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Panel discussion: how I treat non-metastatic castration-resistant prostate cancer (CRPC)


panel discussion how i treat non-metastatic castration-resistant prostate cancer

Gain an understanding of how oncologists are treating non-metastatic castration-resistant prostate cancer (CRPC) in our latest panel discussion, featuring experts insights from Catherine Marshall and Channing Paller (Johns Hopkins School of Medicine, MD, USA) and Judd Moul (Duke University Medical Center, NC, USA). The panelists discuss the past, present and future of the treatment landscape for non-metastatic CRPC, and detail the treatments and sequencing used in their own practice. Marshall, Paller and Moul also present their own case studies and discuss how they would approach each other’s cases.

If you would like to access a downloadable version of this panel discussion, for free, click here.

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HER2 breast cancer  What treatments and treatment sequencing do you currently use to treat non-metastatic CRPC?

HER2 breast cancer  What are the major challenges for CRPC treatment? How do you think they can be overcome?

  CRPC is often diagnosed at later stages. Could you give us a bit of a background to why this is?

  What are your hopes for how the treatment landscape of non-metastatic CRPC will evolve over the next 5 years?

  Case studies

  Get to know the panelists

What treatments and treatment sequencing do you currently use to treat non-metastatic CRPC?

Marshall: Before talking about non-metastatic CRPC, we first need to talk about non-metastatic prostate cancer. The treatment landscape in this space is still undefined. With new imaging techniques, the number of people we consider to have non-metastatic disease is shrinking. But we do not have great evidence to support when we should start continuous hormone therapy for these patients and many of these patients will still do quite well even without hormone therapy. The pivotal clinical trials – SPARTAN, PROSPER, and ARAMIS – that demonstrated overall survival (OS) benefit of Erleada® (apalutamide), Xtandi® (enzalutamide), and Nubeqa® (darolutamide), respectively, do not have information on when or why patients were started on continuous androgen deprivation therapy in the first place. So, all of that being said, I have not increased my use of androgen deprivation therapy in the non-metastatic space. But, if patients are on it, and progress to non-metastatic CRPC with a PSA doubling time of 10 months or less, I will start one of those approved agents.

Choosing which one to start with, for me, usually comes down to side effect profile, interactions with other medications, and which one is easiest for the patient to get and take every day. Cost and pill burden factor into the ease of taking. With all of this, darolutamide seems to be the option I most often use first. In terms of subsequent treatment, if patients have disease that is still non-metastatic, I will switch to one of the other oral anti-androgens approved for non-metastatic CRPC, recognizing that the benefit of a second agent in that space is unknown and a response to a second line anti-androgen for non-metastatic CRPC will likely be lower than the first. Clinical trials are always an option, and these patients should also undergo genetic testing to determine whether they would benefit from PARP inhibitors or other clinical trials in the future.

Moul: I am a urologist, but I work in a multidisciplinary clinic with genitourinary medical oncology. However, a lot of the patients with non-metastatic CRPC are in our urology practices. So, this is a topic that at least in the USA that urologists need to be very familiar with.
These patients are on hormone therapy for biochemical recurrence and then they have a rising PSA and are found to have non-metastatic CRPC. Up until 2018, we really did not have any novel treatments for the condition and the standard of care was just to monitor the patients until they developed metastasis.

Then in February of 2018, apalutamide was the first drug to get FDA approved in the USA for non-metastatic CRPC. So, that opened the door for this oral therapy, and it was initially based on an improvement in metastasis-free survival and the increase in survival was close to 2 years or over 2 years. This was a real clinically significant benefit where a once-a-day oral medication could actually improve metastasis-free survival by a really long-time, 2 years.

Then subsequently enzalutamide also received FDA approval in July 2018 and then roughly a year after that, darolutamide was the third oral agent approved in non-metastatic CRPC.

I guess the good news is we now have three oral agents that we can use in the United States to treat non-metastatic CRPC. They are all effective. One of the challenges we face is they are very similar, and so sometimes it is challenging to know which one of the three to prescribe.

