Triple-Drug Therapies Usher in Sea Change for Men With High-Risk Prostate Cancer - Rashid Sayyid & Zachary Klaassen

December 15, 2023

Rashid Sayyid and Zach Klaassen discuss the amended AUA guidelines for advanced prostate cancer, focusing on triplet therapy for metastatic hormone-sensitive prostate cancer (mHSPC) and non-metastatic castrate-resistant prostate cancer (M0 CRPC). They delve into the role of triplet therapy in mHSPC, examining its benefits across disease volume and risk subgroups, as evidenced by the ARASENS and PEACE-1 trials. The discussion highlights the consistent benefits of adding darolutamide to ADT plus docetaxel in both high and low-volume disease patients. They also explore the use of prostate radiotherapy in low-volume mHSPC, noting its potential survival benefits in specific patient subgroups. For M0 CRPC, the guidelines recommend continued ADT with apalutamide, darolutamide, or enzalutamide for high-risk patients, defined by a PSA doubling time of less than 10 months. They close by emphasizing the importance of assessing disease volume, risk, and timing in mHSPC and the efficacy of AR antagonists in M0 CRPC.


Rashid Sayyid, MD, MSc, Urologic Oncology Fellow, Division of Urology, University of Toronto, Toronto, Ontario

Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Well Star MCG, Georgia Cancer Center, Augusta, GA

Read the Full Video Transcript

Rashid Sayyid: Hello everyone and thank you for joining us in this UroToday recording. I'm Dr. Rashid Sayyid, Urologic Oncology Fellow at the University of Toronto along with Dr. Zach Klaassen, Associate Professor and Program Director at Wellstar MCG Health. We'll be discussing the recently amended AUA guidelines for advanced prostate cancer. And in this six-part series, we'll be discussing the different facets of these guidelines. In this recording specifically, we'll be discussing triplet therapy for mHSPC by disease volume, risk, and timing, and non-metastatic or M0 CRPC. These guidelines were initially published in 2020 and were recently amended in 2023, led by Dr. Michael Cookson.

As we see in the outline here, we've previously discussed advanced prostate cancer epidemiology. We've also discussed the statements pertaining to early evaluation and counseling. We've also discussed the diagnosis, evaluation, and treatment of patients with evidence of biochemical recurrence without metastatic disease after exhaustion of local treatment options. And we've touched upon metastatic hormone-sensitive prostate cancer. But in this recording, we'll be delving further into metastatic hormone-sensitive prostate cancer, particularly with regards to the role of triplet therapy and prostate radiotherapy in the low-volume setting, as well as discussing the trials and evidence for non-metastatic castrate-resistant prostate cancer.

So, moving on to the triplet therapy for mHSPC, we've established in the prior recordings that there is strong evidence in certain subsets of patients for triplet therapy, either with the addition of darolutamide to ADT plus docetaxel or abiraterone to ADT plus docetaxel. The next step is trying to figure out which patients are most likely to benefit from such a triplet approach. And we have some data from the ARASENS Trial whereby an ad-hoc analysis by Dr. Hussain, published in JCO 2023, looked at the benefits of triplet therapy, specifically with darolutamide addition to ADT plus docetaxel, stratified by disease volume, disease risk.

We can see that the benefit is consistent across these disease volume and risk subgroups whereby, specifically in the high-volume disease subgroup, we see that there is a benefit with the hazard ratio of 0.69 and also concurrently in low-volume disease patients with a similar magnitude of effect with a hazard ratio of 0.68. We note that the 95% confidence interval crosses the null effect of one, but this is due to the fact that there were only 300 patients in the low-volume subgroup. When stratified by risk status, we again see a benefit in both the high-risk and low-risk patients with similar magnitudes of effect. So, the take-home message from the ARASENS Trial is that adding darolutamide to double therapy with ADT and docetaxel has a benefit across the disease volume and risk subgroups.

Next, we also have some data from the PEACE-1 trial. And of note, in the PEACE-1 trial, all patients had de novo mHSPC. And in contrast to the results that we saw from ARASENS, there was only an overall survival benefit to the addition of abi to standard of care ADT with or without docetaxel only to those patients with high-volume disease. And if we look at the Kaplan-Meier curves to the right here, we see that in the low-volume patients, we do not see a significant benefit to the addition of abiraterone to the standard of care ADT plus or minus docetaxel, whereas in the high-volume patients, we do see a significant benefit.

