Darolutamide Tablets Usher in New Standard of Care in mHSPC


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Jacob Berchuck, MD, discusses the effect of the approval of darolutamide tablets on the standard of care for patients with metastatic hormone sensitive prostate cancer.

Jacob Berchuck, MD

Jacob Berchuck, MD

Treatment with androgen deprivation therapy (ADT) in combination with docetaxel is the current standard of care for patients with treatment-naïve metastatic hormone sensitive prostate cancer (mHSPC). However, the treatment paradigm may shift following the August 5, 2022, FDA approval of darolutamide (Nubeqa) tablets with docetaxel in addition to ADT, according to Jacob Berchuck, MD.1

Results from thephase 3 ARASENS trial (NCT02799602), which evaluated the safety and efficacy of ADT plus docetaxel and the androgen receptor (AR) inhibitor, darolutamide vs ADT plus docetaxel, supported the approval. The median overall survival (OS) was not reached (NR; 95% CI, NR-NR) in the darolutamide plus docetaxel arm compared with 48.9 months (95% CI; 44.4-NR) in the docetaxel plus placebo arm (HR 0.68; 95% CI, 0.57- 0.80; P<.0001). The darolutamide combination also resulted in a statistically significant delay in time-to-pain progression (HR 0.79; 95% CI, 0.66-0.95; 1-sided P=.006).2

“The trial demonstrated that the triplet therapy improved upon a current standard of care or prior standard of care, which was ADT plus docetaxel alone,” Berchuck said. “In my mind, consistent with the FDA approval, the triplet of ADT, docetaxel, and darolutamide is the new standard of care for the first-line treatment for men with mHSPC.”

In an interview with OncologyLive®, Berchuck, a medical oncologist in the Lank Center for Genitourinary Oncology at Dana-Farber Brigham Cancer Center, in Boston, Massachusetts, further discussed the effect of the approval on the standard of care for patients with mHSPC.

How does this approval shift the treatment paradigm in mHSPC?

Men with mHSPC have several treatment options based on randomized prospective data that has demonstrated intensifying first-line treatment beyond ADT by adding either docetaxel or a potent AR inhibitor improves OS when used in the first-line setting.

ARASENS [evaluated] whether the triplet regimen improves outcomes relative to ADT and docetaxel plus placebo. The [triplet] improved OS for patients with mHSPC relative to ADT and docetaxel. This is the first FDA approval specifically for triplet therapy for the first-line treatment of patients with mHSPC.

How do you see the approval of this combination affecting current practice patterns?

The question is: Which patients are going to benefit from triplet therapy and which patients need triplet therapy? ARASENS did not completely answer this, [but], for most patients, ADT plus an AR signaling inhibitor such as darolutamide, enzalutamide [Xtandi], or apalutamide [Erleada] is the preferred option.

ADT plus docetaxel in my clinic is reserved for patients with high volume mHSPC. That is a subset of [approximately] one-third of men with metastatic prostate cancer, but I reserve chemotherapy for that subset.

In most patients, I prefer an AR pathway inhibitor. The design of the ARASENS doesn’t answer the question of does adding chemotherapy to ADT plus an AR inhibitor improve upon ADT and the AR inhibitor alone. The way that I’m using these data and the FDA approval in my clinic [starts with asking] is [the patient] fit for chemotherapy. If the answer is no, then I am not going to be using this triplet therapy and will favor an ADT plus an AR inhibitor.

For patients who are chemotherapy fit, I ask: Is there compelling evidence that chemotherapy is going to benefit this patient? What we know from the charted data is that this benefit [seems] to be most pronounced in men with high-volume disease. If a patient has high-volume disease, and I think that they are chemotherapy fit and are likely to benefit, those are the patients I am treating with the triplet therapy.

For patients who are not chemotherapy fit or have low-volume mHSPC, I am still favoring ADT with an AR inhibitor. Other factors [are also considered such as] age, comorbidity, etc. The data are going to evolve to identify out which patients are most likely to benefit from the triplet therapy as opposed to the standard doublet regimen.

