Insights on Hyperuricemia From Kidney Week 2021

Anthony J. Bleyer, MD
Wake Forest School of Medicine

Nephrologists recently gathered for the virtual American Society of Nephrology’s (ASN) Kidney Week 2021 to discuss the latest research, insights, and innovations in kidney care. This year’s conference had a compelling program comprising more than 3000 abstracts, including presentations on COVID-19 with a global focus on kidney health.
 
Anthony J. Bleyer, MD, professor of nephrology in the Department of Internal Medicine at the Wake Forest School of Medicine in Winston-Salem, North Carolina, provided his insight into, and key takeaways from, the most recent research on hyperuricemia presented at Kidney Week 2021.

Among the presentations on hyperuricemia at this year’s meeting, which abstracts were the most interesting or clinically impactful?

Like many other fields, nephrology research was affected by COVID-19, which resulted in fewer presentations on hyperuricemia than in prepandemic years.
 
An important presentation, however, in the context of the ongoing pandemic was the study on prevalence and outcomes associated with hyperuricemia in hospitalized patients with COVID-19.1 In this study, investigators from the Icahn School of Medicine at Mount Sinai, in New York City, included 834 adult patients with COVID-19 who were hospitalized and underwent at least 1 serum uric acid measurement. They evaluated the association between the first serum uric acid level and major adverse kidney events (defined as a composite of all-cause in-hospital mortality, renal replacement therapy, and 100% increase in serum creatinine from baseline), as well as markers of inflammation and cardiac injury.
 
The median first serum uric acid level was 5.9 mg/dL, and findings showed that doubling in serum uric acid level was associated with increased risk of major adverse kidney events (odds ratio [OR], 2.5 per doubling) and in-hospital mortality (OR, 1.7 per doubling). This was interesting because it suggests that serum uric acid level measurement obtained early in the COVID-19 disease course could serve as an important prognostic factor both in hospital and outpatient settings, and help us better identify patients with COVID-19 who may have poor outcomes. If a patient is identified early as an outpatient, it could be possible to intervene with COVID-19 treatments before their symptoms worsen based on measurement of uric acid levels.
 
This was a retrospective study, and future studies will need to collect data prospectively to reduce the risk of bias. It may be helpful to measure serum uric acid levels at the time of hospital admission or when patients are seen in the clinic and tested for COVID-19.
 
Another exciting study involved the use of contrast-enhanced ultrasound imaging as a diagnostic tool for early detection of renal injury caused by hyperuricemia.2 In this study, the investigators found a lower peak intensity value in renal cortical perfusion and prolonged time to reach peak intensity in a hyperuricemic rodent model (with hyperuricemia induced by feeding a mixture of adenine and potassium oxonate for up to 4 weeks) compared with control rats at 1 week and 4 weeks. The changes were more pronounced at 4 weeks, suggesting a greater impact on blood flow to the kidney.
 
The same investigators then went on to evaluate patients with stages 1 to 4 chronic kidney disease vs healthy volunteers. Similar to the findings seen in the rodent model component of the study, patients with stage 1 disease showed a decrease in the peak intensity in renal cortical perfusion compared with the control group. This decreased progressively in patients with more severe chronic kidney disease. The time to peak intensity also lengthened progressively with more advanced kidney disease.
 
This new imaging technique could be very helpful in our ability to diagnose chronic kidney disease and better determine prognosis. We need better biomarkers of activity and progression of kidney disease, and I hope that this technique will be a useful tool in the future.

Another noteworthy study3 (abstract PO1812) was a meta-analysis of interventional trials with urate-lowering therapy in individuals with asymptomatic hyperuricemia. The study showed that uric acid-lowering treatment of these patients may be beneficial in those with elevated creatinine and blood pressure, and decreased estimated glomerular filtration rate (eGFR). Can you provide your perspective on these study results and comment on research on the horizon for early detection and treatment of hyperuricemia?

There has always been an interest in the potential benefits of the treatment of asymptomatic hyperuricemia. However, randomized clinical trials have disappointedly shown no benefit. Most of these studies have been small in nature with relatively short-term follow-up.
 
A number of years ago, a large study found that veterans (≥40 years of age) who were on allopurinol had lower mortality rates than those who were not,4 with a hazard ratio (HR) of 0.77 after adjusting for other prognostic factors. A subsequent study in the general population showed a similar result (HR, 0.89), and the risk of mortality was even lower among individuals with gout (HR, 0.81).5 However, clinical trials evaluating the efficacy of reducing uric acid levels have not corroborated these findings.6,7 
 
More recently, 2 short-term clinical trials evaluated whether lowering uric acid levels with allopurinol was associated with improvement in chronic kidney disease outcomes. Unfortunately, in both studies, allopurinol had no beneficial effects on renal function.6,7
 
This recent meta-analysis conducted by researchers who are respected in the field showed really provocative data.3 Patients who received uric acid-lowering treatment had higher eGFR along with nonsignificant decreases in carotid intima-media thickness, which are both positive findings. Nonetheless, high-sensitivity C-reactive protein was also higher, which is unfavorable.
 