Next, we see an even more nuanced approach in the ENZAMET data. As we have described before, the ENZAMET data looked at the addition of enzalutamide to ADT, but also almost half the patients received docetaxel. So, this was a unique situation where we could also assess the benefits of triplet therapy. The first question they asked was whether there was a benefit in those with synchronous disease only or those with synchronous or metachronous disease. Synchronous meaning patients had metastasis at the time of presentation. We clearly see that the addition of enzalutamide to docetaxel significantly improves survival in these synchronous patients, but we don't see a benefit in the metachronous patients, meaning those patients who presented with seemingly localized disease and then progressed to metastatic disease later on. This makes sense, as patients with de novo metastasis are the higher-risk patients. So, it is not surprising that we saw a benefit in this subgroup specifically.

Next, after the investigators established that there was a benefit in those with synchronous disease, they tried to see whether this was more specific to those with low-volume synchronous or high-volume synchronous. And surprisingly, they saw that the benefit was more pronounced in those with low-volume, synchronous disease. However, it's hard to draw any firm conclusions given the small sample size in these subgroups. Obviously, the study was not powered to assess these questions, and we see that with sample sizes of 44 and 48 specifically in the low-volume disease subgroups, but nonetheless, this is important data and food for thought for later trial design.

Next, for Statement number 17, the AUA guidelines state that in selected mHSPC patients with low-volume metastatic disease, clinicians may offer primary radiotherapy to the prostate in combination with ADT. This is a conditional recommendation with evidence-level Grade C. This recommendation at the time of the guidelines was informed by the results of two randomized control trials, the Dutch HORRAD trial and then the British Swiss STAMPEDE trial. But more recently, we also have data from the PEACE-1 that was presented at ASCO 2023, and we'll also touch upon the results of this trial.

The HORRAD was a Dutch phase three RCT of mHSPC patients who had a PSA of greater than 20 and evidence of bone lesions on the bone scan between 2004 and 2014. This was an older trial. 431 patients were randomized one-to-one to either ADT alone plus prostate radiotherapy or ADT alone. There was no treatment intensification in these patients, so they did not receive docetaxel or an androgen receptor synthesis inhibitor. It's important to realize this when trying to translate these results to patients in our clinic. Another important point was that the median baseline PSA was quite high at 142 nanograms per ml, much higher than the baseline PSA in the other trials.

At a median follow-up of just under four years, we saw that there was no significant difference in median overall survival, whether radiotherapy was given or not. However, when a subgroup analysis by the number of metastatic lesions was performed, this suggested a potential overall survival benefit for those patients with fewer than five metastatic sites, with a hazard ratio of 0.68. This was the first signal in a prospective trial that there may be a benefit to prostate radiotherapy in patients with a low metastatic burden.

Next, we saw the British Swiss STAMPEDE Arm H trial, which was a phase three randomized trial that randomized just over 2000 men with de novo metastatic hormone-sensitive prostate cancer between 2013 and 2016 to either standard of care alone plus prostate radiotherapy versus standard of care alone. I want to highlight here that the median baseline PSA was 97, compared to 142 in the HORRAD trial, and 18% of patients in this trial had received prior docetaxel. I also want to bring to your attention that this was radiotherapy to the prostate only, and this is a common theme across all three trials that we'll discuss, and that the pelvic lymph nodes were not included in the prostate radiotherapy template.

Similar to the HORRAD trial, in the overall cohort, radiotherapy to the prostate did not significantly improve overall survival, but once stratified by metastatic burden, as we see in the Kaplan-Meier to the right, there was an overall survival benefit observed in the low-volume group where the median overall survival was improved by four months and the hazard ratio was 0.68. More recently, at ASCO 2023, we saw the initial results of PEACE-1 that answered the question of prostate radiotherapy for patients with de novo low-volume mHSPC only. It's important to note in this trial that the standard of care arm evolved here. Some patients received ADT alone, others received ADT plus docetaxel. This is about a fifty-fifty split. Another unique aspect of this trial is that the investigators were able to assess whether there was a differential benefit to the addition of radiotherapy to patients receiving standard of care alone or standard of care plus abiraterone.

