COMMENTARY

Prostate Cancer Care Is 'Changing Rapidly': ESMO 2017

Johann S. de Bono, MD, PhD

Disclosures

November 17, 2017

Hello. My name is Professor Johann de Bono. I am professor of experimental cancer medicine at the Royal Marsden Hospital and the Institute of Cancer Research in London, United Kingdom. I was the track chair for the European Society for Medical Oncology (ESMO) 2017 prostate program. Welcome to Medscape Oncology Insights coming to you from this ESMO 2017 congress.

Benefit of Adding Abiraterone: STAMPEDE, LATITUDE

I want to discuss with you some of the highlights of the outstanding genitourinary prostate cancer sessions at this meeting. Let me start first with the STAMPEDE[1] and LATITUDE[2] trials. These trials evaluated abiraterone and luteinizing hormone-releasing hormone (LHRH) analogs against LHRH analogs alone in patients with metastatic disease at diagnosis. They have shown impressive overall survival benefits for the abiraterone treatment arms. However, these trials did not compare early vs late abiraterone, and there are concerns that many patients in the control arms who passed away had never received abiraterone before they died. Therefore, these data may not be entirely reflective of a comparison of early vs late treatment with abiraterone.

Clearly, we now have evidence that abiraterone improves survival from diagnosis if given with LHRH analogues. STAMPEDE studied not only M1 patients but also M0 patients, although I think that we should focus on using these drugs in M1 disease, particularly with regard to [use] in the clinic today.

LATITUDE data presented at ESMO confirmed the significant quality-of-life benefits. Neither of these trials, however, compared abiraterone and the LHRH analog with standard of care. The standard of care during these trials was indeed an LHRH analog and docetaxel.

However, an unplanned post hoc analysis of STAMPEDE compared concurrently recruited M1 patients at diagnosis receiving either abiraterone with LHRH analog or LHRH analog and docetaxel—the two standards of care. Essentially there was no overall survival difference when comparing 18 weeks of docetaxel (6 courses of 75 mg/m2) vs continuous abiraterone to progression.

How do we interpret these data? It would be fair to say that in 2017, for patients with M1 prostate cancer at diagnosis, we have two standards of care: LHRH analog and docetaxel, and LHRH analogs and abiraterone.

The data presented at this meeting would indicate that both are entirely satisfactory options, and I think that the patient should have the data explained to them and be allowed to choose whether to have one drug or the other at diagnosis. What I think is critical is that both drugs, and indeed all of the drugs that affect survival, are given to the patient at some point in their lifespan and their fight against advanced prostate cancer. Therefore, abiraterone or enzalutamide, docetaxel, radium if there has been bone metastasis only, and cabazitaxel preferably should be given to our patients to maximize survival benefit at some point in their lifetime. I do not endorse giving both abiraterone and enzalutamide. I would recommend giving one or the other. And I do not delay giving the taxanes because these are much more active after the first new hormonal agent; that is, abiraterone or enzalutamide.

Radioimmunoconjugates

At ESMO 2017, there were presentations on radioimmunoconjugates for targeting prostate cancer, such as anti-prostate specific membrane antigen (PSMA) antibodies with a radioactive payload. We heard data on lutetium-177 bound to an anti-PSMA antibody in an investigator-initiated trial from Peter MacCallum Cancer Centre in Australia.[3]

These investigators have shown that beta-particle emitters have promising biochemical and tumor activity with evidence of improvement in the PSMA scans post treatment. They selected patients with high PSMA expression or anti-PSMA antibody uptake with diagnostic pretreatment scans, and they did not recruit patients who had discordance with high choline PET uptake and low PSMA PET uptake. They used PET choline and PET PSMA to optimize patient selection. If patients had high choline uptake in their metastasis and low PSMA uptake with the anti-PSMA PET scan, they were not recruited. Nonetheless, these data were very encouraging.

Emerging data suggest that the alpha-particle emitters, such as actinium and thorium, and the alpha-particle radioimmunoconjugates are coming along. Investigators are studying small molecules that actually bind PSMA on the cell surface and also bind to the alpha-particle emitter, thus targeting prostate cancer. Promising results are being seen with actinium from work in Heidelberg.[4]

A lot of excitement is being generated by these drugs, although it appears that the duration of benefit is still uncertain. Indeed, with the lutetium trial presented at this meeting, the median time to progression was roughly 6 months with two infusions of the radioimmunoconjugate. More data certainly are needed on durability of response. However, these data are encouraging. Thorium alpha-particle radioimmunoconjugate trials are planned, as are actinium radioimmunoconjugate trials with PSMA, and there may be a need to look at other antigenic targets too.

Research on Liquid Biopsies, Targeting CXCR2, and Targeting PI3Kβ

Another highlight of this meeting was a focus on liquid biopsies, specifically circulating tumor cells and circulating free DNA[5] and ARV7 in circulating tumor cells.[6] The consensus today is that these assays are not yet ready for prime time. They are not ready for routine use in the clinic and should be primarily utilized only in clinical trials.

There were interesting data[7] on targeting the chemokine receptor CXCR2. Preclinical studies indicated that targeting CXCR2 may affect macrophages and myelomonocytic primitive cells that the cancer manipulates and hijacks to fuel its growth. Data suggest that targeting the CXCR2 chemokine receptor may be beneficial to patients suffering from prostate cancer. This work came from Andrea Altamonte's laboratory in Bellinzona, Switzerland.

There were also data from the GSK Group with a compound targeting phosphoinositide 3-kinase (PI3K) enzyme PIK3CB p110-β,[8] a key enzyme signaling in prostate cancer phosphatase and tensin homolog (PTEN) loss. Preliminary data showed some early promise in early clinical trials in combination with novel hormonal agents such as enzalutamide. I am sure we will have abiraterone data soon.

Germline DNA Repair Defects

Finally, research confirmed that roughly 9%-10% of all Spanish patients with metastatic prostate cancer had germline DNA repair defects.[9] Similar data are coming from all over the world that at least 1 in 10 advanced prostate cancer sufferers have germline deleterious mutations and DNA repair genes. This is highly impactful not only for our patients but also their families. This work from David Olmos and Elena Castro in Madrid strengthens the argument that perhaps we should be considering, as with ovarian and breast cancer, routine screening of all men with advanced prostate cancer for germline DNA repair deleterious aberrations. Testing could affect targeted screening for cancer in their families and preventive measures in their children and their siblings from getting cancers such as ovary, breast, prostate, pancreas, and leukemia.

Conclusion

Overall, we had a phenomenal program at ESMO this year. Some of these presentations will change clinical practice. To date, we have two standards of care for M1 prostate cancer at diagnosis: docetaxel and chemical castration, and abiraterone and chemical castration. I urge you to ensure that your patients get all of the drugs that improve survival at some point in their lifetime. Perhaps by giving docetaxel earlier at diagnosis, you may ensure that patients can get all of these drugs for maximum benefit.

This is a very exciting time in prostate cancer research and prostate cancer medicine; the field is changing rapidly. I would like to thank you for your attention, and I hope you have found this useful to care for your patients suffering from prostate cancer.

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