This study, although interesting, did not provide enough data for us to prescribe urate-lowering therapy to patients with asymptomatic hyperuricemia. The existing randomized trials were not beneficial in slowing progression of chronic kidney disease.6,7 Hence, I think it will be difficult to move forward from this meta-analysis to randomized trials. Current recommendations are against the treatment of asymptomatic hyperuricemia,8 and this study should not lead us to treat asymptomatic hyperuricemia.



Hyperuricemia is often a risk factor/comorbid condition in the context of other conditions such as gout, hypertension, diabetes, chronic kidney disease, and heart failure. What insights did you gain from your recent studies that evaluated hyperuricemia in these settings?

At Kidney Week, I presented a large cross-sectional study in which we evaluated risk factors and outcomes of gout in patients undergoing dialysis using US Renal Data System (USRDS) data including nearly all Medicare patients on chronic outpatient dialysis.9 We compared patients who were dialysis dependent and had at least 1 claim for gout with those without gout in 2017.
 
Of nearly 300,000 patients, 15% had at least 1 gout claim following initiation of chronic outpatient dialysis. Patients who had gout (vs no gout) were more likely to be men (62% vs 54%) and had other comorbidities including diabetes (67% vs 62%), hypertension (93% vs 74%), and cardiovascular conditions (heart failure [49% vs 30%], ischemic heart disease [49% vs 30%], peripheral vascular disease [32% vs 22%], stroke [12% vs 8%], acute myocardial infarction [7% vs 3%], and angina [4% vs 2%]). The 3 most significant factors associated with gout diagnosis were older age (OR, 4.23 for ≥65 vs <65 years), previous transplant (OR, 2.37), and comorbid hypertension (OR, 2.71). Additionally, their risks of hospitalization and mortality were 11% and 9% higher, respectively, than those of patients without gout within a year after diagnosis.
 
The key point from our study is that gout still occurs, even in dialysis patients. Gout is something that we need to be observant and ask our patients about because it can really affect quality of life in our patients. More importantly, it is treatable. We have a number of therapeutic options for gout, though they must be used carefully in patients with end-stage kidney disease.

Have you treated patients with COVID-19-related acute kidney injury (AKI), and have you evaluated serum uric acid levels in these patients?

Yes, I have treated patients with COVID-19-related AKI. However, we have not looked at uric acid levels. In terms of AKI, COVID-19 vaccinations and treatments, such as monoclonal antibodies, have improved outcomes for COVID-19 and reduced the occurrence of COVID-related AKI.

Are there any final comments that you would like to add about Kidney Week 2021?

I think there is indirect evidence that high uric acid levels may have deleterious effects on the kidney, but no studies have definitively shown that treatment of hyperuricemia could be beneficial. The meta-analysis showed that treatment of asymptomatic hyperuricemia could potentially be beneficial, but based on the results of prior randomized trials, there is no indication for treatment of asymptomatic hyperuricemia at this time.3-8
 
Gout remains a prevalent disorder and is especially common in individuals with chronic kidney disease. We need to move away from thinking of gout as a lifestyle disease due to consumption of purine-rich foods and instead realize the high contribution of decreased renal excretion of uric acid as the primary cause of gout.10 Treatment with urate-lowering therapy can be highly effective in improving quality of life in these patients.
 
I think there was less research in hyperuricemia and kidney disease over the last year due to the effects of COVID-19. I am hoping that the incidence of COVID-19 will markedly decrease, and that we will be able to increase research into the causes and treatment of kidney disease in the future.

Key Takeaways

  • In a study of hospitalized adult patients with COVID-19, a doubling in serum uric acid level was associated with increased risk of major adverse kidney events and in-hospital mortality, suggesting serum uric acid level measurement early in the COVID-19 disease course could serve as an important prognostic factor to identify patients with COVID-19 who may have poor outcomes. However, the findings will need to be confirmed with further studies.
  • Contrast-enhanced ultrasound imaging appears to be useful for detection of renal injury caused by hyperuricemia, and its associated parameters could potentially serve as much needed markers in chronic kidney disease.
  • A new study suggested that treating asymptomatic hyperuricemia with uric acid-lowering treatment may be beneficial in patients with elevated creatinine and blood pressure, and decreased eGFR. However, this meta-analysis was not concordant with recent randomized clinical trials, which showed no benefit from treating asymptomatic hyperuricemia in chronic kidney disease. Current recommendations are against the treatment of asymptomatic hyperuricemia.
  • Among nearly 300,000 patients undergoing dialysis according to the USRDS, 15% had gout. Within a year of diagnosis, patients with gout had higher risk of hospitalization and mortality than patients without gout, highlighting the need to monitor for gout in patients undergoing dialysis.

