Jingsong Zhang, MD, PhD
Moffitt Cancer Center

Key Takeaways

  • Nonmetastatic castration-resistant prostate cancer (M0 CRPC) is characterized by a rising prostate-specific antigen (PSA) level, castrate levels of testosterone, and no detectable metastases on imaging scans.
  • Although the patient population with M0 CRPC is not large and is generally fit, patients with M0 CRPC tend to have more aggressive disease.
  • Second-generation androgen receptor blockers apalutamide, enzalutamide, and darolutamide are effective therapeutic options for M0 CRPC but have different safety profiles.
  • The selection of a second-generation androgen receptor blocker is based primarily on the drug’s safety profile and the potential for drug-drug interactions in an individual patient.

Jingsong Zhang, MD, PhD, is a genitourinary oncologist and interim vice chair of the Department of Genitourinary Oncology at Moffitt Cancer Center, Tampa, Florida. Dr Zhang’s work has been published in multiple medical journals. He is board certified in medical oncology and internal medicine, and his primary interest is in developing new treatments for prostate cancer

How is nonmetastatic castration-resistant prostate cancer (M0 CRPC) defined?

The clinical definition is very straightforward: Essentially we see a rise in PSA with a low testosterone level on serum testing and no metastases on imaging studies.1 So, CRPC is when the serum testosterone level is <50 ng/dL due to androgen deprivation therapy, but the PSA is rising.

What are the typical characteristics of patients with M0 CRPC?

Typically, this is not a very sick patient population. These patients are on androgen deprivation for biochemical recurrence after initial treatment for localized prostate cancer with either surgery or radiation as the primary treatment. Despite rising PSA levels with low testosterone levels, there is no detectable cancer on the diagnostic imaging scans.

This is not a large patient population in prostate cancer, particularly nowadays, with the widely used application of more sensitive PET [positron emission tomography] scans that detect early metastases, but we do still see these patients in the clinic.  They are generally fit, but prostate disease that has progressed tends to be much more aggressive than biochemical recurrence.

What is the current standard of care for M0 CRPC?

For patients with a PSA doubling time of less than 9 or 10 months, it’s justified to use the second-generation androgen receptor blockers, such as apalutamide, enzalutamide, and darolutamide. In the “old days,” we used the first-generation androgen receptor blocker bicalutamide. We still use it in the clinic. It is well tolerated and probably the least expensive prostate cancer treatment. If a patient does not have a rapid PSA doubling time, treatment can start with bicalutamide.

We haven’t seen much concern about potential drug-drug interactions with darolutamide, so that’s another advantage for patients who are taking blood thinners; for these patients, darolutamide is probably a better option.

Please tell us how the approvals of second-generation androgen receptor blockers changed the therapeutic landscape for patients with prostate cancer.

Before the approval of these newer agents, we had bicalutamide and the antifungal drug ketoconazole. Ketoconazole was started at a high dosage — 200 mg 3 times a day — and given along with hydrocortisone twice a day to prevent adrenal insufficiency. Sometimes, we’d also administer female hormones like the synthetic estrogen DES [diethylstilbestrol] or Premarin [conjugated estrogens] to treat M0 CRPC. The newer agents provide more treatment options for sure — options with proven survival benefit — and this has, indeed, changed the [therapeutic] landscape for patients with M0 CRPC.

The challenge, even with these agents, is that not everyone responds to them and sometimes the duration of response is not as durable; for instance, the patient may experience progression within a year while the scan remains clean (M0 stage). All 3 second-generation agents have very similar mechanisms of action, so we tend to pick one based on tolerance — and that would be darolutamide.

How is darolutamide different compared with the other 2 second-generation androgen receptor blockers?

Darolutamide is associated with much less fatigue. Also, because it is a bulkier molecule compared with the other 2 agents, it seems to have less potential for blood/brain barrier penetration and therefore poses a lower risk of dizziness, falls, and mental impairment.2 These are its potential advantages.

Darolutamide adverse effects
Adverse effects commonly reported with darolutamide include fatigue, pain in an extremity, and rash.

How do physicians decide which androgen receptor blocker to use in a given patient? Are there certain patient-related factors to consider?

The decision is really based on the safety profile.3 Darolutamide has a better safety profile. Also, with apalutamide and enzalutamide there is concern about potential drug-drug interactions for patients undergoing treatment with blood thinners such as warfarin or clopidogrel.4 We haven’t seen much concern about potential drug-drug interactions with darolutamide, so that’s another advantage for patients who are taking blood thinners; for these patients, darolutamide is probably a better option.


Jingsong Zhang, MD, PhD, reported affiliations with Bayer AG, Janssen Pharmaceuticals, and Pfizer, Inc.


  1. Saad F, Bögemann M, Suzuki K, Shore N. Treatment of nonmetastatic castration-resistant prostate cancer: focus on second-generation androgen receptor inhibitors. Prostate Cancer Prostatic Dis. 2021;24(2):323-334. doi:10.1038/s41391-020-00310-3
  2. Halabi S, Jiang S, Terasawa E, et al. Indirect comparison of darolutamide versus apalutamide and enzalutamide for nonmetastatic castration-resistant prostate cancer. J Urol. 2021;206(2):298-307. doi:10.1097/JU.0000000000001767
  3. Srinivas S, Mohamed AF, Appukkuttan S, et al. Physician preferences for non-metastatic castration-resistant prostate cancer treatment. BMC Urol. 2020;20(1):73. doi:10.1186/s12894-020-00631-4
  4. Shore N, Zurth C, Fricke R, et al. Evaluation of clinically relevant drug-drug interactions and population pharmacokinetics of darolutamide in patients with nonmetastatic castration-resistant prostate cancer: results of pre-specified and post hoc analyses of the phase III ARAMIS trial. Target Oncol. 2019;14(5):527-539. doi:10.1007/s11523-019-00674-0

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Reviewed October 2021