Paller: We consider several variables when treating non-metastatic prostate cancer. We use conventional imaging studies (Technetium 99 Bone Scans and Cat Scans) to ensure there is no evidence of metastatic disease and that their disease is growing slowly (the prostate specific antigen doubling time is less than 10 months). If it is greater than 10 months, we often recommend continuing androgen deprivation therapy alone. Based on recent developments, many patients request more sensitive imaging with PSMA-based molecules that detect metastatic disease earlier than conventional imaging, but we do not know yet if detecting it earlier improves outcomes. Once we are sure the patient’s disease is non-metastatic, we have three FDA approved treatments: apalutamide, darolutamide and enzalutamide. To choose the best treatment option, we consider the patient’s comorbidities and other medications. For example, 24% of patients develop a rash with apalutamide, so I usually avoid apalutamide in patients with sensitive skin. Similarly, enzalutamide is contraindicated in patients with seizure disorder.

Further, both enzalutamide and apalutamide can induce cytochrome P450 (CYP) 3A4 enzymes that inhibit the activity of P-glycoprotein and could reduce the effectiveness of other medications. Darolutamide is generally well tolerated.

What are the major challenges for CRPC treatment? How do you think they can be overcome?

Marshall: I think the major challenge for non-metastatic CRPC treatment is what to do about subsequent therapy. We have three options for first line treatment but no great information yet on what to do next. If patients have a slow subsequent PSA doubling time, you might not need to switch therapy right away. In the future, it will be important to get some real-world data on this, as clinical trials sequencing these agents are unlikely to be done. We do still also need more research on the best timing of initiating ADT for these patients. Finally, as we learn more about the genetics of prostate cancer and targeted treatment, more non-hormonal treatment strategies will likely be incorporated into the treatment paradigm.

CRPC is often diagnosed at later stages. Could you give us a bit of a background to why this is?

Moul: I think it’s multifactorial. I mean sometimes men who have prostate cancer sometimes they are not as proactive as females, for example. I think a lot of times females with breast cancer are more proactive.

A lot of guys with prostate cancer don’t necessarily pay that much attention to their own disease, that must be one factor. They are on hormone therapy and they see their PSA rising but may not be as knowledgeable or do anything about it. The healthcare providers are busy. There is a shortage of urologist in the USA, and so sometimes the doctors are so busy that they overlook a rising PSA while the patient is on hormone therapy.

Then thirdly these medications are expensive and even though there is really pretty good insurance coverage in the USA these drugs are expensive and sometimes the patients just don’t get put on the proper medications due to financial considerations.

What are your hopes for how the treatment landscape of non-metastatic CRPC will evolve over the next 5 years?

Moul: We have these three oral agents that are now available and they all now show OS advantage. At ASCO in 2020 the trials came out that all three of these agents (apalutamide, enzalutamide and darolutamide) all showed an OS benefit.

So, in 2018, we knew that they extended the metastasis-free survival but now in 2020, we learnt that they extended OS. That was positive news, and for any of the doctors who were still on the fence as to whether they have used these agents, we now had survival advantage. Again, it took another barrier away from potentially doctors who may not believe that these drugs were beneficial.

We still face challenges with cost. They are expensive and you must go to a specialty pharmacy and work with the benefits manager to make sure the patient has coverage. Again, I can just speak for the situation in the USA – some patients can have as much as $10,000 per year in out-of-pocket expenses because of the way the system is structured as far as coverage and that is a challenge. As far as advancements through the future, I think eventually we will have other combination agents and potentially other mechanisms of action of drugs that may work but again, this has been a real advance having three effective agents approved in the space in a matter of essentially 1 year.

Paller: We have made extraordinary progress in treating prostate cancer during the past 5 years, with many new drugs and imaging techniques approved by the FDA that increase survival and quality of life for metastatic prostate cancer patients. I am very hopeful that we will continue to make advances in treatments in three ways: (1) moving the newly approved treatments earlier in the disease spectrum to delay metastasis. (2) combination therapies to delay resistance to treatments and improve quality of life, (3) and improved targeting of therapies using genetic biomarkers. Further we are just beginning to understand the clinical significance of finding cancer with more sensitive imaging (such as Pylarify®; (piflufolastat F18) approved by the FDA in May 2021 or 68Ga-PSMA approved December 2020) compared to conventional imaging. Thus, in the next 5 years we will better equipped to understand whether patients with detectable disease, with these next-generation imaging modalities, are better served. I hope this will lead to reducing toxicity and improving efficacy of therapeutic options for both metastatic and non-metastatic CRPC.

Marshall: I think with the recent approvals of Lynparza® (olaparib) and Rubraca® (rucaparib) for metastatic CRPC, genetic testing will be used more and more in practice. I also think that we will increasingly be using genomically targeted therapies in the treatment of men with CRPC.

