ASCO 2024 will soon be upon us, bringing unfortunate news on the prostate cancer front: the readout of Lilly’s CYCLONE-2 trial for its CDK4/6 inhibitor Verzenio (abemaciclib), which failed to significantly improve the duration before tumor progression or death when used with Zytiga (abiraterone acetate) and prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC).

However, prostate cancer is still a hot topic at this year’s meeting, with over 200 abstracts on this disease alone.

Prostate cancer remains one of the most common cancers amongst men, responsible for approximately 375,000 deaths worldwide each year. Additionally, according to a recent article in the Lancet, the number of prostate cancer cases are expected to rise annually from 1.4 million in 2020 to 2.9 million by 2040, with changing age structures and improved life expectancy contributing to this increase. While many cases are manageable with early detection and treatment, advanced stages such as mCRPC can become more challenging.

Effective management of mCRPC necessitates a strategic approach to treatment sequencing to maximize patient outcomes, prolong survival, and improve quality of life. In mCRPC, prostate cancer cells adapt to grow and spread even with minimal androgen levels, rendering conventional hormone therapies ineffective. This stage of the disease requires more aggressive and multifaceted treatment strategies, including chemotherapy, androgen receptor pathway inhibitors, immunotherapy, radiopharmaceuticals, and newer targeted therapies like PARP inhibitors.

The sequence in which treatments are administered can significantly influence their effectiveness. For instance, starting with novel hormonal therapies (NHTs) such as abiraterone acetate or enzalutamide before moving on to chemotherapy agents like docetaxel can delay disease progression and extend patient survival. Proper sequencing ensures that each therapy is used when it is most likely to be effective, preventing premature resistance and preserving future treatment options.

Additionally, individual patient factors, including genetic mutations and overall health, play a crucial role in determining the best sequence of treatments. Advances in genetic profiling and biomarker research are enabling more personalized treatment plans. For example, patients with BRCA1/2 mutations may benefit more from PARP inhibitors, which can be strategically sequenced to optimize outcomes.

Doctors often find that guidance on treatment sequencing for prostate cancer, particularly mCRPC, is insufficient and complex. Despite numerous available therapies, optimal sequencing remains unclear, leading to a reliance on clinical judgment and individualized patient considerations.
A significant issue is the evolving nature of treatment options and the lack of definitive guidelines for sequencing therapies. For instance, the 2023 ASCO GU meeting highlighted that while various agents for mCRPC are approved, there is no clear consensus on the best sequencing strategy. This lack of clarity is partly due to the fact that clinical trials often do not reflect the latest standard therapies, making it challenging to apply trial results to current practice​ (UroToday)​.

Novartis’s Pluvicto (Lutetium (177Lu) vipivotide tetraxetan) has already been approved as a treatment for mCRPC, albeit in a post-NHT, post-taxane, PSMA+ population, but is looking to move earlier in the sequencing pathway based on data from its Phase 3 PSMAfore trial.


What do the experts say?

Below we asked a group of Solici’s experts in prostate cancer – Consultants Cecilia Boz (CB), Sarah Macklin (SM) and Maria Zygouropoulou (MZ), and Special Advisor Rob Drury Dryden (RDD) – to share their views on how this may impact the future of mCRPC treatment.

Novartis has already messaged positively about patient survival data after a preplanned analysis of the trial – but what hurdles do you see to this drug’s approval as an earlier line of treatment?

MZ: One of the issues raised so far is the control arm of the trial, which involved changing from one NHT to another, which isn’t ideal. But, there’s been a precedent of the FDA approving other agents in mCRPC with the same control arm, as it has to do with the standard of care essentially shifting as the trial was being designed and recruited. So, I don’t think that would be enough to prevent the approval. There may also be some question marks around the crossover-adjusted OS data because a great number of patients [84%] crossed over to Pluvicto after progression on NHT, but again this was a pre-specified analysis which will likely be accepted by the regulatory authorities.

CB: From the regulatory perspective, I don’t think it’s going to be a problem; however, I do think uptake as an earlier line of treatment in practice will be more challenging. I think there are two areas of concern: the ease of treatment, and that’s a huge issue with the radioligand therapy and more advanced therapies like ADC’s, etc., when there are oral molecules available for prostate cancer. It really restricts their use of academic centres, whereas community centres are going to be less able to offer these treatment types. Additionally, if you move RLT treatments earlier and they don’t work, what are the patient’s options afterwards?

RDD: For me, there are three key areas: the toxicity profile – we got some pretty nasty fatigue in the VISION trial, and that might be a factor as it’s a patient-relevant endpoint. Although moving Pluvicto up one line is probably not going to make a big difference, there could be more concerns if it is being used in hormone-sensitive patients.  Secondly, sequencing: Where is the data that will help physicians say it’s better to use Pluvicto pre-chemo and leave chemo for afterwards? We don’t have any data for that.
And finally, it’s not all about the data; it’s about what experience HCPs and patients have. If they have really good experience with Pluvicto in the third line it becomes difficult to convince them to use it in a second-line setting. We’ve seen strong growth of Pluvicto this year in sales, so Novartis is doing a good job getting into that third-line position, but the behavioural shift to a second- or first-line is going to be a challenge.
It’ll be interesting to see the ASCO presentations (1,2,3) on Pluvicto use in a real world setting to capture HCP sentiments on its current positioning.

