Looking Beyond Survival

26 Jan 2021
Looking Beyond Survival


This feature has been funded by Janssen UK and written on the company’s behalf by M&F Health.

The feature is based on an interview with Professor Joe O’Sullivan, Clinical Professor of Radiation Oncology at the Patrick G. Johnston Centre for Cancer Research, Queens University, and Consultant Clinical Oncologist at the Northern Ireland Cancer Centre, Belfast. The views expressed here are his personal opinions.

Prostate Cancer – Time to Look Beyond Survival?

We are in an era where due to significant advances in recent decades, prostate cancer treatments are showing increasingly smaller gains under the current health technology assessment process focused on overall survival as the key clinical endpoint. Where there are ongoing prostate cancer studies there is a need to explore the different clinical endpoints that can be used to assess and measure patient benefits, particularly in the absence of overall survival data.

What challenges do you expect to see during clinical trials when assessing the effectiveness of new
prostate cancer treatments?

In my opinion, one of the greatest challenges when assessing the effectiveness and tolerability of new prostate cancer treatments in clinical trials is the difficulty in demonstrating the overall survival (OS) benefit of a new drug over the currently available therapies. This is particularly relevant with recently approved therapies in castration sensitive and castration resistant disease leading to further improved overall survival, meaning that there is less chance that we are going to see OS emerging from clinical trials.1,2

In this crowded therapeutic landscape, I am a firm believer that focusing on benefits other than OS will now be necessary. OS has improved significantly over the last number of years so now we are expecting to see a reduced relative gain in OS when assessing new treatments.3

How are patient benefits currently measured within clinical trials and what clinical endpoints are

OS remains the gold standard – we still look at this when assessing a new therapy, especially in advanced prostate cancer.4 It offers us an honest, definitive objective measure which is meaningful to patients.4

Second to this is progression-free survival (PFS) which in my opinion can be more subjective than OS. In castration resistant prostate cancer patients (CRPC), radiographic PFS, symptomatic PFS and quality of life measures are commonly assessed.5 Radiographic PFS may be dependent on how often and which scans are undertaken, symptomatic PFS usually looks at pain symptoms relating to the disease, and when measuring quality of life changes we can encounter difficulty due to its subjectivity amongst different populations making it difficult to compare. This is particularly true when we contrast different countries and health systems, as well as health sectors and societal cultures which has led to disagreements around the effectiveness of various quality of life measures.

Patient reported outcomes have become an important additional solution to this challenge, and if conducted and collected correctly, these results may provide us with valuable insights and estimation of quality of life changes through increased frequency of conversation between clinician and patient.There is a good evidence base to show that patient reported outcomes and physicians’ interpretation of patients’ tolerance are very different when compiled centrally, this patient reported data can be quite useful in providing unbiased feedback of treatments and disease progression.7

Why has overall survival historically been the data used to assess the effectiveness of a new treatment during a clinical trial, and why is this now changing?

OS provides us with a definitive, objective measure and indicates disease modification - this is very understandable and meaningful to patients.8 OS for prostate cancer patients has significantly increased in the past 40 years.9 However, with the introduction of many different effective therapies, we are now seeing reduced relative gain when using this measurement.10 This suggests that it is unlikely that new therapies will modify survival rates dramatically, although this does depend on the existing standard of care patients receive. As with breast cancer treatments, prostate cancer is likely to move on from OS as the main endpoint to PFS amongst other measures.

How can intermediate endpoints be used to highlight effectiveness and patient benefits in future clinical trials for prostate cancer treatments?

We are already seeing intermediate endpoints being used in clinical trials, particularly in the non-metastatic CRPC setting where patients may live with the condition for a long time.1,11,12 Clinical trials studying this cohort of patients can take up to seven years before reaching a conclusion of whether a drug is going to improve OS. This timeframe is too long from a patient perspective, and so an intermediate marker is required to show efficacy especially when treating patients further upstream in the patient pathway - both at the castration sensitive end or the non-metastatic end.

In my opinion, the real test will be demonstrating how those intermediate endpoints convert into more of an objective measure such as OS. So, in addition to using intermediate measures, we should also be making sure that research is taking place to validate them. 

Why and how are intermediate endpoints particularly relevant and important in certain types of prostate cancer such as non-metastatic CRPC?