This Q&A was edited for clarity and length.

Disclosure

Anthony Bleyer, MD, reported affiliations with Horizon Therapeutics plc.

References

  1. Chauhan K, Pattharanitima P, Piani F, et al. Prevalence and outcomes associated with hyperuricemia in hospitalized patients with COVID-19. Presented at: Kidney Week 2021, November 2-7, 2021. Abstract PO0073.
  2. Fan Y, He L, Li Z, et al. Evaluation of changes in renal microperfusion in hyperuricemic-induced kidney injury by contrast-enhanced ultrasound imaging. Presented at: Kidney Week 2021, November 2-7, 2021. Abstract PO2427.
  3. Gala DN, Said KS, El-Shahat NA, et al. Potential benefits of asymptomatic hyperuricemia treatment: a systematic review and meta-analysis of randomized control trials. Presented at: Kidney Week 2021, November 2-7, 2021. Abstract PO1812.
  4. Luk AJ, Levin GP, Moore EE, Zhou XH, Kestenbaum BR, Choi HK. Allopurinol and mortality in hyperuricaemic patients. Rheumatology (Oxford). 2009;48(7):804-806. doi:10.1093/rheumatology/kep069
  5. Dubreuil M, Zhu Y, Zhang Y, et al. Allopurinol initiation and all-cause mortality in the general population. Ann Rheum Dis. 2015;74(7):1368-1372. doi:10.1136/annrheumdis-2014-205269
  6. Badve SV, Pascoe EM, Tiku A, et al. Effects of allopurinol on the progression of chronic kidney disease. N Engl J Med. 2020;382(26):2504-2513. doi:10.1056/NEJMoa1915833
  7. Doria A, Galecki AT, Spino C, et al. Serum urate lowering with allopurinol and kidney function in type 1 diabetes. N Engl J Med. 2020;382(26):2493-2503. doi:10.1056/NEJMoa1916624
  8. FitzGerald JD, Dalbeth N, Mikuls T, et al. 2020 American College of Rheumatology guideline for the management of gout. Arthritis Care Res (Hoboken). 2020;72(6):744-760. doi:10.1002/acr.24180
  9. Bleyer AJ, Zhang Y, Kshirsagar OS, Marder B, LaMoreaux B. Risk factors and outcomes of gout in dialysis patients: a cohort study of the United States Renal Data System (USRDS). Presented at: Kidney Week 2021, November 2-7, 2021. Abstract PO0792.
  10. Ichida K, Matsuo H, Takada T, et al. Decreased extra-renal urate excretion is a common cause of hyperuricemia. Nat Commun. 2012;3:764. doi:10.1038/ncomms1756

Posted by Haymarket’s Clinical Content Hub. The editorial staff of Renal and Urology News had no role in this content’s preparation.

Reviewed December 2021

Expert Insights: Rare Kidney Diseases at Kidney Week 2021

David S. Goldfarb, MD
NYU Langone Health

Nephrologists recently congregated for the virtual American Society of Nephrology’s (ASN) Kidney Week 2021 to discuss the latest research, innovations, and insight in kidney care. David S. Goldfarb, MD, clinical director of the division of nephrology at NYU Langone Health, in New York City, shared his assessment of research into rare kidney disease presented at the annual conference. 

What were some highlights of rare kidney disease research presented at Kidney Week 2021?

The research presented on lumasiran is clearly important for the treatment of the rare kidney disease, primary hyperoxaluria type 1 (PH1).1 Lumasiran is a small-interfering RNA therapy targeting HAO1 in advanced PH1. This is potentially a life-saving drug because it lowers oxalate to a degree that has never been achieved by any other means. The ability to reduce urinary oxalate has a direct correlation to kidney failure prevention. While there are no available data yet, this level of urinary oxalate reduction may enable patients to avoid a liver transplant.
 
That said, lumasiran is an expensive drug. Prior to its development, pyridoxine and other forms of vitamin B6 were used to reduce oxalate in patients with certain PH1 genotypes. Some of my patients still required liver transplantation — and have had to undergo kidney transplantation due to kidney failure — despite therapy with pyridoxine, pyridoxal, and pyridoxamine.
 
I would like to participate in a study to evaluate lumasiran as a treatment option for patients with elevated urinary oxalate who do not have PH. While it is not yet known whether this type of therapy is practical from a cost perspective, we do know that some patients have idiopathic hyperoxaluria not related to PH. Very often, this idiopathic condition is thought to have a dietary cause, and patients are asked to modify their diets to reduce the amount of oxalate in their urine. In patients without a known type of PH, interfering with hepatic oxalate production is a very interesting and novel idea.

