Clinical trials for metastatic castrate-resistant prostate cancer—who is looking after the control patients? Questions for the future

Whilst there has been considerable success over the last 20 years in the treatment of men with metastatic castrate-resistant prostate cancer (mCRPC), in this commentary we suggest that recent trends in control arms in several mCRPC trials threaten the efficient and ethical development of new therapies. We highlight that solutions must be found to accommodate commercial development with definable clinical benefit, whilst ensuring that there is robust transparency and long-term efficiencies in treatment evolution.

Generally, the purpose of oncology clinical trials is to advance care by providing evidence of improved overall survival or quality of life. Inherent in this principle is that a clinical trial should be built on the results of previous trials and provide a direct or indirect comparison with a current standard therapy. Traditional models of linear drug development (Figure 1A) offer significant advantages to both physicians and patients by defining the most efficacious therapy based on validated trial endpoints. This was the case with the development of mitoxantrone, docetaxel, and cabazitaxel in mCRPC, in addition to some of the trials supporting abiraterone or enzalutamide. Recently, there have been several examples of prostate cancer trials with orthogonal (where the study uses a control arm that doesn’t appear in guidelines or has a strong evidence base, Figure 1B), selected (a biological or otherwise defined subset, Figure 1C), or multi-linear [utilising a common standard of care, but developing two or more novel treatments, Figure 1D(i–ii)] drug development pathways.

Figure 1. Overall strategic design, and examples of drug development pathways in metastatic castrate resistant prostate cancer.

(A) The principle of linear drug development. An example is the TROPIC study, comparing cabazitaxel and mitoxantrone following prior docetaxel in men with metastatic castrate-resistant prostate cancer (mCRPC). A, mitoxantrone; B, best supportive care (BSC); C, cabazitaxel. (B) An example of orthogonal drug development as seen in the VISION study, comparing 177Lu-PSMA-617 and BSC following prior taxane chemotherapy and anti-androgen therapy in men with mCRPC. A, mitoxantrone; B, BSC; C, cabazitaxel; G, 177Lu-PSMA-617. (C) An example of selected drug development as seen in the PROfound study, comparing olaparib and physicians’ choice of enzalutamide or abiraterone, following abiraterone or enzalutamide, respectively, but not necessarily taxane chemotherapy in men with mCRPC and a qualifying alteration in prespecified genes with a direct or indirect role in homologous recombination repair. A, abiraterone; B, BSC; C, cabazitaxel; S, olaparib. (D) (i) An example of sequential multi-linear drug development as seen in many studies for advanced prostate cancer, e.g.comparing addition of various treatments to androgen deprivation therapy (ADT) in the metastatic hormone-sensitive prostate cancer (mHSPC) and non-metastatic castration-resistant prostate cancer (nmCRPC) setting. A, trial drug; B, ADT; J, options of enzalutamide, apalutamide, darolutamide, and docetaxel. (ii) An example of serial multi-linear drug development [multi-arm, multi-stage (MAMS) type] as seen in the STAMPEDE study. A, ADT; B, zoledronic acid; C, docetaxel; D, celecoxib; E, zoledronic acid plus docetaxel; F, zoledronic acid plus celecoxib; G, abiraterone; H, radiation; J, enzalutamide plus abiraterone; K, metformin.

Multi-linear development pathways can facilitate more choice based on patient preference, cost, comorbidities, or drug toxicities, whilst also maintaining therapeutic evolution (in particular, sequential multi-linear trials of the multi-arm, multi-stage design). However, as recently suggested,¹ serial development pathways involving multiple drugs of the same therapeutic class (‘me-too’ type trials) create choice, but may negatively impact long-term resourcing and innovation.

Orthogonal and selected drug development strategies pose significant challenges for efficient therapeutic development and patient care. Whilst biomarker selected strategies may represent an optimal therapeutic approach, the critical decision in a clinical trial remains the comparator arm. Without an appropriate control arm, patients may be disadvantaged when trials are designed without the ability to compare or even infer therapeutic options accurately on the basis of any common clinical denominator.

The ability to develop both of these non-linear pathways has in part been facilitated by (i) the use of inappropriate, non-standard-of-care comparators and (ii) a commercial reluctance to randomise against active control arms. For example, there are no listed studies currently randomising against cabazitaxel or radium-223, both of which have demonstrated survival advantages for men with mCRPC. Specifically, enzalutamide or abiraterone has been used as comparators in patients whose disease has already progressed on the alternative (or even identical) drug without further lines of therapy as seen in the PROfound, IMbassador250, CONTACT-02, and KEYNOTE-641 studies.^2–4 This approach has limited, if any, clinical utility^5–10 and does not represent an evidence-based standard of care.

Acceptance of these control arms lowers the bar for drug approval and creates a false impression of an acceptable magnitude of clinical benefit since the comparator is weak.^11,12 Inclusion of inappropriate control arms in clinical trials may also reinforce community use of substandard therapies and have a feed-forward effect on prescribing practices. The main arguments in favour of these control arms include reference to real-world evidence and patient autonomy. The former seeks to justify that a control treatment used widely in the community should displace an evidence-based alternative because of its widespread use (or lack thereof)¹³—in part, so that a trial will accrue quickly and be broadly applicable. This practice, if accepted, could facilitate unregulated medical practice becoming mainstream by default and impair the development of evidence-based quality care, especially as trials will accumulate before a perceived ‘bottleneck’ in therapy such as the receipt of chemotherapies. Another justification for real-world comparators is that many patients in the community are perceived to be too unwell to receive the current standard of care,^14,15 without any formal assessment of fitness for treatment and documentation thereof as part of trial eligibility. This is an extraordinary omission from an otherwise highly regulated and protocol-driven industry and implies a disturbing de facto tolerance for physician discretion at enrolment. Another critical fault in this argument is that the same patients are randomised to receive the experimental drug. This is often as, or more, toxic than the current (omitted) optimal standard of care, and indeed, standard treatments are still often administered as post-protocol therapy.

The latter argument for patient autonomy implies that patients may wish to willingly consent to a clinical trial in which they may be randomised to a control arm that does not represent optimal current treatment. For patients to make an informed decision to enrol in such a clinical trial, they should be provided with full disclosure of the evidence supporting the standard of care that they are not being offered, in addition to the lack of evidence supporting the comparator that they may receive. The onus is on the investigator to ensure that their patients are fully informed about all aspects of their enrolment, both at the individual and trial levels. Almost universally, this information is not presented in consent forms that should include appropriate statements such as: “The treatment that you would receive if randomised to the control arm of the study, although sometimes administered in routine practice, is not the most effective treatment to improve survival as supported by clinical trial evidence. By consenting to this trial, you may be enrolled into a treatment arm where you will receive a non-standard treatment for your stage of prostate cancer, which may carry with it additional risks. There may be reasons for this strategy that you should discuss with your doctor”.

Additionally, regulatory agencies such as the United States Food and Drug Administration (FDA) and European Medicines Agency have a mixed record in ensuring that the design and execution of clinical trials are appropriate. The FDA has insisted on post-registration trials to optimise the dose of some agents^16–18 yet has been relatively indifferent to, or placed little emphasis on, the safety of patients in control arms in registrational studies and whether the use of suboptimal therapeutic pathways exposes patients to risk, or indeed if the patients have been warned of those risks. It is well within their mandate to ensure that there is clear guidance and documentation around not only informed decision making, but the criteria for deeming a patient unfit for the standard of care, and documenting refusal of this if applicable.

Whilst we accept that these problems may be insurmountable in the short term, the next step is to acknowledge and adapt to this evolving environment – for better or worse.