Case studies

Case 1 (Marshall):

Let’s say there is a patient with a PSA doubling time of greater than 3 months, PSA of 5ng/mL, no evidence of disease on imaging so this patient was started on continuous androgen deprivation therapy. After 6 months, with a suppressed testosterone, the patient again has a rising PSA with a PSA doubling time of 6 months and negative imaging and would be considered to have non-metastatic castration resistant prostate cancer. Let’s say the patient has a mechanical heart valve so is on warfarin anticoagulation but no other medications or comorbidities. For this patient, I would choose darolutamide.

Some other considerations:

  • If the patient had a very long doubling time, let’s say 15 months, I would not necessarily start any of these agents. The inclusion criteria for the trials was, with a PSADT <= 10 months, so the benefit to patients with a slower PSADT is unknown.
  • If a provider has more experience treating patients with one or two of the drugs over the others, I would go with the one that the provider has the most experience with using.

Paller comments: Daralutamide is better tolerated because it effectively does not cross the blood brain barrier and thus has less fatigue and no seizures. A Phase III study of patients with M0 castration resistant prostate cancer and a PSA doubling time of less than 10 months show that darolutamide at 600 mg twice daily improved the primary end point of metastases free survival over placebo (40.4 months versus 18.4 months). OS at 3 years was 83% compared to 77% of the placebo group. Adverse events that occurred more frequently with darolutamide included fatigue (12.1% versus 8.7%), pain in extremities (5.8 versus 3.2%), and rash 2.9 versus 0.9%. (PMID32905676)

That said there is recent data by Beer et al in a network meta-analysis suggesting that enzalutamide may be superior in terms of efficacy. In clinical practice one must also consider comorbidities and drug-drug interactions. Specifically, Xarelto (rivaroxaban) and Eliquis (apixaban) are contraindicated with enzalutamide because they are less effective in combination. With warfarin and enzalutamide, the international normalised ratio (INR) can fluctuate, if we still wanted to use enzalutamide, we would just monitor the INR more frequently.

Moul comments: This is very reasonable to start darolutamide. The possible advantage of darolutamide would be less fatigue, less risk for falls and seizure due to its mechanism of action not crossing the blood-brain barrier. However, the dosing is twice daily versus enzalutamide and apalutamide once a day dosing. Based on the ARAMIS trial update from ASCO 2020:

  • 31% reduction in the risk for death for darolutamide vs placebo.
  • Median follow-up of 29.1 month
  • 3-year OS rates were 83% and 77% for the darolutamide and placebo
  • Darolutamide associated with significant delays in the time to pain progression, first cytotoxic chemotherapy, and first symptomatic skeletal event.

Case 2 (Moul):

I can think specifically of one gentleman. He was about 70 years old. He was an executive in a very prominent grocery store chain in the USA. He had been the CEO of the major grocery chain, and he is now retired. I had met him several years earlier when he had localized prostate cancer and underwent a radical prostatectomy.

I had initially treated him for surgery and then about 2 years after the surgery, he had an initial rising PSA and received salvage radiation therapy to the prostate bed and the pelvis. That was effective for a period and then the PSA started to rise again. Eventually he went on androgen deprivation therapy with leuprolide acetate, and I believe even at that point in time he was on bicalutamide oral therapy with leuprolide acetate.

Then, that lasted a period and then his PSA actually started to rise on this hormone therapy. His PSA started to rise fairly slowly while he was still on the leuprolide acetate and once his PSA went above two, I was very concerned that he had non-metastatic castrate-resistant prostate cancer or well at that point, I wasn’t sure if it was non-metastatic.

Once his PSA rose above two, I obtained a bone scan and a CAT scan to make sure he did not have metastatic disease and those were negative, and I also did a serum testosterone level and that was less than 50 indicating that he was castrate and he was compliant with his hormone therapy. Then I checked another PSA a month or so later and it had risen to approximately four.

Clearly this gentleman at this point, again, he has a rising PSA on traditional hormone therapy. He has a castrate testosterone less than 50 and he had negative bone scan and CAT scan indicating no obvious metastatic disease.

This occurred in March 2018 and that was soon after apalutamide was FDA approved in USA and so he was a perfect patient, if you will on label, for the new oral agent. I wanted to get some experience in prescribing this and so he started on apalutamide and quite frankly, he is still doing fine. That was in spring of 2018, and we are now in the spring of 2021. So, he has been on that drug for 3 years and continues to do well.