There were statistical considerations for this, and clearly, there was an interaction effect. For this reason, the authors looked at two questions here: standard of care plus radiotherapy and also looking at standard of care plus abiraterone plus radiotherapy. The authors and investigators were able to demonstrate that the addition of prostate radiotherapy to standard of care plus abiraterone was associated with a significant rPFS benefit in the range of about three years, going from 4.4 to 7.5 years. Conversely, when the investigators assessed the addition of radiotherapy to standard of care alone, there was no significant benefit. So, we see that adding radiotherapy to standard of care plus abiraterone was associated with an rPFS benefit.

To date, we don't see an overall survival benefit irrespective of whether prostate radiotherapy was added to standard of care alone or standard of care plus abiraterone. The data is not mature yet, and we await the results of this analysis at future meetings. One unique aspect that was highlighted by the investigators is that the addition of prostate radiotherapy to standard of care alone or standard of care plus abiraterone was associated with significant improvements in time to serious GU events. Although when we look at the definition of GU events, the requirement for prostate radiotherapy was considered one of the events that met the definition for this outcome, and so many have argued whether this was of any clinical significance. However, it's important to be aware of this when counseling our patients moving forward.

At this point, I'll turn it over to Zach to go over Statement number 18 and the remainder of the statements in this section.

Zach Klaassen:
Thanks so much, Rashid. That was a great breakdown of triplet therapy and also radiotherapy for low-volume metastatic hormone-sensitive prostate cancer. So, to finish off this section, we'll have a couple more statements. This is Statement 18, based on Grade A evidence, that clinicians should not offer first-generation antiandrogens, which are bicalutamide, flutamide, or nilutamide, in combination with LHRH agonists in metastatic hormone-sensitive prostate cancer, except to block testosterone flare. Historically, this has been a short-term blockade of less than four weeks that can be considered in patients to prevent the testosterone flare. This testosterone flare occurs in about 10% of patients, which may lead to worsening of disease symptoms such as bone pain, urinary tract obstruction, et cetera.

Statement 19 also, based on expert opinion, states that clinicians should not offer oral androgen pathway-directed therapy such as abiraterone acetate plus prednisone, apalutamide, bicalutamide, darolutamide, enzalutamide, flutamide, or nilutamide without ADT for patients with metastatic hormone-sensitive prostate cancer. Older evidence from roughly 11 studies in just over 3000 patients suggests that the use of older nonsteroidal antiandrogens without ADT is associated with worse overall survival, clinical progression, treatment failure, and treatment discontinuation due to adverse events compared to the use of ADT plus nonsteroidal antiandrogens. Of note, there's no high-quality evidence to support the use of ARSI's without ADT, as all of these trials combined these agents together.

So let's switch gears and discuss non-metastatic castrate-resistant prostate cancer. There's been a lot of activity in this disease space over the last several years. Statement 20, based on the clinical principle related to prognosis, suggests that in non-metastatic CRPC patients, clinicians should obtain serial PSA measurements at three to six-month intervals and calculate a PSA doubling time starting at the time of development of castration resistance. We know that patients with shorter PSA doubling times are at increased risk of development of metastatic disease and dying from prostate cancer. And PSA doubling times less than 10 months have been used to identify high-risk populations for inclusion in the three trials which we'll discuss, that led to approval of the AR antagonists for men with non-metastatic CRPC. Of note, though, despite this PSA doubling time less than 10 months, FDA approval was granted to these three agents with no specificity to doubling time.

Again, prognosis for Statement 21, based on expert opinion, states that clinicians should assess non-metastatic CRPC patients for development of metastatic disease using conventional or PSMA PET imaging at intervals of roughly six to 12 months. The exact interval determined by PSA doubling time calculation for imaging, as well as development of symptoms and patient-physician preference, should be used as there's a wide variety in timing of obtaining imaging. Of note, non-metastatic CRPC is an iatrogenic disease state in that it is likely due to the limited sensitivity of conventional imaging at low PSA values for men that are continued on ADT.

