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Integrating New Agents and Advances Into Current Prostate Cancer Treatment

Daniel W. Lin, MD

Professor and Chief of Urologic Oncology
Department of Urology
University of Washington
Seattle, Washington


Daniel W. Lin, MD, has disclosed that he has received funds for research support from Decipher, Genomic Health, MagForce USA, and MDxHealth; consulting fees from Astellas, Clovis Oncology, and Janssen; and other financial or material support from AstraZeneca.


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Alicia K. Morgans, MD, MPH

Genitourinary Medical Oncologist
Dana-Farber Cancer Institute
Boston, Massachusetts


Alicia K. Morgans, MD, MPH, has disclosed that she has received funds for research support from Bayer, Dendreon, Myovant, Sanofi, and Seattle Genetics and consulting fees from AAA, AstraZeneca, Astellas, Bayer, Blue Earth, Clovis, Dendreon, Exelixis, Janssen, Myovant, Myriad, Novartis, Pfizer, Sanofi, and Seattle Genetics.


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David F. Penson, MD, MPH

Professor and Chair
Department of Urology
Vanderbilt University School of Medicine
Nashville, Tennessee


David F. Penson, MD, MPH, has no relevant conflict of interest to report.


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Released: November 2, 2021

Prostate cancer treatment paradigms continue to evolve, particularly in the setting of androgen deprivation therapy. In this commentary based on a symposium from the 2021 American Urological Association (AUA) annual meeting, Daniel W. Lin, MD; Alicia K. Morgans, MD, MPH; and David F. Penson, MD, MPH, discuss promising recent advances in metastatic and nonmetastatic prostate cancer.

Advances in GnRH Antagonists

Daniel W. Lin, MD:
Key to prostate cancer therapy is ablating the androgen axis with androgen-deprivation therapy (ADT). For many years, gonadotropin-releasing hormone (GnRH) receptor agonists (eg, leuprolide) were mainstays of treatment, but more recently, GnRH antagonists, including degarelix and relugolix, have become available.

Relugolix is a once-daily oral GnRH receptor antagonist that was recently approved based on data from the phase III HERO study, which compared relugolix with leuprolide as ADT for patients with prostate cancer (N = 930). In this trial, the sustained castration rate at 28 days was 97% with oral relugolix vs 89% with subcutaneous leuprolide, with noninferiority demonstrated for relugolix. Similar to what has been observed with degarelix, relugolix treatment resulted in a more rapid decline in testosterone levels vs leuprolide, although no difference was evident by 28 days. With longer follow-up, leuprolide was associated with more major adverse cardiovascular events (MACE) compared with relugolix (6.2% vs 2.9%), particularly in patients with a history of MACE (17.8% vs 3.6%).

Advances in Nonmetastatic Castration-Resistant Prostate Cancer

David F. Penson, MD:
Three next-generation androgen receptor inhibitors are currently available for treating nonmetastatic castration-resistant prostate cancer (nmCRPC): apalutamide, enzalutamide, and darolutamide. All are effective and recommended. Apalutamide and enzalutamide have very similar molecular structures, and there is overlap between their adverse events profiles. Darolutamide, on the other hand, has a distinctly different structure than apalutamide and enzalutamide and is characterized by lower blood–brain barrier penetration. It appears to have improved tolerability as well, in my clinical experience.

The registrational trials for these agents (SPARTAN/apalutamide, PROSPER/enzalutamide, and ARAMIS/darolutamide) had very similar designs. These were placebo-controlled randomized trials with a primary endpoint of metastasis-free survival (MFS).

Results from SPARTAN showed a significant MFS advantage: Median MFS was 40.5 months with apalutamide vs 16.2 months with placebo. This translates into a 72% reduction in the risk of distant progression or death, along with an additional 24 months of MFS. Results from PROSPER were similar, with a highly significant HR of 0.29 for the MFS benefit from enzalutamide vs placebo. Again, there was a similar reduction in the risk of distant progression or death, plus nearly 2 years of extended MFS. ARAMIS showed that darolutamide was significantly superior to placebo, with median MFS of 40.4 months vs 18.4 months, respectively (HR: 0.41). In this study, there was a 59% reduced risk of distant progression and 22 months of additional MFS benefit.

With the caveat that cross-trial comparisons are challenging, it is clear that all 3 of these drugs are effective in treating nmCRPC. In all 3 trials, overall survival was improved vs placebo and discontinuation of treatment was rare, as these agents are well tolerated. I would point out that the patients likely to benefit the most from these novel androgen receptor inhibitors are those with a prostate-specific antigen doubling time shorter than 10 months.