One of the abstracts presented at Kidney Week 2021 examined modification of Oxalobacter-derived peptides as a potential therapeutic target for reducing oxalate in the urine by promoting excretion through the colon.2 What are your thoughts on that approach as opposed to targeting DNA or RNA?

I think it’s a brilliant idea and I approve of this approach. SLC26A6, the oxalate transporter in the intestinal lumen, appears to be stimulated by some product from Oxalobacter formigenes. Hatim Hassan, MD, PhD, associate professor of medicine at the University of Chicago, has been studying the induction of colonic oxalate excretion by O formigenes, which results in reduced urinary oxalate excretion via a secretagogue. His work in locating the secretagogue and demonstrating its efficacy will be key in developing a novel targeted drug for hyperoxaluria.2 This stimulation of oxalate secretion appears to be a reasonable target for a molecule that will move oxalate from the blood into the intestinal lumen, causing less oxalate to be presented to the kidney.



Would adding exogenous protein have any potential impact on the state of O formigenes?

If the intestinal Oxalobacter colony is well fed and proliferates, that is a good thing. It is not a pathogen; it is a symbiotic microorganism. Oxalobacter is an important part of the intestinal microbiome in that it protects against kidney stones, for example, but it is not likely to be completely self-sufficient. The presence of other bacteria is likely required in order for Oxalobacter to thrive in the colonic lumen. Other organisms may be an important part of the process, either by degrading oxalate directly or by downstream effects, and that interplay will allow Oxalobacter to be successful.

Are there any final thoughts you would like to share with your colleagues regarding the current state of nephrology?

As many are aware, kidney stones cause a lot of pain and suffering for patients and are very expensive to treat. I am a patient with kidney stones myself, and I have been treating kidney stones for more than 25 years. In that time, there has been an increasing focus within the pharmaceutical industry on kidney stone management. That is wonderful because I can recall a time when kidney stones were not considered an important topic of medical research.
 
In the kidney stone session, there was a discussion about the important progress made regarding the pharmacology and genetics of kidney cancer. While I think our understanding of kidney stones may be lagging a bit compared with renal cancer research, there has been good progress in uncovering the genetics of kidney stone diseases and that is very gratifying.

Key Takeaways

  • Current research into PH1 shows that kidney failure may be prevented by reducing urinary oxalate.
  • Modification of Oxalobacter-derived peptides may protect against kidney stones in PH1 by promoting oxalate excretion through the colon and thereby reducing oxalate levels in the urine.
  • Lumasiran, a small-interfering RNA, targets hydroxy acid oxidase 1 and is part of a drug class that may be a cornerstone of therapy for patients with certain rare kidney diseases.

This Q&A was edited for clarity and length.

Disclosure

David S. Goldfarb, MD, reported an affiliation with Alnylam Pharmaceuticals.

References

  1. Michael M, Groothoff JW, Shasha-Lavsky H, et al. ILLUMINATE-C, a single-arm, phase 3 study of lumasiran in patients with primary hyperoxaluria type 1 and CKD stages 3b-5, including those on hemodialysis. Presented at: Kidney Week 2021, November 2-7, 2021. Presentation FR-OR64.
  2. Hassan H, Alshaikh A, Zerweck, J. Optimization of Oxalobacter formigenes-derived small peptides with therapeutic potential for hyperoxalemia, hyperoxaluria, and related kidney stones. Presented at: Kidney Week 2021, November 2-7, 2021. Abstract PO0524.

Posted by Haymarket’s Clinical Content Hub. The editorial staff of Renal and Urology News had no role in this content’s preparation.

Reviewed December 2021

AUA2021 Program Dives Into Advances in PH1 Research and Therapy

David S. Goldfarb, MD
NYU Langone Health

From September 10 to 13, 2021, urologists and nephrologists came together to attend the American Urological Association (AUA) 2021 Annual Meeting (AUA2021), a virtual experience that connected clinicians and experts from around the world. In a program filled with cutting-edge research, a number of abstracts were presented on primary hyperoxaluria type 1 (PH1), the most severe of a group of a rare genetic metabolic disorders characterized by accumulation of oxalate in the kidneys.
 
David S. Goldfarb, MD, clinical director of the Division of Nephrology at NYU Langone Health, provided his perspective on important PH1 research presented at AUA2021.

Which of the abstracts on PHI presented at AUA2021 were most interesting or clinically impactful?

All of them are very important, and they are dramatic. I have personally sent patients with PH1 to the operating room for combined kidney-liver transplantation. People often don’t take kidney stones seriously; this disease is something different.

