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Rashid Sayyid: Hello everyone, and thank you for joining us in this special edition of the Journal Clubs. I'm Rashid Sayyid, a Urologic Oncology Fellow at the University of Toronto, along with Zach Klaassen, an Associate Professor and Program Director at Wellstar MCG Health. We'll be discussing the recently published subgroup analysis of ARASENS, specifically looking at the outcomes of Black patients in this trial. We'll also delve into some insights into the disparities for minorities in randomized controlled trials, both historically and currently, and discuss the need for increasing enrollment, along with some of the strategies behind this.

This subgroup analysis of the ARASENS trial was recently published in The Oncologist with Dr. Neal Shore as the first author.

So, we've had a couple of reports from ARASENS already. To recap, ARASENS evaluates the triplet combination of ADT plus docetaxel, plus or minus darolutamide, with patients in the intervention arm receiving darolutamide, in patients with metastatic hormone-sensitive prostate cancer.

In the first report, published in the New England Journal of Medicine by Smith and all, this triplet therapy approach, as opposed to a doublet therapy, reduced the overall mortality rate by about 33% and meaningfully prolonged time to CRPC. Importantly, for our patients, when talking about health toxicity, there were similar rates of serious adverse events in both arms.

Next, in 2023, we saw the second report from ARASENS, that showed that the addition of darolutamide to ADT and docetaxel improved overall survival for patients with high volume disease, with a hazard ratio of 0.69; high-risk disease, with a similar magnitude effect; and low-risk disease as well, with a hazard ratio of 0.62. Notably, there was a non-significant benefit in the low-volume disease patients, but this didn't reach the pre-specified cutoff.

So why is this question relevant in Black or African-American patients? In other words, why are the authors specifically reporting the results from ARASENS in this specific racial subgroup? First, we know that there's a higher incidence of prostate cancer and a higher mortality rate in Black and African-American men. This increased rate of adverse events is secondary to numerous factors, among which include longstanding wealth inequalities. And this may lead to longstanding differences in risk factor exposure that may eventually lead to differences in the incidences and mortality. We know there are differences in socioeconomic status between African-American Black patients and other racial ethnic cohorts, and this affects access to healthcare. There are also differences in access to equitable cancer prevention, screening, and treatment. What's interesting is that results coming out of the SEER and the VA cohorts suggest that outcomes by race are similar when access to care disparities are neutralized within the context of an equal access healthcare system. So, in other words, when you provide Black versus other racial groups equal opportunity to seek medical care and receive treatment, it appears that the results are the same.

There's also further evidence in the mHSPC setting that treatment intensification neutralizes racial differences in long-term outcomes. And if we look at the CHAARTED trial, which looked at ADT plus or minus docetaxel in this setting, when we look at the control arm of ADT alone, Black men had a median overall survival of 34 months, whereas White non-Hispanic men had a median overall survival of 45 months. So, almost a difference of one year, which is very meaningful in this setting. However, when we look at the treatment arm of ADT plus docetaxel, so the treatment intensification arm, the overall survival was 58 months for both Black and White non-Hispanic men. So not only did it improve in both arms, but also the improvement neutralized any differences. So again, this emphasizes the importance of treatment intensification in this setting for these patients.

And so, based on this rationale and many other factors, the authors conducted a subgroup analysis in the Black patients, where they evaluated specifically the efficacy and safety results within the context of ARASENS.

And so, just to briefly recap, ARASENS is a double-blind placebo-controlled Phase III trial that was conducted across almost 300 centers in 23 countries between 2016 and 2018. This trial randomized patients with conventional imaging-detected metastatic hormone-sensitive prostate cancer in a one-to-one fashion to either darolutamide, that's given at 600 milligrams twice daily, plus ADT and docetaxel, versus placebo with ADT and docetaxel. And in this trial, treatment was continued until there was evidence of symptomatic disease progression, there was a change in the chemotherapy regimen, there was unacceptable toxicity, or either the patient or physician decided to discontinue, obviously death or non-adherence.