MZ: There have also been reports of side effects such as xerostomia being prevalent in addition to fatigue, and I think as you bring Pluvicto to earlier stages, these types of unpleasant side effects can really impact quality of life and might become much more important decision factors. This is clearly something that Novartis is considering, as there will be a presentation on health-related quality of life outcomes from the PSMAfore study at ASCO this year.

SM: I agree. Fatigue is much more tolerable for patients if they see a survival benefit from Pluvicto as a first line in mCRPC. However, if this drug were to move into earlier stages of treatment, such as hormone-sensitive prostate cancer, I agree; I think there’s more of an argument to be made about not subjecting those patients to these side effects.

As the cornerstone of advanced prostate cancer treatment, what are the strengths and weaknesses of NHTs in PC and how might they be sequenced in relation to chemotherapy, PARPi and RLTs?  

MZ: That’s the million dollar question! It’s very difficult because there’s insufficient data on sequencing to answer this, and the emerging clinical data will not be able to give a definite answer. Nonetheless, the value of NHTs is clearly demonstrated and widely recognized, so they are likely to remain the mainstay as monotherapy, and increasingly in combination, in earlier treatment lines and settings.
Some of the sequencing data will inevitably come from real-world evidence, but that’s a long way down the line, however, it is good to see that there is a case-based session at ASCO specifically on treatment sequencing and symptom management in advanced prostate cancer.

CB: Treatment attrition in prostate cancer is something we don’t talk about very much. For example, in later stages, not many patients actually get sequenced onto other therapies, and even just talking about sequencing suggests that the patients are on treatment longer than they currently are. So, without that data, we aren’t going to be able to make an informed decision on sequencing.  I think we also need to discuss patient segmentation; for example, the PARPs and PARP combos are currently restricted to the HRR mutated (HRRm) population, with Pluvicto for PSMA-positive non-HRRm patients. However, could Pluvicto move before PARPs in PSMA positive, HRRm patients?

RDD: I don’t think so. In an article supporting the PSMAfore study design it was argued that any HRRm patients should be excluded and should instead be included in studies with PARP inhibitors. So I think there is a clear understanding from the community that any HRRm patients should not be treated with radioligand therapy until they’ve had PARP therapy.

SM: I agree. I think the PARPs also have a number of advantages – they are oral therapies and are easier to take than an RLT, which can have significant side effects. Additionally, the price and availability of HRR testing is going to be more straightforward that a PSMA PET scan, so these HRRm patients can then be funnelled into PARP treatments.

RDD:  One thing we haven’t mentioned is high risk localized prostate cancer and I think that’s where we’ll see NHTs really taking hold. You’re going to have radical prostatectomy and radiotherapy as curative intent options and hopefully, functional cure through NHTs in the future. So I think we’ll see all of that happen up front, and hopefully, we’re going to see fewer patients coming into the later lines of therapy.

What might the optimum treatment sequence look like in 5 years time?

SM: I think treatment is going to be much more segmented as we move forward; for example, PARPs are going to have the 25%-30% of mCRPC patients who have HRR mutations, and then there’s EZH2 inhibitors coming up, and that could have a specific population who would benefit from it. As more treatments are developed, I think we’re going to see fragmentation, especially in later-line CRPC, and that will help with sequencing.
I’m a big fan of the RLTs – I think that they’re quite incredible in what they’re doing. But right now, it looks like NHTs are going to be the backbone, but I hope to see RLTs included in the first line and then as you progress, it will be more targeted treatments.

RDD: The targeted therapies, like PARPs, will come in before the RLTs and RLTs are going to struggle to come early in the treatment algorithm. I think there will be a much stronger uptake for the PARP inhibitors. I’m also hoping to get to the point where we have enough novel, innovative products to no longer need chemo anymore.

What other prostate cancer drugs are you currently excited about?

RDD: The data coming through on relugolix is pretty strong, but I’m not sure where it is going to fit on the treatment pathway – probably still at a fairly late line in the mCRPC setting, but that’s really going to be a useful drug.  Also, Prof. Nick James led the first UK trial of gene therapy in prostate cancer, so that’s pretty exciting, but very early stages. We should be aiming for a functional cure in many more patients in the early setting and whatever we can do to enhance that is what we should be focusing on.

SM: I’m really excited about Pfizer’s EZH2 inhibitor, mevrometostat. It is a drug that has the potential to treat all PC patients, not selected for a specific mutation, and has the potential to solve the patient segmentation question that PC experts are grappling with. On top of that, it is a small molecule oral drug which can be administered across community settings whereas these more complex therapies (RLTs, ADCs, TCEs) are largely restricted to academic centers for treatment, making it a much more accessible option for patients. It has shown promising early data from its phase one trial, and we expect an update at ASCO. So I think if that works, it’s a big game changer and may help to reduce the sequencing complexity question that HCPs are facing in prostate cancer.


Article written by Solici Manager, John Acord.

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