In some ways PH1 is the most serious kidney disease in that it affects young people. It causes a lot of kidney stones and nephrocalcinosis, which leads to kidney failure. So I think that reducing urinary oxalate and normalizing oxalate excretion in a significant number of people is dramatic. It’s great science and it’s even a little miraculous.
 
Here’s a new technology: molecular biology, brought to the point of being therapeutically important. Beyond lowering urine oxalate, which we’ve known for some time — since lumasiran has already been approved — the next question is: Do reduced oxalate levels have an effect on outcomes that are relevant to these patients? Those outcomes are reduction of kidney stones and reduction of progression of kidney failure. That takes a long time to happen, so these studies haven’t gotten to that point. The signal was positive in the sense of reducing the number of kidney stones and reducing the grade of nephrocalcinosis. They’re not definitive from that point of view.
 
I’ve participated in telephone calls for the Oxalosis & Hyperoxaluria Foundation — a foundation that should be credited for supporting this work — during which people ask, “Can I stop drinking a lot of water?” or “Can I stop taking citrate?” The answer is that we’re not sure yet; it hasn’t been shown at this point.
 
But the hope is that all of these abstracts show that reducing urinary oxalate occurs in a dramatic fashion and should be associated, ultimately, with prevention of clinical outcomes that we care about: kidney stones, nephrocalcinosis, and progression of kidney failure.



One abstract1 discussed a case of compassionate use of nedosiran injection in a 17-year-old woman with PH1 and end-stage renal disease who was awaiting combined kidney-liver transplantation. According to the authors, nedosiran “transformed” the clinical outcome for this patient. Does this report give you hope for the future about the use of nedosiran injection as a treatment for PH1?

I think that’s exactly what I was saying: I have had the experience of patients under my care going into renal failure and then needing kidney-liver transplantation. That experience is sobering for me.
 
The case report you mention is an interesting study. Here’s the conclusion: The graph at the bottom of the abstract shows a big reduction in urinary oxalate. What happened to this patient was deferral of an offer of combined kidney-liver transplantation in favor of continued treatment. What I don’t understand is: Why didn’t they do kidney transplantation? The patient is in kidney failure; reducing urinary oxalate is good. But just looking at the abstract, you’d say, well, what happened as result of your beautiful reduction in urinary oxalate? Did you now not transplant a kidney? They deferred combined kidney-liver transplantation, but what I’d expect, with the patient on dialysis, is that they would still have to do a kidney transplantation. Perhaps you can avoid liver transplantation because you’ve been able to turn off hepatic production of oxalate. But I think the kidney transplantation is still necessary, and that was what I found a little odd about that abstract. I should ask my friend Marshall Stoller [professor and vice chair of Urology at UCSF Department of Urology and coauthor of the abstract] what happened.

If you find that answer, let us know as it would be interesting to our readers. If you have that question, others probably do, too.

Dr Stoller is my business partner, so I have a conflict of interest here. But at the end of the “Results” section of the abstract, the authors say that the patient had no new nephrolithiasis events. But I have to say: People on dialysis—their kidneys don’t work, they don’t get kidney stones. So, what are you talking about, Marshall?
 
I want to be optimistic, and I want to be supportive of all this; I think it’s a big deal. But this wasn’t the most convincing abstract. What I loved about it was that the accompanying Figure is convincing: You reduced urinary oxalate, but that’s not exactly news. We know that’s going to happen, and this is a beautiful example of that. I think it’s true that you’re going to be able to avoid liver transplantation, but it’s not clear what happened to the patient after that.
 
[Editor’s note: Dr Goldfarb reached out to Dr Stoller for clarification about these results. Dr Stoller replied that the patient deferred kidney-liver transplantation and is awaiting kidney transplantation only. The reduction in plasma oxalate allowed reduction of dialysis from 6 to 3 times a week, which Dr Stoller termed “a big deal.” He agreed that people on dialysis are, presumably, much less likely to develop a kidney stone despite a high plasma level of oxalate.]

Results of a phase 2, open-label extension study2 (ClinicalTrials.gov Identifier: NCT03350451) of lumasiran for the treatment of PH1 were described as “encouraging”; kidney stone-related adverse events decreased and improvements in nephrocalcinosis were reported. What aspects of this treatment would you like to see studied in upcoming phase 3 research?

I think these findings are confirmatory. In another cohort of patients they’ve gotten the same results with lumasiran that were expected, which speaks to the efficacy of the drug. I think that the duration of follow-up is a little too short for us to be confident about its effect on kidney stones, but the kidney-stone community would generally expect that lowering urinary oxalate to this degree would be associated with a reduction in kidney stones and nephrocalcinosis.
 
We would consider this a positive result and expect, again, that this is another study that calls for long-term follow-up.