The primary outcome for this analysis was overall survival, that was estimated using Kaplan-Meier estimates. And also, Cox regression modeling, adjusting for the extent of disease and ALP level, was used to estimate hazard ratios across racial groups. So in other words, the investigators controlled for the extent of disease and the ALP level when estimating hazard ratios across racial groups.

Secondarily, they looked at time to CRPC, which is a very meaningful clinical outcome, and they looked at treatment-emergent adverse events. What was interesting, they looked at this in a unique way, which was the exposure-adjusted incidence rate, which essentially looks at the number of patients with an emergent adverse event divided by the treatment duration in year. So it's adjusting for the treatment duration, not just reporting the frequencies, as most trials do, but also taking into account how much treatment the patient received and how many patients had an adverse event of interest.

At this point, I'll turn it over to Zach to go over the results, and we'll go over the discussion together for this trial.

Zach Klaassen: Thanks so much, Rashid. So, this is the table of demographics and clinical characteristics, and there are several important points to point out here from this subgroup analysis.

The first point is that there were 26 patients in the darolutamide plus ADT plus docetaxel arm that were Black, and subsequently, there were 28 in the placebo plus ADT plus docetaxel arm. And so, this is side by side, as you can see here, with the overall population. When we compare these two cohorts, we see several important points specific to the Black population. So, generally, these patients in the Black subgroup were younger, they had more recurrent disease. Remember that both de novo and recurrent metastatic hormone-sensitive prostate cancer was included. You can see here, 19.2% in the treatment arm, 28.6% in the control arm, compared to roughly 13% in both arms in the overall population. Notably, in the Black population, this is truly a high-risk population. You can see the median PSAs were higher, 38.2 in the treatment arm, 33 in the placebo arm, compared to 30.3 and 24.2 in the overall population, respectively. So, this gives us some insight into the characteristics of the Black subgroups in this ARASENS trial.

So, again, by way of overview, this is the ITT (intent-to-treat) population overall survival. As we know, this was a positive trial. The median overall survival was not reached in the darolutamide plus ADT plus docetaxel arm, and was 48.9 months in the placebo plus ADT plus docetaxel arm, for a hazard ratio of 0.68. So, a 32% reduction in mortality, which was statistically significant. The other thing to point out here is that the four-year OS (overall survival) rate was 62.7% in the treatment arm, and 50.4% in the control arm.

Now, looking specifically at the Black population, this is data we have not seen until now. There was a treatment benefit for Black patients, so darolutamide plus ADT plus docetaxel, median was not reached, compared to 38.7 months in the control group. Hazard ratio, clinical benefit of 0.41. Statistically not significant, but certainly looking at the Kaplan-Meier curves, and looking at the splitting of these curves that were early and consistent, we see a benefit here, specifically when we look also at the four-year OS rate of 61.7% in the treatment arm, and 40.9% in the control arm.

As Rashid mentioned, time to CRPC, a very important subgroup analysis and important for the patients and the clinicians. This is basically time to the next therapy. When we drive this PSA down early with triplet therapy, it delays time to metastatic CRPC. And so, this is both clinically important to both stakeholders, in terms of the physicians and the patients. And we see in the intention-to-treat population very wide splitting of the Kaplan-Meier curves, and we see a hazard ratio of 0.36. So, a 64% reduction in time to CRPC for the triplet therapy versus the control in the ITT population.

In the Black population, we see a massive benefit in time to CRPC. So, darolutamide plus ADT plus docetaxel median was not reached. And only 12.6 months in the control arm for a hazard ratio of 0.09, 95% confidence interval of 0.02 to 0.30. So, a 91% improvement in time to CRPC for triplet therapy among this Black population.

