A paradigm for the future?

Not so long ago, one of the new immunotherapeutic agents (a PD-1 inhibitor called pembrolizumab or Keytruda) was approved by the US Food and Drug Administration (FDA) for the treatment of so-called microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) solid tumors — regardless of the biological site of origin of those tumors.

Such tumors are well known to be relatively unusual, but we do know that they can be found in men with advanced and metastatic forms of prostate cancer, and — consequently — many men with advanced or metastatic prostate cancer who are not responding well to traditional forms of treatment get tested for the presence of one of other of these genetic abnormalities.

A new set of data reported by Abida et al. in JAMA Oncology has now given us what would seem to be a highly accurate idea of the prevalence of this type of genetic abnormality in prostate cancer. They were able to identify 32 such cases among 1,033 patients treated at the Memorial Sloan-Kettering Cancer Center (MSKCC) who could provide tissue samples of adequate tumor quality for the necessary MSIsensor analysis.

Out of these 32 patients,

  • 23 had high MSIsensor scores and were classified as having the MSI-H phenotype.
  • 9 had intermediate MSIsensor scores with evidence of the dMMR phenotype.
  • 11 patients with MSI-H/dMMR castration-resistant prostate cancer received PD-1/PD-L1 immunotherapy.
  • Of these 11 patients
    • 6 had a > 50 percent decline in the PSA level (or whom 4 also had radiographic responses to treatment).
    • 5 of the 6 responders were still on therapy at up to 89 weeks.

Abida et al. conclude that:

The MSI-H/dMMR molecular phenotype is uncommon yet therapeutically meaningful in prostate cancer and can be somatically acquired during disease evolution. Given the potential for durable responses to anti–PD-1/PD-L1 therapy, these findings support the use of prospective tumor sequencing to screen all patients with advanced prostate cancer for MSI-H/dMMR.

What the abstract of the paper does not tell us, and, in all honesty, what we don’t yet know, is when patients with advanced prostate cancer should be screened for the presence of this type of genetic abnormality. We also don’t yet know the potential response rates for men with the MSI-H/dMMR phenotypes if they are treated with PD-1/PD-L1 immunotherapy as soon as possible after their phenotype can first be recognized (and potentially long before they are either metastatic or castrate resistant).

This specific set of abnormalities only occurs in 3 percent of men with advanced prostate cancer — and most of these men being managed at MSKCC probably had very advanced forms of the disease. The ones who got treated with appropriate immunotherapy were all castrate resistant. Only about half of these 11 men showed a clinically significant response.

We should also note that the prevalence of these phenotypes in the wider population is still unknown. The average patient getting treatment at MSKCC is not exactly an “average” American with prostate cancer. They tend to be people from all over the world who have the financial resources to get treatment at one of the best cancer centers in the world, and they may only be getting there after they have failed several other forms of treatment. The prevalence of the MSI-H/dMMR phenotypes could therefore be significantly lower among the prostate cancer patient community in the US as a whole.

The “New” Prostate Cancer InfoLink is of the opinion that this type of finding for new treatments that are coming available and which are only truly impactful in small subsets of men with definable subtypes of prostate cancer is probably the future norm.

We know that there are multiple subtypes of aggressive prostate cancer which respond to very specific types of treatment. We know that at least some men with the MSI-H/dMMR phenotypes respond to treatment with the PARP inhibitors too. Will the men who respond to the PARP inhibitors be the same men as the ones who respond to the PD-1/PD-L1 immunotherapeutics? Or might they include men who didn’t respond so well to immunotherapy?

Our suspicion is that a decade or so from now we may have a dozen different types of treatment that are active in small subsets of men with advanced forms of prostate cancer; that these men will all be definable in terms of certain types of genetic/genomic information; that genetic/genomic screening will have become the norm — at least for all men who do not respond well to first-line androgen deprivation therapy (ADT); and that we will be starting to look at genetic/genomic screening for all patients who are initially diagnosed with at least unfavorable intermediate-risk prostate cancer.

This “new normal” is going to come with all sorts of implications for the management of prostate cancer over time, and one of those implications will be the ability of our health systems (here in America but also around the rest of the world) to adapt reasonably quickly to ensure adoption of life-enhancing tests and therapies without these becoming so expensive that access is limited to the very few who can afford to pay for this type of care out of their own pockets.

New doors are opening for the treatment of aggressive and advanced forms of prostate cancer … but we have a long way to go if we are to ensure that men with these types of prostate cancer are getting the most appropriate and relevant treatment as early as they may need such treatment.

One Response

  1. Sitemaster’s excellent commentary on this study is the essence of personalized medicine and precision drugs … the very point that some, albeit perhaps very few, respond to a particular drug. Twelve years ago when I was diagnosed, I heard these discussions and thought it was pie-in-the-sky — now it is practical.

    The availability of such treatment to the few eligible patients is not and should not be elitist. It is available to all today, even those in community settings — especially with the approval of genomic sequencing by Medicare. The constraint is education — both for the medical community and the patient. The patient has to know to ask for the right test at the right time in disease progression; and the doctor has to know how to respond. This is an issue I have been working on personally … largely because it can save lives and suffering.

    Three percent is not a large number — but add up the 3% here, the 0.5% there, the 1% elsewhere and the aggregate of patients that benefit from personalized medicine is, as Sitemaster points out, burgeoning. Ten years from now I too expect genomic sequencing will be an essential tool in diagnosis and treatment selection, benefiting a lot more than the small group today.

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