So, a good question is: what percentage of patients with non-metastatic CRPC on conventional imaging have evidence of metastasis on PSMA PET? There is data to suggest that this is a very high number. This is a paper from Fendler and colleagues in 2019, a retrospective analysis of 200 patients, men that had non-metastatic CRPC, PSA of greater than two, and high risk of metastatic disease defined as either PSA doubling time less than 10 months and/or a Gleason greater than or equal to eight disease. In these 200 patients, 98% were PSMA PET positive. This includes 44% of patients that had pelvic disease and 24% of patients that had local recurrence in the prostate bed. Over half of the patients, 55%, had metastatic M1 disease with risk factors suggestive of M1 disease, including a PSA greater than or equal to 5.5, pathological N1 disease, a history of primary radiotherapy, or a history of primary salvage radiotherapy. Clearly, conventional imaging negative, the majority of these patients do have lesions on PSMA PET/CT.

Statement 22 relates to treatment. This is Grade A evidence that clinicians should offer apalutamide, darolutamide, or enzalutamide with continued ADT to non-metastatic CRPC patients at high risk for developing metastatic disease, defined as PSA doubling time less than or equal to 10 months. We'll talk about these three trials, but apalutamide in SPARTAN, darolutamide in ARAMIS, and enzalutamide in PROSPER were FDA approved following documented metastasis-free survival benefits in these high-risk patients, with subsequent overall survival benefit noted in all three of these trials. We'll go through the data, but you'll see that the outcomes are quite similar between these three trials, but there are several notable trial differences. First, ARAMIS allowed the inclusion of patients with seizure predisposing conditions. Secondly, SPARTAN and ARAMIS permitted chemotherapy if given in the neoadjuvant or adjuvant settings, and local lymphadenopathy less than two centimeters in ARAMIS and less than 1.5 centimeters in SPARTAN below the aortic bifurcation was allowed as part of their inclusion criteria.

So let's talk about these three trials. The first was PROSPER, looking at enzalutamide, which met the primary endpoint of metastasis-free survival benefit, hazard ratio, very impressive, 0.29, 95% confidence interval of 0.24 to 0.35. We can see in the final overall survival analysis, which is depicted in the Kaplan-Meier curve on the right, that enzalutamide also improved median overall survival from 56 to 67 months with a statistically significant hazard ratio of 0.73.

Moving to the SPARTAN trial, also published in 2018, this looked at apalutamide and met the primary endpoint of metastasis-free survival with the benefit of a hazard ratio of 0.28. And you can see on the right here a wide, consistent splitting of the curves for the hazard ratio for MFS. The final overall survival analysis also demonstrated improvement for apalutamide versus placebo, from 60 to 74 months, hazard ratio 0.78, 95% confidence interval, 0.64 to 0.96.

And finally, in 2019, darolutamide met the primary endpoint of metastasis-free survival, hazard ratio of 0.41, 95% confidence interval of 0.34 to 0.50. And again, similar to the other two trials, it also had an overall survival benefit, reducing mortality by 31%, as we can see in the Kaplan-Meier curve here on the right, hazard ratio of 0.69.

Statements 23 and 24 are related to treatment, both based on clinical principle, and these state that clinicians may recommend observation with continued ADT for non-metastatic CRPC patients, particularly those that are at lower risk, such as PSA doubling time greater than 10 months. This is due to the inherent lower risk of development of metastasis compared to those with shorter PSA doubling times. And this is where the risk-benefit ratio of additional treatment potential toxicity versus observation needs to be discussed with the patient. Also, clinicians should not offer systemic chemotherapy or immunotherapy to these patients outside the context of a clinical trial.

So in conclusion, we discussed that triplet therapy is a new option for metastatic hormone-sensitive prostate cancer patients and should be assessed in the context of disease volume, risk, and timing of metastatic disease. Radiotherapy to the prostate should be considered for men with low-volume metastatic hormone-sensitive prostate cancer. M0 CRPC with a PSA doubling time less than 10 months are at increased risk of metastasis and death. And as such, darolutamide, apalutamide, and enzalutamide are all approved in the M0 CRPC space, irrespective of their PSA doubling time.

We thank you very much for your attention. We hope you enjoyed this UroToday discussion of the AUA Advanced Prostate Cancer Guidelines.