Sandy Srinivas, MD
Stanford University School of Medicine, Palo Alto, California

Key Takeaways

  • In 3 clinical trials investigating the use of androgen receptor pathway inhibitors (ARPIs) in nonmetastatic castration-resistant prostate cancer (nmCRPC), the primary endpoint of metastases-free survival (MFS) was met and improvements in overall survival (OS) were observed in each trial.
  • ARPIs are recommended for nmCRPC patients with a short prostate-specific antigen doubling time (PSA-DT), defined as less than 10 months, while those with a long PSA-DT can be watched with androgen deprivation therapy (ADT) alone.
  • The most common side effects associated with the use of ARPIs include fatigue, fractures, falls, and cognitive dysfunction.
  • For older adult patients who experience adverse effects, especially fatigue, dose adjustments or holds may be required. Clinicians should be mindful of comorbidities, polypharmacy, and the potential for drug-drug interactions in this population.
  • In patients treated with ARPIs, the effectiveness of therapy should be assessed every 6 to 12 months via serum PSA and imaging.

With the US Food and Drug Administration’s (FDA) approval of apalutamide and enzalutamide for nmCRPC in 2018, and with darolutamide obtaining approval for nmCRPC in 2019, patients and providers gained novel treatment options associated with longer survival and greater quality of life; these ARPIs received FDA approval based on MFS as an endpoint in clinical trials.1-3
Sandy Srinivas, MD, is a urologic oncology specialist and professor of medicine at Stanford University School of Medicine in Palo Alto, California, and is medical director of the inpatient hematology oncology unit at Stanford Health Care. Dr Srinivas is the clinical research group leader for the Urologic Program at Stanford and vice chair on the National Comprehensive Cancer Center (NCCN) Prostate Cancer Panel. In this article, Dr Srinivas discusses the impact of ARPIs in the treatment of patients with nmCRPC, as well as important prescribing considerations and potential side effects associated with these therapies.

The use of ARPIs in prostate cancer has expanded beyond metastatic castration-resistant prostate cancer (mCRPC) in the past several years. In your experience, how have ARPIs affected outcomes for patients with nmCRPC?

There are currently 3 FDA-approved novel ARPIs: enzalutamide, apalutamide, and darolutamide. Enzalutamide has a broad approval for nmCRPC and mCRPC in patients who have previously received docetaxel.4 Apalutamide is approved for nmCRPC, and darolutamide is approved for nmCRPC and in combination with docetaxel for mHSPC.5,6
Abiraterone, which is approved for use in pre- and post-docetaxel metastatic castration-resistant prostate cancer, exhibits significant cross-resistance with androgen receptor pathway inhibitors.7-9
The use of these ARPIs in nmCRPC has resulted in delayed time to metastases and improved quality of life for patients.10 Patients are very reassured that they are on active therapy and do not suffer from the physical or mental distress of the consequences of bone metastases. The efficacy has to be weighed against the toxicity of these potent drugs; the most common side effects are fatigue, fractures, falls, and cognitive dysfunction.4-6
Many older adult patients do require dose adjustments or holds based on adverse effects, most notably fatigue. Given the age of these patients and their risk of comorbidities, it is important to pay attention to polypharmacy and the potential for drug-drug interactions.

Can you provide an overview of the NCCN guidelines for preferred regimens utilizing ARPIs for nmCRPC?

The definition of nmCRPC as presented in the large phase 3 trials that led to the approval of these ARPIs was based on conventional imaging with computed tomography/magnetic resonance imaging and bone scan. NCCN starts with defining these patients based on conventional imaging and then assessing the PSA-DT. Those patients with long PSA-DT can be watched with ADT alone and do not need to start the ARPIs. However, those patients with a short PSA-DT — defined as less than 10 months — are recommended to receive an ARPI.
All 3 drugs — enzalutamide, apalutamide, and darolutamide — have a category 1 recommendation. These recommendations are based on the following clinical trials: PROSPER ( identifier: NCT02003924), which evaluated enzalutamide; SPARTAN ( identifier: NCT01946204), which evaluated apalutamide; and ARAMIS ( identifier: NCT02200614), which evaluated darolutamide. These trials had very similar design, entry criteria, and endpoints, and all 3 trials were evaluated against placebo. All 3 trials met the primary endpoint of MFS. These were landmark results in the history of advanced prostate cancer in that they were the first times drugs had been approved on the basis of MFS. The difference between the 2 arms was more than a doubling of MFS, with hazard ratios ranging from 0.28 to 0.41. This was highly significant and meaningful to patients. All 3 trials showed improvements in OS and maintenance of quality of life.11-13 All of these results account for NCCN’s recommendation, with the ARPIs listed in alphabetical order.

All 3 trials investigating ARPIs for nmCRPC met the primary endpoint of MFS. These were landmark results in the history of advanced prostate cancer in that they were the first times drugs had been approved on the basis of MFS.

What key factors do you consider when weighing the potential risks and benefits of ARPI treatment for patients with nmCRPC?