Could you go into detail about the pivotal efficacy data from ARESENS?

Patients were randomized to receive ADT and docetaxel for 6 cycles and to receive darolutamide 600 mg, twice [daily] or placebo. The primary end point was OS and men in the darolutamide arm had a 32% reduction in the risk of [death] during the study period. Two of the key secondary end points were time to castration resistance and time to pain progression, which both significantly favored the addition of darolutamide to ADT plus docetaxel.

We [saw a clear] improvement on a standard of care in terms of efficacy, with very little in the way of toxicity and all these results [show] that this is a new standard of care for men with mHSPC.

Are there patients with contraindications for whom you would not recommend this regimen?

There really are not. What is exciting about this approval and the expanded opportunity to use darolutamide is that it is a very well tolerated drug.

[Darolutamide] is an AR inhibitor that was specifically designed to have 2 favorable features. It has very little crossing of the blood brain barrier, so the cognitive and neurologic adverse effects of AR inhibition are minimized with darolutamide relative to other AR inhibitors. Second, it has very few clinical drug interactions and it is a favorable drug when we think about using it in combination with other treatments such as ADT and docetaxel. Those features make it a very safe drug to use for most patients.

What does the future hold for this patient population?

The big unanswered question in my mind is: Which patients are candidates for and benefit from adding docetaxel to those drugs [ADT plus an AR inhibitor]? We do not have that answer from ARASENS. The short answer is that darolutamide is well tolerated and had very little toxicity beyond ADT and docetaxel alone.

In addition to ARASENS, there was a very similar study that was reported at [The European Society of Medical Oncology Congress 2021]. The [phase 3] PEACE-1 study [NCT01957436] looked at a similar question of adding abiraterone [Zytiga] to ADT and docetaxel; the study’s results were very similar [with] improvement in OS when adding the AR signaling inhibitor abiraterone[to] ADT and docetaxel.

Is there any ongoing research in the space that you would like to highlight?

Two areas that that I think are important to highlight are, No 1, developing better treatments for men with early-stage prostate cancer to prevent them from developing metastatic recurrence—increasing cure rates. The second is developing better biomarkers for treatment selection and personalizing therapeutic decision-making for individual men in clinic.

Mary-Ellen Taplin, MD at Dana-Farber [Cancer Institute] is leading the PROTEUS study [NCT03767244], which is a randomized phase 3 study of looking at perioperative neoadjuvant and adjuvant ADT plus apalutamide or placebo for men undergoing radical prostatectomy for localized high-risk prostate cancer. The idea here is that we know that a lot of men with high-risk localized prostate cancer recur following surgery, [so] the study is asking: Does early initiation of intense hormone therapy lead to sterilization of micro metastatic disease [and] downsizing of the primary tumor [resulting in] higher cure rates [with] radical prostatectomy to prevent men from developing metastatic recurrence? That trial is nearing the end of accruel and I think we’re all really excited to see whether that approach is going to help increase cure rates and decreased prostate cancer mortality.

To the second point, there’s a lot of exciting work being done here at Dana-Farber developing novel biomarkers to predict which therapies are going to be most effective for individual patients. This spans from looking at prostate cancer genomics to identify men with more or less aggressive disease [as well as] identify patients who will benefit from PARP inhibitors. We need better biomarkers to predict response to FDA-approved PARP inhibitors. Beyond that I think there’s some exciting work being done to identify new subtypes of prostate cancer.


  1. FDA approves darolutamide tablets for metastatic hormone-sensitive prostate cancer. FDA. August 5, 2022. Accessed August 12, 2022. bit.ly/3p7oDN5
  2. Nubeqa. Prescribing information. Bayer HealthCare Pharmaceuticals Inc; 2022. Accessed August 12, 2022. bit.ly/3QBMqRh
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