The changing treatment paradigm in non-metastatic castration-resistant prostate cancer

This article was commissioned by Bayer Australia Ltd.

The treatment paradigm for men with non-metastatic castration-resistant prostate cancer (nmCRPC) is changing, thanks to the survival benefits shown with second-generation androgen receptor inhibitors (ARIs).1 However, access to these newer agents has been limited to date, due to not being listed on the Pharmaceutical Benefits Scheme (PBS) for this indication.2 In an important move for men with nmCRPC, the Pharmaceutical Benefits Advisory Committee (PBAC) recently approved darolutamide (Nubeqa®) for PBS-subsidised treatment for nmCRPC.3

 We spoke with Prof. Anthony Joshua, Head of Medical Oncology at the Kinghorn Cancer in Sydney, about the importance of expanding treatment options for men with nmCRPC, and how darolutamide can be incorporated into the current treatment paradigm in accordance with its PBS criteria.

Treatment approaches for patients with nmCRPC

Before the introduction of second-generation ARIs, the standard of care for men with nmCRPC was continued androgen deprivation therapy (ADT) alone or with additional hormone therapy until metastasis.4 “This watchful waiting strategy wasn’t ideal, as it could lead to anxiety and impaired quality of life for patients – really highlighting the need for more active therapeutic interventions to delay disease progression and prolong survival in these men,” explains Prof Joshua.

Similar to first-generation ARIs, second-generation ARIs were developed to inhibit the androgen receptors that drive prostate cancer, but possess greater potency and higher binding affinity to the earlier generation agents, while avoiding agonistic activity toward androgen receptors.4,5 Unlike the first-generation ARIs, the second-generation ARIs have demonstrated benefit for improving both metastasis-free survival (MFS) and overall survival (OS) in men with high-risk nmCRPC.1,4 The approval of these newer ARIs for treating nmCRPC now offer this patient population options beyond ADT and watchful waiting.

Changing the paradigm: PBS criteria for darolutamide

Despite evidence for survival benefits for men with nmCRPC using second-generation ARIs,1 access to these treatments to date has been limited to private prescription due to not being available on the PBS for this indication.2 However, from 1st November 2021, darolutamide was listed on the PBS for nmCRPC.3 Prof. Joshua emphasises the importance of this approval: “This is the first PBS-listed ARI for men with nmCRPC, men who have had very few treatment options available up until now,” he said.

To be eligible for PBS-subsidised treatment with darolutamide, men with nmCRPC must have an absence of distant metastases on their most recently performed conventional imaging, as well as a prostate-specific antigen (PSA) doubling time of 10 months or less and a World Health Organisation (WHO) Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1. Treatment with darolutamide must be given in combination with ADT.6

Considerations for using darolutamide in clinical practice

For physicians looking to understand how darolutamide fits into the new treatment paradigm for their patients with nmCRPC, Prof. Joshua highlighted two key areas that should be considered.

Identifying appropriate patients

First, it is important to identify which of your patients will benefit from treatment with darolutamide and to ensure that they meet the eligibility criteria to receive PBS-subsided darolutamide. “Accurate measurement of PSA doubling time within the previous 10 months is really important for prognosis in these patients, which is reflected in the PBS eligibility criteria,” says Prof Joshua. Physicians prescribing darolutamide are instructed to calculate PSA doubling time using at least three PSA values measured during the preceding 10 months while the patient was receiving ADT, with the third measurement taken at least one week after the second measurement.6

Recent studies using newer prostate-specific membrane antigen positron emission tomography (PSMA-PET) suggest that conventional imaging lacks the sensitivity to detect early metastatic disease in patients with biochemical recurrence.4 However, benefit of staging with PSMA-PET to clinical outcomes have yet to be demonstrated in clinical trials, while survival benefits for the second-generation ARIs including darolutamide were demonstrated in patients with nmCRPC defined by conventional imaging and PSA doubling time alone.1 “You don’t need the PSMA-PET; you only need conventional imaging to demonstrate an absence of metastases,” 6 explains Prof. Joshua.

