The treatment landscape for men with metastatic castration-resistant prostate cancer really has been changing over the last decade. Despite many new approaches over the last decade, clinical outcomes really remain poor and mCRPC is universally a lethal disease. There is information lacking on the optimal sequence of treatments to be used in the pre- and post- mCRPC setting to really improve outcomes, especially across the board and internationally. So really that was the background to evaluate the sequencing of treatment received by men with newly diagnosed mCRPC and investigate before and after what are those treatments using a real-world dataset from the international IRONMAN registry.

Why is understanding treatment sequencing in mCRPC important in real-world clinical practice?

It’s really important for us to understand what the treatment sequences are that really are associated with the most optimal outcomes. There are multiple life-prolonging therapies that are available. mCRPC remains a universally undertreated disease and many patients don’t see all of the life-prolonging therapies that are available to them. So understanding what is happening in the mHSPC setting that may be driving treatment choice and selection in the mCRPC setting is really important and identifying the sequences that are associated with the best outcomes is critical to improving how our patients do clinically.

What was the study design?

This study utilised the prospective IRONMAN registry to analyse outcomes of patients. So we identified 520 men from IRONMAN from ten countries with treatment data. The investigation period utilising mCRPC data diagnosis as the index state was really between 2018 and 2021, so a little bit more contemporaneous. IRONMAN was a prospective cohort study that was enrolling men with both hormone-sensitive disease and castration-resistant prostate cancer internationally. For this specific study we utilised those patients that had a diagnosis of mCRPC from January 2018 to 2021 and they were followed through July of 2022. What we really looked at, our key objectives were to look at treatments prior to the mCRPC diagnosis in the pre-mCRPC setting, to look at the treatments post-mCRPC diagnosis, so after this diagnosis, and actually the sequence. So what were the common this-then-that kind of options that were deployed in this registry.

What were the results?

With regards to the baseline characteristics for the patients that were enrolled, we had a pretty typical population for those with mCRPC. The median age was around 72 years. We did enrol about 73% white individuals with a smattering of other ethnicities and races. With regards to sites of metastases, as would be expected, about 75% had bone metastases. We did see a higher percentage of individuals with visceral  metastases, close to 40% in this cohort, as well.

With regards to the pre-mCRPC diagnosis treatment regimens, the most common regimen that was utilised in the pre-mCRPC diagnosis was actually androgen deprivation therapy alone, around 57%. Then most commonly was the use of chemotherapy with docetaxel at almost 20%. The use of the ARPIs in this context was actually low, it was only at 11% in the context of this data, again keeping in mind that this was an international registry.

With regards to the post-mCRPC treatments, the most commonly utilised treatments were abiraterone and enzalutamide – over 50% of individuals had received one of those two agents. 12% had received docetaxel and then a smattering of other treatments.

With regards to the most common sequence, the most common sequence was going from ADT monotherapy to ARPI followed by chemotherapy and enzalutamide was the most common monotherapy in the pre-mCRPC space. Enzalutamide was also utilised in the post-mCRPC treatment setting as well. So there was tremendous variability in the sequences but we did track that in the context of the study.

So the key limitations are that the landscape is evolving and changing very quickly. There’s a risk of missing variables, certainly the generalisability of the data. No outcomes data was included in this analysis and it pre-dates much of the standard of care. So those are the key limitations; with regards to the key takeaways is in the pre-mCRPC setting in this dataset ADT really dominates and there are few ARPIs being utilised. In he post-mCRPC setting ARPIs were the highest utilised drugs. Then the most common sequence was ADT to ARPI. So there are still a lot of unmet needs to align clinical practice with guideline-based evidence.

What is the significance of these results?

As I stated, it’s understanding the dynamics of the different treatments that patients are utilising in difference sequences. These results really show that there still continues to be guideline-discordant care. Now most patients should be receiving ADT and an ARPI or ADT and some other escalated treatment in the mHSPC setting. We’re seeing that there are still low rates of that, especially when we look at data in the context of an international cohort, and need to ensure that patients have access to escalated treatments and that those are being deployed clinically.

What is next for this study?

With regards to next steps it’s basically educating around this piece and ensuring that clinicians that are seeing patients in the clinic are abiding by guidelines-based care.