Local radiotherapy for the treatment of metastatic hormone-naïve prostate cancer

Patients with metastatic cancers are typically treated with systemic therapy; however, recent research has indicated that local treatment of the primary tumor may have a greater beneficial impact than previously believed. Local radiotherapy of the primary tumor has been evaluated across many different clinical trials, including prostate cancer, kidney cancer, lung cancer, and breast cancer.1

In 2018, the HORRAD trial, a randomized trial comparing the outcomes of patients with metastatic prostate cancer treated with androgen-deprivation therapy (ADT) with or without local treatment of the primary tumor with external beam radiation therapy (EBRT), reported that there was no evidence of an overall survival benefit with the addition of EBRT. The HORRAD trial did, however, report that survival there may be a survival benefit with the addition of primary tumor-directed EBRT for patients with fewer than five bone metastases.2

At the European Association of Urology (EAU) Virtual Meeting 2021, Piet Ost, MD, PhD, of the Ghent University, Ghent, Belgium, discusses the latest updates on the use of radiation therapy for the local treatment of metastatic hormone-sensitive prostate cancer, in particular highlighting results from the STAMPEDE trial (NCT00268476).  The STAMPEDE trial is an ongoing multi-stage, multi-arm, randomized trial which is comparing the safety and efficacy of novel therapeutic strategies with the current standard of care regimens for the treatment of high-risk locally advanced or metastatic prostate cancer, previously untreated with ADT.

In one arm of the STAMPEDE trial, the potential benefits of adding prostate radiotherapy to ADT were explored. In patients with low-volume disease, a 17% absolute improvement in 3-year failure-free survival was reported (HR, 0.59; 95% CI, 0.49-0.72; P < 0.0001), with an 8% absolute benefits for 3 years in overall survival (HR, 0.68; 95% CI, 0.52-0.90; P = 0.007).3

Dr Ost commented on the impact of these findings saying: Following the data that the STAMPEDE trial offered, we immediately saw that it’s a great opportunity where we can prolong survival of our patients just by irradiating the prostate locally. 

And those data really changed the world a bit for us as this is clearly a new indication where despite patients having metastasis, we can still treat the primary tumor and patients survive longer. But it is only limited for patients with up to three metastases independent of whether or not they have lymph node metastasis or not”.

Dr Ost explains that there are many unknowns. For example, novel anti-androgen drugs have recently demonstrated great potential for survival prospects; however, it is currently unknown whether radiotherapy can be used in adjunct with these novel agents to improve outcomes, a matter being explored in the PEACE-1 trial (NCT01957436). The first results from this multi-center Phase III study appear promising with significant improvement in radiographic progression-free survival, although mature overall survival data will provide a better indication of its efficacy.4

Another question yet to be answered is whether the metastases themselves should be treated with therapies such as stereotactic body radiotherapy. This will be investigated in Arm M of the STAMPEDE trial. Although various trials have shown initial promising results there is still work to be done to ensure radiation therapy is feasible in combination with other emerging treatments.

Fluorescent EMI-137 tracer for improved margin assessment in PSCC surgery

Penile squamous cell carcinoma (pSCC) is the most prevalent form of penile cancer, accounting for 95% of penile cancer cases.5 Treatment is dependent on the tumor stage and can include wide local excision of the cancerous tissue, penectomy, and radiotherapy; however, there is room for the refinement of visualization of tumors and margin assessment precision to minimize the unnecessary excision of healthy tissue, improving recovery prospects.

At this year’s European Association of Urology (EAU) Virtual Meeting, Hielke-Martijn De Vries, MD, of the Netherlands Cancer Institute, Amsterdam, Netherlands, presented the initial findings of a pilot study investigating the use of the c-MET receptor-targeted fluorescence tracer, EMI-137.

The EMI-137 tracer has previously been investigated in a single-center feasibility study (NCT03360461) for the visualization of colon polyps during colonoscopy where it was found to be both feasible and safe.6

A prospective feasibility study initially assessed the EMI-137 tracer performance ex vivo in excised pSCC tissue, before being trialed in patients. “We saw in immunostaining that the tissues also expressed c-MET. So, we continued to administer this tracer intravenously in five penile cancer patients to see if we would be able to visualize the tumor as well intraoperatively. All five penile cancer patients expressed a c-MET and were visualized by the fluorescent tracer. This was actually very promising” reported Dr De Vries.

Other crucial initial findings included the absence of tracer-related adverse events, and that c-MET was expressed highest around the rim of the tumors, thus increasing the tracer’s potential to reduce mutilation with minimal impact on healthy tissue. It was also found that this tracer was compatible with the use of lymphatic mapping to assess cancer progression.7

Dr De Vries commented that research will now focus on modifying the tracer to see if it can be used as PET tracer, further expanding its function in the field of oncology and beyond.

Combinatorial immunotherapy for urothelial cancer

Platinum-based chemotherapy combined with tumor resection is the standard of care for the treatment of urothelial carcinoma; however, 40-50% of patients experience recurrence and subsequently have poor survival outcomes.8 Recently, trials investigating novel combinations of various immunotherapies have reported promising results for patients with urothelial carcinoma.