Because PH1 is a rare genetic disorder, there are numerous challenges surrounding recruitment of eligible clinical trial participants. In an AUA2021 abstract,4 researchers evaluated the utility of the PEDSnet network [of hospitals, researchers, and patients and their families] in identifying patients with likely primary hyperoxaluria and found that the use of a model might improve recruitment efficiency and effectiveness. As a researcher and clinician, what kind of meaningful changes in PH1 research might be on the horizon with the availability of a large cohort of patients with a rare urologic disease?

I do think that it’s possible that there are patients out there whose disease has not been diagnosed or who are not aware of these breakthroughs. And so, getting the news out and enrolling those patients is important for nephrologists who care for these patients. Many of these patients have had access to these kinds of studies because they’re taken care of in centers where this disorder isn’t so rare. But finding these patients, to develop cohorts, is difficult because it’s a rare disease.

Given the shift in the clinical research community toward decentralized clinical trials, do you think that a condition like PH1 lends itself to the decentralized clinical trial model or does it require more in-person site visits? There are benefits to decentralized clinical trials because you can cast a wider net for participants, but those models might not be appropriate for every condition.

That’s an interesting question. As we have become more “virtual” in healthcare, kidney stones are something that is often amenable to that. You can get patients to do 24-hour urine collection without going to the hospital and without bringing the urine to a laboratory; the patient can ship it by FedEx. Patients can also have imaging studies done wherever they are, that are then sent by email or compact disc to a trial center. We’re always talking about enrolling patients in studies remotely and maintaining their participation in studies remotely as well.

Any last thoughts that you’d like to add?

As someone who has seen PH1 at its worst — causing kidney failure and leading to combined kidney-liver transplantation — I find this work extremely encouraging and positive.

Key Takeaways

  • The scope of current PH1 research shows that reduction in urinary oxalate can be associated with clinical outcomes of greatest interest to nephrologists: kidney stones, nephrocalcinosis, and progression of kidney failure.
  • Study outcomes confirm that lumasiran reduces urinary oxalate. For nephrologists, the next step is to determine whether this therapy also reduces kidney stones, nephrocalcinosis, and progressive chronic kidney disease.
  • Results of a 12-month analysis of the ILLUMINATE-A trial of lumasiran are encouraging, even with a brief follow-up period. However, more long-term research is warranted.

The Q&A was edited for clarity and length.

Disclosure

David S. Goldfarb, MD, reported an affiliation with Dicerna Pharmaceuticals, Inc.

References

  1. Shee K, Ahn J, Hamouche F, Mena J, Chi T, Stoller M. MP47-17 Edosiran dramatically reduces serum oxalate in dialysis-dependent primary hyperoxaluria 1: a compassionate use case report. J Urol. 2021;206(suppl 3):e830. https://doi.org/10.1097/JU.0000000000002068.17
  2. Lieske JC, Garrelfs SF, Michael M, et al. MP07-08 Effect of lumasiran on kidney stones and nephrocalcinosis in patients with primary hyperoxaluria type 1. J Urol. 2021;206(suppl 3):e142. https://doi.org/10.1097/JU.0000000000001980.08
  3. Assimos D, Saland JM, Groothoff J, et al. MP07-09 12-month analysis of ILLUMINATE-A, a phase 3 study of lumasiran: sustained oxalate lowering and kidney stone event rates in primary hyperoxaluria type 1. J Urol. 2021;206(suppl 3):e142. https://doi.org/10.1097/JU.0000000000001980.09
  4. Ching C, Dickinson K, Razzaghi H, et al. MP58-17 Leveraging clinical research networks to identify patients with primary hyperoxaluria for clinical trials. J Urol. 2021;206(suppl 3):e994-e995. https://doi.org/10.1097/JU.0000000000002088.17

Posted by Haymarket’s Clinical Content Hub. The editorial staff of Renal & Urology News had no role in this content’s preparation.

Reviewed October 2021

Insights Into Metastatic Prostate Cancer From the AUA 2021 Annual Meeting

Neal D. Shore, MD, FACS
Medical Director, Carolina Urologic Research Center
Atlantic Urology Clinics

From September 10 to 13, 2021, the American Urological Association (AUA) presented its annual conference, AUA2021. This year’s virtual experience included a range of cutting-edge research on metastatic prostate cancer, which is a disease that is on the rise. According to data from the Centers for Disease Control and Prevention, more than 8% of men living with prostate cancer will experience distant or metastasized disease.1
 
Neal D. Shore, MD, FACS, US chief medical officer of Surgery and Oncology and director and certified principal investigator at the Carolina Urologic Research Center, Myrtle Beach, South Carolina, provided his perspective on the newest research focused on metastatic prostate cancer presented at AUA2021.

Which of the presentations at AUA2021 did you find to be most interesting or clinically impactful with regard to metastatic prostate cancer?