What about tolerability? So, in terms of the incidence of treatment-emergent adverse events, essentially, this is comparable amongst the Black subgroup compared to the overall subgroup. And I will highlight, as you can see listed in the box here, serious adverse events in the overall population, roughly 40 to 45% in both the treatment and the experimental arm. And this is comparable in the treatment arm of the Black patients, 42.3%, but only 25% in the placebo plus ADT plus docetaxel arm. So, in general, whether it be serious or even grade one to grade four adverse events, tolerability, no major differences between the Black subgroup and the overall population.

In terms of the treatment-emergent adverse events associated with ARPIs, we do see a couple of nuances here. Generally, these are quite similar between the two groups, with maybe slightly higher fatigue in the Black subgroup for both the treatment and the experimental arm, and slightly higher hypertension in the Black subgroup compared to the overall population. But generally, as you can see from the list of treatment-emergent adverse events on the left, they are quite comparable between this Black subgroup and the overall population.

I now want to bring Rashid back in to discuss the disparities, specifically as they pertain to metastatic hormone-sensitive prostate cancer.

Rashid Sayyid: Thank you, Zach. A very important point is that many of the trials in this space have really done a poor job of recruiting Black patients. And we know these are international multicenter studies across very vast geographic settings. So, really, there's not a strong excuse for not enrolling these patients in these trials.

And so, if we look at the major trials in this space, and these are select four, it seems that CHAARTED has done, compared to the others, the best job. So if we look at the percentage of Black patients, it's almost 10% in this trial. And you may say, well, 10% may not be good enough, but when we compare it to TITAN and ARCHES, it's less than 2% for each of them, whereas ARASENS was a little bit better at almost 4%. And so, that's a very important point.

First of all, they're not recruiting as many patients as we probably should, given that we need a representative cohort for the external validity of the results. The second thing is, many of them have done a very poor job at reporting the median overall survival in this vulnerable subgroup. So, if we look at CHAARTED, they've also done a great job showing us that the median overall survival is pretty much equivalent. As we said before, when we intensify treatment, and when we look at the control arm down below, we see that White patients do better than Black patients. That's a very important takeaway, showing us and proving the importance of treatment intensification in these patients.

Conversely, when we look at TITAN and ARCHES, the median overall survival of Black patients isn't even reported. And so, this is likely because of the poor numbers, and the limited power, and the limited follow-up for these patients. But nonetheless, again, this shows us that we need to do better.

And then the next question is, well, are these results limited to trials in the GU space? And so, I'll turn it over to Zach, who will show us that historically, this isn't an issue that's limited to urology or GU medical oncology trials but also is pervasive in other facets of clinical trial design and conduct.

Zach Klaassen: Yeah, thanks so much, Rashid. So, I think the previous slides have really set the table for the discussion, which I think is really important with regards to minorities in clinical trials, not just in the GU space but also across other malignancies. This is some work from Cheryl Lee’s excellent keynote address at ASCO GU 2024. She showed that, when you look at the clinical trials across many disease spaces, 2.5% of Black patients and 2.3% of Hispanic patients are represented, so clearly an underrepresentation in these major clinical trials across many disease spaces.

This is excellent work from Jeunice Owens-Walton, published in JCO in 2022. The objective of this study was to look at representation in Phase II/III trials in urologic oncology. So, looking at both prostate, kidney, and bladder cancer, they took trials from clinicaltrials.gov, and then they used the SEER database to look at the US prevalence of these cancers. And then, essentially, with a little bit of mathematics, they looked at what was called the representation quotient. This is calculated to assess the relative proportion of each racial ethnic group enrolled in clinical trials over the proportion of persons from each group in national cancer cases by cancer type. So basically, what this means is, over one is overrepresentation, under one is underrepresentation.

And this leads us to the results of this analysis. So, they looked at 341 trials, roughly 50% reported race and ethnicity. So, not even doing subgroup analysis, but even reporting race and ethnicity was only 50%. When we look at prostate cancer on the right here, which I've circled, you can see the quotient of one is essentially perfect representation. Over one, as we can see here for White patients, is overrepresentation in red. And we see both in Black and Asian-American and Pacific Islanders underrepresentation in prostate cancer trials. When we look at Hispanic versus non-Hispanic, you can see here again, this blue line is the Hispanic population RQ of less than one, so underrepresentation. So, this is some very elegant data looking at a huge cohort of trials in the Phase II/Phase III setting, showing underrepresentation of minorities in these trials.

