAMPEDE clinical trials consortium had previously demonstrated that ADT, plus 6 cycles of docetaxel versus monotherapy ADT showed a delay in progression, a delay in castration-resistant prostate cancer, as well as an overall survival benefit. The combination of ADT and 6 cycles of docetaxel, in those 2 trials demonstrated the advantage over monotherapy ADT.

Those 2 studies really were the basis for moving forward with darolutamide and positing, if ADT docetaxel couplet therapy is better than monotherapy ADT, how about triplet therapy ADT docetaxel and darolutamide versus ADT docetaxel?

OLN: Can you discuss the ARASENS trial, which led to the recent approval of darolutamide for metastatic hormone-sensitive prostate cancer?

The approval under the FDA’s Real-Time Oncology Review pilot program was based on the pivotal phase 3 ARASENS trial, which demonstrated a statistically significant increase in overall survival with a 32% reduction in risk of death with darolutamide plus ADT and docetaxel compared to ADT and docetaxel. Treatment with darolutamide plus ADT and docetaxel also resulted in a statistically significant delay in time to pain progression.

OLN: What is the current landscape for patients with metastatic hormone-sensitive prostate cancer?

Dr Shore: Prior to the recent FDA approval of darolutamide plus ADT and docetaxel, we had a important phase 3, globally-conducted trial that demonstrated adding docetaxel to ADT was beneficial for metastatic castration-sensitive prostate cancer. Also, the combination of ADT and abiraterone acetate, the combination of ADT plus enzalutamide, and the combination of ADT plus apalutamide were all superior to ADT monotherapy.

OLN: What is the safety profile of darolutamide?

Dr Shore: It is important to note that the ARASENS trial very nicely correlated with the already well-established safety and tolerability profile that we saw in the ARAMIS trial, where ADT plus darolutamide in non-metastatic castration-resistant prostate cancer led to the first regulatory approval of darolutamide. If you look at the product information, there are only 3 aspects noted that had significant adverse events reported in greater than 10% of patients. That was in comparison of the ADT plus darolutamide arm versus the ADT monotherapy in the non-metastatic castration-resistant prostate cancer population. That led to the product information on the label of pain in the extremities, urinary infection, and fatigue, if I am not mistaken.

I am not going to make cross-drug comparative studies, but if you look at the label of adverse events, what is in the product information of the other androgen receptor blocking drugs, they are more extensive. What we found in ARASENS was there were no new safety signals for patients receiving darolutamide. It very nicely corroborated the well-described adverse event profile that we had previously seen in the ARAMIS trial. That was in castration-resistant patients. We saw a similar safety profile in castration-sensitive patients, and especially these were patients who were getting the darolutamide in combination with 6 cycles of docetaxel.

OLN: Will this approval have an immediate impact in real-world practice?

Dr Shore: Yes, especially for patients who are chemotherapy eligible. The PEACE-1 trial which was similar to the ARASENS trial in that it was patients with metastatic castration-sensitive prostate cancer who were randomized to ADT plus docetaxel and abiraterone acetate versus ADT plus docetaxel, showed, particularly in patients with high-volume metastatic castration-sensitive prostate cancer, that the triplet therapy statistically significantly outperformed the couplet therapy of just ADT plus docetaxel. That study, in totality with now ARASENS, is teaching us that patients who are chemotherapy-eligible who tend to be younger also tend to have a better performance status. And frankly, it is only 6 cycles of docetaxel with concomitant ADT and darolutamide. They clearly do better than just couplet therapy alone.

OLN: What are the next steps in the investigation of darolutamide in this or other prostate cancer populations?

Dr Shore: That is a good question, because many have said, what if there had been an arm that was just ADT and darolutamide, that did not include docetaxel? But at the time that the study was designed, there was no level one evidence for the benefit of ADT and androgen receptor blockers in combination. Right now, we have studies that are looking at ADT and darolutamide in both low- and high-volume metastatic castration-sensitive prostate cancer in comparison to just monotherapy ADT.

There are similar trial concepts, parallel to what we saw in the TITAN trial for apalutamide and the ARCHES and ENZAMET trials for enzalutamide. The ARANOTE trial is a global trial that has virtually completed accrual, looking at ADT plus darolutamide versus ADT monotherapy. And in the US, we have the ARASEC trial, which is a 200-patient open-label study of ADT and darolutamide, using the monotherapy control arm of the CHARTED trial with a propensity match score analysis. It is actually a pretty cool way of doing it. Because in the US, from an equipoise standpoint, monotherapy ADT for metastatic castration-sensitive prostate cancer is really no longer accepted as a standard of care.

OLN: Is there anything else about this approval or the study results that you would like to add?

Dr Shore: I would just say to my colleagues, to medical oncologists, urologists, and radiation oncologists, that we now have another important, very well-done, global phase 3 trial that adds to our armamentarium when discussing with patients that vital patient-physician, shared decision-making conversation.