We saw important data come across regarding the VISION trial (ClinicalTrials.gov Identifier: NCT03511664)2 and the importance of ushering in a new class of medication, prostate-specific membrane antigen-targeted radioligand therapy. The novel mechanism of action of this class will certainly be additive to our existing life-prolonging, approved prostate cancer indications. Like so many other approved indications, clinical trials will provide a great opportunity to look at combination therapies as well.

Can you describe the results of your post-hoc analysis of the ARCHES trial3 (ClinicalTrials.gov Identifier: NCT02677896), and what do these conclusions mean for physicians treating patients with metastatic prostate cancer?

Importantly, patients who present with metastatic castration-sensitive prostate cancer (mCSPC) — whether low volume or high volume — absolutely will benefit from intensified therapy or combination therapy. These patients really should no longer receive only androgen deprivation therapy (ADT) as monotherapy.
 
We have several studies that have demonstrated, through phase 3 trial methodology, that combining testosterone suppression with docetaxel, or with enzalutamide, apalutamide, or abiraterone acetate, not only delays radiographic progression but enhances survival. ARCHES further demonstrated that, regardless of tumor burden — high-volume or low-volume — and regardless whether the patient received an early first-generation androgen receptor inhibitor, such as bicalutamide, there was no difference in the benefit of delaying progression for patients who received ADT and enzalutamide compared with those who received ADT monotherapy only.
 
Importantly, at the ESMO [European Society for Medical Oncology] Congress 2021,4 we’ll present conclusive evidence that overall survival, as a key secondary endpoint, has also been met in ARCHES. [Editor’s note: This interview with Dr Shore was conducted prior to ESMO 2021.]

Researchers described second-line antiandrogens as contributing to extended survival in metastatic prostate cancer but noted that median overall survival improved by only 4 months.5 What role do these drugs play in improving overall survival in the population with metastatic prostate cancer?

Historically, many of our urologist and medical oncologist colleagues have been comfortable sequencing novel hormonal agents, specifically abiraterone, enzalutamide, apalutamide, and darolutamide. But what we recognize is, regardless when the androgen receptor axis drug is given — either as a first-line or second-line therapy in mCSPC— when a patient experiences progression after an adequate course of one androgen receptor inhibitor, they do not benefit from sequencing to another androgen receptor inhibitor. These patients will do much better if they are given the opportunity to choose another approved, survival-prolonging agent that has a novel mechanism of action — for example, one of the taxanes; a radiopharmaceutical such as radium-223; immunotherapy such as sipuleucel-t; or a poly (ADP-ribose) polymerase inhibitor such as olaparib or rucaparib.

Results of one study reported in an AUA2021 abstract6 showed that overall and cancer-specific survival rates were similar in regard to radiotherapy to the prostate and no local therapy. Given those findings, should physicians shift the focus to radiotherapy, or must other factors be considered before making this kind of determination?

In the STAMPEDE trial (ClinicalTrials.gov Identifier: NCT00258476), patients received a combination of ADT and an androgen receptor inhibitor plus localized radiation for a total of 37 Gy. The investigators looked at low-volume compared with high-volume disease and found clear demonstration that patients benefited from getting radiation to the prostate, despite having low-volume mCSPC.
 
This finding has also been amplified in recent presentations of data from the PEACE1 trial7 (ClinicalTrials.gov Identifier: NCT01957436). I think it’s important that physicians have a full and thorough discussion with patients who have low-volume mCSPC to consider radiation to the prostate. We don’t, as of yet, have data to support prostatectomy, but there are ongoing trials evaluating this as an option as well.

A group of researchers evaluated the process of balancing efficacy with toxicity in docetaxel in treating metastatic castration-resistant prostate cancer.8 They identified 3 risk categories that correlated with overall survival. Do you believe that this prediction model is sufficient for balancing treatment efficacy and toxicity? What changes might you make when evaluating this risk in your own patients?

I think that docetaxel is an extremely active agent, and perhaps, given the recent pandemic, we’ve moved away from using docetaxel, given that it is clinic-required therapy that is delivered intravenously.
 
Also, there are some grade 3/4 toxicities that are very manageable; however, they are real risks, particularly neutropenia, febrile neutropenia, and even neuropathy, which can develop after chronic utilization of more than several cycles.
 
The rest of the adverse effects are actually manageable and well tolerated. Because docetaxel is a highly active drug, we see both prostate-specific antigen responses and palliative responses, and it is clearly survival-prolonging. I do think that the same is certainly a considerable advantage of using cabazitaxel for patients who have experienced progression on docetaxel.
 
Based on some of the data that we’ve seen from the TITAN trial (ClinicalTrials.gov Identifier: NTCT02489318) and from ARCHES, among patients who received docetaxel and then entered the trials of mCSPC in those studies, as well as in PEACE1, there seems to be an advantage to triple therapy, especially for patients who have high-volume disease.
 