What are strategies for increasing minority enrollment? Again, looking at some previous data. This was presented by Paskett and colleagues at ASCO in 2023. This is looking at the Alliance trials, and some of the work they’ve done to increase accrual in their trials. So, I'm going to go through stepwise, because these are important points on the left. Basically, their goals and their strategy for increasing enrollment.

One thing is leadership promotion: 20% accrual of underrepresented minorities and leadership for all the Alliance trials, in terms of funding, funding underrepresented junior investigators and their research, establishing outreach and accrual working groups, assigning disparity co-chairs to trials to provide input on underrepresented minority enrollment. Translation of patient-facing materials to enroll patients speaking other languages, a very important factor. Focusing on sites where there is a high incidence of underrepresented minority populations. So, really targeting those sites. Monitoring accrual by demographics, and by site and time, so that we're not overrepresenting without even knowing that we are. Protocols developed with aims for specific populations. So, really, again, targeting aims of trials for underrepresented minorities. I think this is important: making eligibility criteria less burdensome and more inclusive. And we'll see that on the subsequent slide as well. And finally, increasing study sample size to enroll more underrepresented minority participants, and closing studies to non-underrepresented minority participants.

And so, this has been their protocol for the last decade or so. And we can see that, from January 2014 to January 2023, with intentional approaches to increasing enrollment, they have accrued 13.5% back in 2014, up to 23.6% in 2023. So, this is a 74.8% improvement in this short decade of time. And so, I think this really highlights that with intentionality and using these factors on the left, we can improve enrollment in these trials.

ASCO and Friends of Cancer Research were also highlighted by Dr. Lee in her presentation, which really also has a number of important bullet points for increasing minority enrollment. So, having washout periods which are favorable for enrolling minorities, allowing concomitant medications, allowing more prior therapies, having laboratory reference ranges which aren't quite as stringent as maybe some of the trials we've had, having performance status which isn't perfect. If you look at the majority of the metastatic hormone-sensitive prostate cancer trials, most of these patients are ECOG zero and one. And we can see at the bottom of this list as well, prior and concurrent malignancies, maybe having some leniency there, as well as being a little more lenient in organ dysfunction.

What's also important is the FDA has had some guidance for the industry, and Dr. Lee highlighted this beautifully in her talk, and I think it's worth pointing out here. Expanding access to these patients, adopting inclusive enrollment retention practices, having community outreach partnerships with advocacy groups, accessible recruitment events, providing trial resources in multiple languages, leveraging social media, and really making it a priority to have underrepresented minority enrollment.

And finally, reducing participant burden. This is important. Visit schedules, sites, and windows having some leniency in follow-up, modes of communication, whether this be telehealth or electronic informed consent. As we've learned in the pandemic, a lot of our follow-up can be done remotely, and this may help with increasing enrollment for underrepresented minorities, as well as financial reimbursement, which may also help with underserved communities.

So to conclude, we saw in the subgroup analysis of ARASENS, Black patients with metastatic hormone-sensitive prostate cancer treated with darolutamide plus ADT plus docetaxel led to improved overall survival and improved time to CRPC, versus ADT and docetaxel alone. And this was very well tolerated.

However, as we've outlined today, there remains a paucity of minorities enrolling in Phase III trials, and governing bodies such as ASCO and the FDA have provided a framework for increasing enrollment. And so, ultimately, and the most important take-home message from our talk today is, it's time for stakeholders to take action for increasing minority enrollment in randomized clinical trials.

We thank you very much for your attention. We hope you enjoyed the special UroToday Journal Club, highlighting the subgroup population of Black patients in ARASENS, as well as discussing improving enrollment of minorities in clinical trials.