Personalising treatment decisions

Men with nmCRPC are often free from disease-related symptoms, but may experience symptoms associated with their age, other comorbidities, medications, or even ADT-related AEs that can impair their quality of life. Therefore, an important goal when starting a new drug to delay disease progression is to preserve quality of life, making assessment of individual risk-benefit profiles based on safety and tolerability is critical.1 In the ARAMIS trial, patient-reported quality of life was similar between the darolutamide and placebo groups, demonstrating that darolutamide did not negatively affect quality of life while delaying metastasis and prolonging survival.7,8 In clinical practice, Prof. Joshua is seeing similar outcomes: “We’re having good patient experiences with it so far. It’s generally well-tolerated. Some patients need to be reminded about compliance because darolutamide is dosed twice per day, but generally these men are quite compliant,” he says.

Efficacy and safety of darolutamide: ARAMIS trial

Regulatory and PBAC approval for darolutamide is based on the positive outcomes from the ARAMIS randomised, double-blind, placebo-controlled trial in 1509 men with nmCRPC and a PSA doubling time of 10 months or less. The trial participants received either darolutamide 600 mg twice daily (n=955) or placebo (n=554) while continuing ADT.7 The primary endpoint was MFS, which is recognised as a valid clinical trial endpoint that correlates with improved OS and quality of life in men with PC.1,4,7

The ARAMIS trial met its primary endpoint, demonstrating improved MFS with darolutamide plus ADT (40.4 months) over placebo plus ADT (18.4 months; HR 0.41; 95% CI, 0.34-0.50; p<0.001).7 “importantly, there is also an OS benefit with darolutamide,” notes Prof. Joshua. The final analysis showed that darolutamide plus ADT improved OS at 3 years, significantly reducing the risk of death by 31% (HR 0.69; 95%CI 0.53-0.88, p=0.003).8 These benefits to MFS and OS with darolutamide are consistent with outcomes from studies with the other two second-generation ARIs.1

The improvement in MFS and OS observed with darolutamide plus ADT were consistent across all prespecified patient subgroups, including stratification by PSA doubling time (≤6 months >6 to ≤10 months, baseline PSA level, age, and baseline lymph node involvement.7,8

Key secondary outcomes evaluated in the ARAMIS trial included time to pain progression, time to cytotoxic chemotherapy, and time to symptomatic skeletal event. Each of these outcomes was significantly improved with darolutamide plus ADT vs placebo plus ADT, at both the primary analysis time point (p≤0.01 for all outcomes) and at 3 years (p≤0.005 for all outcomes).7,8

The ARAMIS trial indicates that darolutamide was generally well tolerated, with a similar incidence of adverse events (AEs) and discontinuations due to AEs in both the darolutamide and placebo study arms. The most common AEs had low incidence of Grade 3 or 4 events and the most frequently reported AE was fatigue.7,8 Importantly, darolutamide was not associated with a higher incidence (versus placebo) of AEs known to be associated with other second-generation ARIs, including seizures, fractures, falls, cognitive or mental impairment disorders, or hypertension.7,8 “Darolutamide is generally well tolerated because it has lower blood-brain-barrier penetration,” explains Prof. Joshua. “So, the side effects that you do see with darolutamide are consistent with its mechanism of action,” 8 he says.


This article was sponsored by Bayer. Any views expressed in the article are those of the expert alone and do not necessarily reflect the views of the sponsor. Before prescribing, please review the Nubeqa product information via the TGA website. Treatment decisions based on these data are the responsibility of the prescribing physician.


Bayer Australia Limited, ABN 22 000 138 714. 875 Pacific Highway, Pymble NSW 2073.

November 2021 | PP-NUB-AU-0167-1


  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.
  2. Pharmaceutical Benefits Scheme. Available: (accessed October 2021).
  3. Pharmaceutical Benefits Advisory Committee. PBAC Meeting Outcomes July 2021. Available: (accessed October 2021).
  4. Esther J, Dorff TB, Maughan BL. Recent developments in the treatment of non-metastatic castration resistant prostate cancer. Cancer Treat Res Commun. 2020;24:100181.
  5. Lavaud P, Dumont C, Thibault C, et al. Next-generation androgen receptor inhibitors in non-metastatic castration-resistant prostate cancer. Ther Adv Med Oncol. 2020;12:1758835920978134.
  6. Pharmaceutical Benefits Advisory Committee. Public Summary Document PBAC Meeting July 2021. Available: (accessed November 2021).
  7. Fizazi K, Shore N, Tammela TL, et al. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2019;380(13):1235-1246.
  8. Fizazi K, Shore N, Tammela TL, et al. Nonmetastatic, Castration-Resistant Prostate Cancer and Survival with Darolutamide. N Engl J Med. 2020;383(11):1040-1049.


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