I think the verdict is still out regarding a paradigm change in our clinical management of triple therapy, but it is becoming more and more encouraging, especially for patients with high-volume disease for whom there might be additional biomarkers that can better inform whether to amplify or intensify therapy. Docetaxel and abiraterone are generic drugs, so this becomes an additional advantage for many of our colleagues and patients throughout the world.

I think the verdict is still out regarding a paradigm change in our clinical management of triple therapy, but it is becoming more and more encouraging, especially for patients with high-volume disease for whom there might be additional biomarkers that can better inform whether to amplify or intensify therapy.

Any final thoughts about the AUA2021 conference?

There was a lot of great energy and effort that went into preparing the virtual conference, with about 3 weeks’ time to create a completely virtual meeting. I am appreciative of the staff who made that happen and of the faculty and the presenters who were able to pivot so successfully.
 
These are the types of things that we all have to become not only nimble about but also patient with, as it relates to dealing with the pandemic.

Key Takeaways

  • During the COVID-19 pandemic, oncologists might have moved away from prescribing docetaxel because of its intravenous route of delivery and potential for adverse effects. However, many of these adverse effects are manageable and well tolerated, and the benefits — in terms of prostate-specific antigen and palliative responses — might outweigh future toxicity concerns.
  • When a patient experiences progression after receiving an adequate course of androgen receptor inhibitor therapy, sequencing to another androgen receptor inhibitor might not be appropriate. Instead, these patients may do better on another approved survival-prolonging agent, such as radium-223, sipuleucel-t, or olaparib or rucaparib.
  • Regardless of tumor volume, patients with mCSPC should no longer receive monotherapy ADT only.

The Q&A was edited for clarity and length.

Disclosure

Neal D. Shore, MD, FACS, reported affiliations with Amgen, Inc.; Astellas Pharma Inc.; AstraZeneca; Bayer AG; Bristol Myers Squibb; Dendreon Pharmaceuticals; Ferring Pharmaceuticals; Janssen Biotech, Inc.; Merck & Co; Myovant Sciences; Pfizer; Roche Holding AG; and Tolmar Holdings, Inc.

References

  1. Siegel DA, O’Neil ME, Richards TB, Dowling NF, Weir HK. Prostate cancer incidence and survival, by stage and race/ethnicity—United States, 2021-2017. MMWR Morb Mortal Wkly Rep. 2020;69(41):1473-1480. doi:10.15585/mmwr.mm6941a1
  2. Morris MJ, De Bono JS, Chi KN, et al. Phase III study of lutetium-177-PSMA-617 in patients with metastatic castration-resistant prostate cancer (VISION). J Clin Oncol. 2021;39(18 suppl):Abstract    LBA4. doi:10.1200/JCO/2021.39.15_suppl.LBA4
  3. Shore ND, Iguchi T, Villers A, et al. Enzalutamide in metastatic hormone-sensitive prostate cancer patients who received prior antiandrogen therapy: post hoc analysis of ARCHES. Abstract PD34-07. J Urol. 2021;206(suppl 3):e585.
  4. Armstrong AJ, Iguchi T, Azad AA, et al. Final overall survival (OS) analysis from ARCHES: a phase III, randomized, double-blind, placebo (PBO)-controlled study of enzalutamide (ENZA) + androgen deprivation therapy (ADT) in men with metastatic hormone-sensitive prostate cancer (mHSPC). Abstract LBA25. Presented at: ESMO Congress 2021; September 18, 2021.
  5. Kim I, Jang T, Skim S, et al. Modest increase in survival among patients with metastatic prostate cancer in the second-line antiandrogen therapy era. Abstract MP32-09. J Urol. 2021;206(suppl 3):e568.
  6. De Bleser E, Lumen N, Buelens S, et al. Newly-diagnosed low-volume metastatic prostate cancer; is there a place for cytoreductive radical prostatectomy? Abstract MP24-10. J Urol. 2021;206(suppl 3):e415-e416.
  7. Fizazi K, Maldonado X, Foulon S, et al. A phase 3 trial with a 2×2 factorial design of abiraterone acetate plus prednisone and/or local radiotherapy in men with de novo metastatic castration-sensitive prostate cancer (mCSPC): First results of PEACE-1. J Clin Oncol. 2021;39:(suppl 15):5000. doi:10.1200/JCO.2021.39.15_suppl.5000
  8. Martini A, Cirulli G, Parikh AB, et al. Balancing efficacy and toxicity of docetaxel in patients with metastatic castration-resistant prostate cancer. Results from a pooled analysis of three prospective randomized trials. Abstract MP24-09. J Urol. 2021;206(suppl 3):e415.

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Reviewed September 2021