Marshall comments: I agree with this approach. The patient had a PSA of 4ng/mL that doubled in about a month and had no evidence of disease on conventional images. Novel imaging using axumin or PSMA based imaging would be appropriate in this setting too. Either way, additional therapy is warranted and apalutamide is a fine choice. There may be long term complications of these medicines as patients are on them for longer periods of time but that remains to be seen.

Paller comments: Apalutamide is a good option and this is a nice long response. A Phase III study of men with non-metastatic CRPC and PSADT <10 months assigned men placebo or apalutamide at 240 mg PO daily and the trial found improved metastases free survival over placebo at 40.5 months versus 16.2 months with the HR for metastasis or death being 0.28 95% CI 0.230.35, p<0.001. After median follow up at 52 months, final overall survival shows improvement in overall survival with apalutamide versus placebo being 73.9 months versus 59.9 months. Adverse events included rash (24% vs. 5.5%), fracture (11% vs. 6.5%), and hypothyroidism (8% vs 2%) PMID: 29420164.
Like enzalutamide, it crosses the blood brain barrier thus has risks of fatigue and seizures, and can also cause similar side effects like hypertension, diarrhea, dizziness, and peripheral edema. In addition it has cyp3A4 interactions that makes it difficult to combine with blood thinners. Finally, unlike the other agent it has a serious risk of fractures as a listed side effect. Darolutamide has fewer side effects as it effectively does not cross the blood brain barrier.

Case 3 (Paller):

A 71-year-old prostate cancer patient with atrial fibrillation on apixaban comes in for a second opinion. His general oncologist suggested he start enzalutamide for non-metastatic CRPC and wants to know what I think. I tell him I am concerned about drug-drug interactions and risk of bleeding and thus recommend he either switch his apixaban or switch the enzalutamide to darolutamide.

Marshall comments: I always want to think about whether or not starting or changing therapy is warranted in the first place. I would first want to know the absolute PSA for this patient and then I would want to see at least two or three PSA values over time to determine the PSA doubling time. If the absolute PSA is still very low, and the PSA doubling time is very long, I might wait on starting any treatment at all. Next I would also consider the time course for the concomitant medications, in this case the apixaban. If it were to be stopped soon, I might wait until after he is off of it to consider starting therapy for his prostate cancer. If he will be apixaban indefinitely, then would tailor my therapy to try and minimize drug-drug interactions. So, if he does need to start on therapy for his non-metastatic CRPC and has a PSA doubling time of 10 months or less, I would switch to darolutamide as well.

Moul comments: Prostate cancer and cardiac disease requiring anticoagulation is quite common in contemporary oncology practice. While all three FDA-approved 3rd generation nonsteroidal antiandrogens (apalutamide, daralutamide, enzalutamide) are associated with improved overall survival in M0 CRPC, the use of darolutamide in this clinical scenario is a prudent choice. It is important for clinicians managing advanced prostate cancer patients to be familiar with some of the subtle differences between these three oral agents.

Get to know the panelists

Catherine Marshall

Catherine Marshall is an Assistant Professor of Oncology at the Johns Hopkins School of Medicine (MD, USA). She specializes in the treatment of patients with prostate cancer. Her research focuses on genetic alterations in prostate cancer and the overlap of cancer and cardiovascular disease.

Judd Moul

Judd Moul is a urologic-oncologist at Duke University Medical Center (NC, USA). He has been at his practice for approximately 17 years. Before that, he was an army doctor at Walter Reed Army Medical Center (WA, USA) and trained in the military. He has been working in the area of prostate cancer for over 25 years, and has been fortunate to have a career involved in clinical trials, basic science research in prostate cancer and clinical care.

Channing Paller

Channing Paller is Associate Professor Of Oncology And Urology at Johns Hopkins Kimmel Comprehensive Cancer Center (MD, USA) and Director For Oncology for Johns Hopkins Clinical Research Network (MD, USA). Her research focuses on translating basic scientific findings into treatments that extend lives and reduce toxicities for men with prostate cancer. She manages a growing portfolio of investigator-initiated clinical trials focused on providing precision medicine to cancer patients using biomarkers and targeted therapies. The largest of those is the PROMISE trial designed to screen 5000 prostate cancer patients to identify those who have rare germline mutations and follow their treatment and clinical progress over time. The goal is to develop new knowledge that will help us improve precision medicine.

The opinions expressed in this panel discussion are those of the author and do not necessarily reflect the views of Oncology Central or Future Science Group.