When looking at non-metastatic CRPC, a key point to note is that we’re dealing with quite a heterogeneous group which can be defined according to, for example prostate specific antigen (PSA) doubling time, where shorter PSA doubling time indicates a group of patients who are in a worse situation.

Even when you look specifically at the worst cases of this group, those with shorter PSA doubling time, the timelines are almost a couple of years until you see survival as an endpoint – this is too long to wait for the cycle of drug development.13,14 In this situation, time to development of metastasis is a particularly relevant intermediate endpoint and comparing this to OS endpoints will be particularly valuable for this group of patients and will allow us to explain, correlate and validate two meaningful endpoints.

How should intermediate endpoints be used in future drug development?

Intermediate endpoints will play a key role in validation of a treatment and we have an obligation to compare how these endpoints manifest against OS results. The pharmaceutical industry should be able to play an important role in spearheading the validation of these endpoints and Health Technology Appraisals (HTAs) should also start to use these as a measure of the broader value of treatments to patients rather than just assessing cost effectiveness, which is a crude method of analysis.

How should these endpoints be used in health technology appraisals to assess treatment’s eligibility for NHS use?

This is an area in which intermediate endpoints will play another important role, especially in the process of assessing the health economic implications of a treatment through economic modelling. These endpoints allow us to provide detailed analysis around the time, cost and resources needed in the interactions between these patients, their healthcare team and clinical settings, which is vital for our healthcare system here in the UK. Not only is it important that we understand the economic implications of these endpoints, but also very important that attention is paid to what these intermediate endpoints mean for patients and the scientific community. In the likely absence of significant or mature OS benefits from new therapies at the time of evaluation, health economists within the National Institute for Health and Care Excellence (NICE) will need to weigh up the benefits of an improvement in a surrogate endpoint such as metastatic-free survival (MFS), in terms not only of cost savings (e.g. fewer hospital visits etc) but also potentially in the societal benefits of better mental health of the patient population. I believe it will also be essential that NICE can use patient reported outcome measures (PROMS) data in assessing new therapies to ensure that the wider economic costs and patient-relevant benefits are taken into consideration during appraisals.

What challenges do you think lie ahead in the development of clinical trials for non-metastatic castration resistant prostate cancer?

The most obvious implication is the emergence of new imaging techniques. Currently, all the non-metastatic CRPC trials to date use conventional imaging, to determine the incidence of metastases. It is clear now that the prostate specific membrane antigen (PSMA) PET scan is a more sensitive test at identifying early metastatic disease than previous techniques used, as it requires a very specific antigen biomarker and may be a game changer in this respect.15 Data has shown that many patients in previous non-metastatic therapy trials in retrospect would have categorised as metastatic by PSMA PET scanning.16 The benefit of PSMA PET compared to conventional CT or bone scans is that it can identify very small metastases very early.

With this in mind, the biggest challenge will occur when PSMA PET scanning becomes more widely available making the non-metastatic CRPC population much smaller. This will impact how we design clinical trials as we will have to acknowledge the fact that a patient may be metastatic on novel imaging however will still benefit from non-metastatic treatments which delay the onset of metastasis.

Date of preparation: January 2021
Job code: CP-196887


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2 Armstrong, A et al. (2019) ARCHES: A Randomized, Phase III Study of Androgen Deprivation Therapy With Enzalutamide or Placebo in Men With Metastatic Hormone-Sensitive Prostate Cancer. Journal of Clinical Oncology 2019 37:32, 2974-2986
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10 National Health Service: Treatment: Prostate Cancer (2018) Available at: Last accessed: January 2021
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13 Jennifer H Lin, Brian Macomson, Ozgur Tunceli et al., (2017) Association of prostate specific-antigen doubling time (PSADT) with metastasis-free survival (MFS) and overall survival (OS) in non-metastatic castration-resistant prostate cancer (nmCRPC), Journal of Clinical Oncology; 35:15_suppl, e16525-e16525
14 Alexander D. Fuld, Yinong Young-Xu et al., (2018) Predictors of overall survival (OS) in veterans with non-metastatic castration resistant prostate cancer (nmCRPC), Journal of Clinical Oncology; 36:15_suppl, e17057-e17057
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