Switching ADT in Patients With nmCRPC

Daniel W. Lin, MD:
Let’s discuss a particular scenario: A patient had treatment for early prostate cancer, experienced disease recurrence, was put on a GnRH antagonist like relugolix, but then showed signs of early nmCRPC. In this situation, as mentioned above, it would often be recommended to add an androgen receptor inhibitor. However, would it be best to keep the same GnRH antagonist, or would it be preferable to switch to a GnRH agonist? Dr. Morgans, how have you navigated this situation in your clinic?

Alicia K. Morgans, MD, MPH:
With the caveat that relugolix is so new that nobody has extensive experience with it outside of the clinical trials, there are extensive safety data from presentations and publications showing that combining this agent with androgen receptor inhibitors is reasonable and safe. Regarding enzalutamide and abiraterone or other agents for metastatic CRPC, those agents may be good for controlling prostate cancer but could raise mortality risk in patients with cardiovascular comorbidities—even push them over the edge. If patients are tolerating relugolix and have cardiovascular concerns, I would keep them on relugolix.

Treatment Intensification in Metastatic Hormone-Sensitive Prostate Cancer

Alicia K. Morgans, MD, MPH:
For patients with metastatic hormone-sensitive prostate cancer (mHSPC), should ADT be intensified with the addition of an androgen receptor inhibitor or chemotherapy when possible? The answer is yes. Treatment intensification is the new standard of care for mHSPC; this typically comprises the addition of abiraterone, apalutamide, enzalutamide, or docetaxel to ADT. Of note, treatment intensification is recommended regardless of prostate-specific antigen velocity. Also, shared decision-making is important to help patients choose the therapy that provides their best quality of life and aligns with their preferences.

Managing Patients With Bone Density Concerns

Daniel W. Lin, MD:
One challenge in clinical practice is managing patients with prostate cancer who require ADT but have existing bone density issues, per a pretreatment dual-energy x-ray absorptiometry (DXA) scan. Dr. Penson, what do you consider for a patient like this?

David F. Penson, MD:
Because it is so important to identify whether a patient is at higher risk of fracture, physicians should routinely conduct DXA scans (bone scans) upon starting ADT. In our clinic, we use the FRAX tool to help assess risk and determine if treatment is needed to prevent osteoporosis. If patients appear to be at higher risk of fracture, denosumab is one option and can be administered in a urologist’s office. Zoledronic acid is well tolerated but requires a clinic that has infusion capabilities. Oral bisphosphonates can also be effective in reducing fracture risk. I try to put all my patients with prostate cancer on vitamin D supplementation. It’s not an exciting new drug and can be underappreciated, but it is worthwhile. I typically do not recommend calcium, except for patients who are to receive denosumab or zoledronic acid.

I also emphasize to patients that exercise is truly helpful with their experience of cancer—it can improve bone density, mental health, their outlook on life, and their overall fitness. In particular, I recommend cardiovascular exercise to my patients.

Managing Patients With Diabetes and/or Hypertension

Daniel W. Lin, MD:
Many men with prostate cancer must also cope with comorbidities like diabetes and hypertension. These can complicate the choice of combination therapies. Dr. Morgans, how have you approached this situation?

Alicia K. Morgans, MD, MPH:

For the rare patients with uncontrolled diabetes, I would not recommend prednisone and abiraterone. For most patients with diabetes, prednisone will have minimal effects on blood glucose when given at the low dose of 5 mg once daily. If there are concerns with prednisone, enzalutamide and apalutamide are options.

For patients with very poorly controlled blood pressure who are starting ADT, I will often wait a few months before starting a partner drug to allow time for the patient and the primary care doctor (or cardiologist) to achieve blood pressure control. I often tell patients with prostate cancer that they would benefit from a partner drug, but when they have very high blood pressure, I can’t safely recommend a combination strategy. This typically motivates men to make the changes needed to lower their blood pressure. These are real concerns: Enzalutamide can cause elevated blood pressure and abiraterone can cause hypertension due to excess mineralocorticoids. So, patients with hypertension may need to remain on ADT alone for 1-3 months while they address their high blood pressure before another drug is added.

Your Thoughts
What challenges do you experience in managing patients with nmCRPC and mHSPC? Please answer the polling question and join the conversation in the discussion box.

To get individualized expert treatment recommendations for your patients with prostate cancer, please visit CCO’s Interactive Decision Support Tool: Expert Guidance on Treatment Selection for Patients With Advanced Prostate Cancer.
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