Many factors should be taken into consideration before prescribing ARPIs to patients with nmCRPC. As with any disease state, patient characteristics, disease characteristics, and drug characteristics should be taken into consideration. The most important disease characteristic would be PSA-DT. In those patients with a short PSA-DT, their risk of developing bone metastases is high. The presence of bone metastases can lead to pain and morbidity and is the key reason to treat these patients.
By definition, these patents with nmCRPC are asymptomatic and have a rising serum PSA with castrate levels of testosterone as their marker of disease. Other patient considerations would be their overall state of health and comorbidities; those patients with poor performance status and significant cardiac comorbidities may not be appropriate candidates to start therapy for an asymptomatic state.
Finally, drug characteristics are important as well. Apalutamide carries the risk of a unique rash and enzalutamide can have significant drug-drug interactions; depending on individual patient-level characteristics, adjustments may have to be made.4,5 Those patients who have a low threshold for seizures would want to avoid enzalutamide.5 Finally, patient motivation and financial toxicity with copayments that pose substantial stress to patients must be taken into consideration.

Turco et al noted that the introduction of ARPIs earlier in the disease course —thus leading to longer periods of exposure to these agents — increases the risk for adverse events that can affect quality of life and treatment adherence.14 What strategies do you use to monitor, prevent, and address ARPI-related adverse events in patients with nmCRPC?

Patients with nmCRPC are on ADT and, by definition, have low levels of testosterone. Much of the side effects in the short term and long term are from low testosterone. When the ARPIs are added in addition to ADT, some of the side effects are increased. In general, side effects include overall fatigue, cardiac effects, impaired bone health, metabolic effects, and sexual effects.14 Patients starting these drugs should be counseled about these side effects and what to expect. They should be seen every 3 months with blood pressure monitoring and blood tests to evaluate anemia, and the effectiveness of therapy should be assessed with serum PSA and imaging every 6 to 12 months.
Patients should be advised about healthy lifestyle habits such as exercising to combat fatigue, quitting smoking, decreasing alcohol consumption, and consuming a diet rich in fiber and low in fat. In addition to blood pressure monitoring, clinicians should obtain baseline lipid levels and institute therapy if appropriate. Patients on anticoagulants and multiple cardiac medications may benefit from teaming up with a cardiologist to share their care. Those patients with severe cardiac comorbidities may benefit from a switch to a luteinizing hormone-releasing hormone (LHRH) antagonist.
Bone health gets affected when testosterone levels are low. Patients should be advised to start calcium and vitamin D supplements and should have their baseline bone mineral density evaluated; if low, they should consider treatment for osteoporosis.15

Key characteristic in prescribing ARPIs
PSA-DT is the most important disease characteristic to consider before prescribing ARPIs, as a short PSA-DT is associated with a high risk of bone metastases.

A review by Lavaud et al described the recent emergence of novel positron emission tomography (PET) imaging approaches that may “redefine the management of prostate cancer in this setting of low-burden CRPC.”16 What is the state of progress in the use of such strategies to discriminate between nmCRPC and mCRPC and guide the treatment of patients with nmCRPC?

Prostate-specific membrane antigen (PSMA)-based PET imaging is approved in the US and is increasingly used for prostate cancer patients.17 It is typically utilized to detect oligometastases in earlier stages of the disease, such as high-risk localized or biochemical recurrence, which can help guide metastases-directed therapy. In patients with very advanced disease refractory to novel hormone therapies and chemotherapy, PSMA PET is used to select patients who are candidates for the recently approved radioligand lutetium Lu-177 vipivotide tetraxetan (Lu-177 PSMA).18
Based on its sensitivity, the use of PSMA PET imaging is able to identify metastases at much lower levels of serum PSA, and some patients who were considered nmCRPC by conventional imaging were indeed found to have metastases with PSMA PET imaging.19 How to approach patients who have negative conventional imaging and have metastases with PSMA PET imaging remains controversial, and there is not a consensus on what the optimum therapy is for these patients. Those patients with identified metastases would be treated with an ARPI or abiraterone, irrespective of PSA-DT.
There are several clinical trials combining a poly-adenosine-diphosphate-ribose polymerase (PARP) inhibitor with either abiraterone or ARPIs, which have shown improvement in radiographic progression-free survival in all patients with first-line mCRPC. However, patients with BRCA mutations appear to achieve the highest level of benefit, and OS results are awaited.20

What are some of the most promising developments currently underway in research investigating novel therapies for nmCRPC?

The approval of the 3 ARPIs was a landmark in the history of drug development in prostate cancer. The ability to use MFS as an endpoint was a remarkable milestone that allows for drugs to be tested and approved with an endpoint that is shorter than OS. In theory, nmCRPC is a good platform for new drugs to be tested; however, with the use of more sensitive imaging, the enthusiasm and ability to study this disease state has become limited. There are currently no large phase 3 trials in this space.

This Q&A was edited for clarity and length.


Sandy Srinivas, MD, reported affiliations with Novartis Pharmaceuticals Corporation; Janssen Pharmaceuticals, Inc; AstraZeneca Pharmaceuticals, LP; Merck & Co, Inc; Seagen, Inc; and Bristol-Myers Squibb Company.


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Reviewed April 2023