At the European Association of Urology (EAU) Virtual Meeting 2021, Matthew Galsky, MD, FASCO, of the Icahn School of Medicine at Mount Sinai, New York, NY, discussed the key immunotherapeutic combinations being explored in clinical trials for the treatment of urothelial carcinoma.  In particular, Dr Galsky talks on the results of the open-label, multicenter, Phase III, DANUBE study (NCT02516241) exploring durvalumab plus tremelimumab versus standard of care for patients with metastatic urothelial carcinoma. The primary analysis suggests no clear survival benefit with durvalumab plus tremelimumab was observed, a secondary analysis demonstrated significant benefits for patients with high PD-L1 expressing tumors.

Another promising approach for the treatment of urothelial cancer is the use of anti-HER2 antibody-drug conjugates in combination with immune checkpoint inhibitors.

Dr Galsky also commented on the pivotal CheckMate 901 study (NCT03036098) investigating the efficacy and toxicity of double-agent immune checkpoint blockades in patients with untreated inoperable or metastatic urothelial carcinoma. In this study, a combination of the CTLA-4 inhibitor ipilimumab and the PD-1 inhibitor nivolumab is being investigated. The study is yet to report any results.

Dr Galsky highlighted the successful use of pembrolizumab plus enfortumab vedotin in previously untreated patients with metastatic urothelial cancer, such as in the EV-301 trial (NCT04223856) which has now progressed to Phase III.

Multi-targeted kinase inhibitors such as sitravatinib, lenvatinib, and cabozantinib with immune checkpoint blockade are also under investigation for the treatment of urothelial carcinoma. Dr Galsky comments: “The mechanism of action of the multi-targeted kinase inhibitors and how they’re conferring immunomodulatory activity isn’t entirely clear, but potentially acting by inhibiting or repolarizing suppressive myeloid cells. So, promise for those combinations and those are being advanced to larger studies as well”.

Novel MRI-targeted screening approach for prostate cancer

Prostate cancer screening based on prostate-specific antigen (PSA) testing in conjunction with systematic standard biopsies can result in earlier detection of prostate cancer and thus reduce mortality; however, this approach has been shown to increase the rate of overdiagnosis and unneeded biopsies.9 The use of magnetic resonance imaging (MRI) has recently gained attention as a means to reduce the rate of minor low-risk tumours being detected whilst maintaining sensitivity in detecting aggressive tumours.

In this video, Peter Albers, MD, of the University of Düsseldorf, Düsseldorf, Germany, highlights the risk-adapted screening tools currently being used in prostate cancer screening. In particular, Prof. Albers speaks on the results from the Phase II STHLM3MR-2 trial (NCT03377881) which is investigating a novel bi-parametric MRI-targeted biopsy approach. The trial demonstrated that clinically significant tumours were diagnosed in 21% and 18% of patients in the experimental biopsy and standard biopsy groups, respectively, thus showing that this approach did not lose sensitivity for clinically significant cancers. Another finding was that clinically insignificant tumours were detected at a lower rate with the use of MRI-targeted biopsies (4% versus 12%).9 The results of the trial are significant for the future of prostate cancer screening: “This is proven to avoid biopsies in half of all patients or half of all men that undergo screening.” reported Prof. Albers.

Prof. Albers also comments on the PROBASE prostate cancer screening trial being conducted in Germany, and the ProScreen trial (NCT03423303) in Finland, both which are based on the fusion of risk-adapted PSA testing and modern imaging techniques. Prof. Albers hopes these trials will show that “the combination of several risk factors is able to determine a group that needs screening and, much more importantly, I guess, about 80 to 90% of all men will have the good message that at age 50, they don’t need high-frequency screening because they have a very low risk of developing prostate cancer in the next 25 years.”

References

  1. Parker CC, James ND, Brawley CD, et al. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. The Lancet. 2018;392(10162):2353-2366.
  2. Liselotte MSB, Hukshof MCCM, Vis AN, et al. Effect on Survival of Androgen Deprivation Therapy Alone Compared to Androgen Deprivation Therapy Combined with Concurrent Radiation Therapy to the Prostate in Patients with Primary Bone Metastatic Prostate Cancer in a Prospective Randomised Clinical Trial: Data from the HORRAD Trial. European Urology. Mar 2019; 75(3):410-418.
  3. Choudhry A, Chen RC, Henry A, et al. STAMPEDE: Is Radiation Therapy to the Primary a New Standard of Care in Men with Metastatic Prostate Cancer?. International Journal of Radiation Oncology. 1 May 2019; 104(1):33-35.
  4. Fizazi K, Maldonado X, Foulon S, et al. A phase 3 trial with a 2×2 factorial design of abiraterone acetate plus prednisone and/or local radiotherapy in men with de novo metastatic castration-sensitive prostate cancer (mCSPC): First results of PEACE-1. Journal of Clinical Oncology. 28 May 2021; 39(15):5000-5000.
  5. Hakenberg OW, Dräger DL, Erbersdobler A, Naumann CM, Jünemann KP, Protzel C. The Diagnosis and Treatment of Penile CancerDeutsches Arzteblatt International. 28 Sep 2018; 115(39):646-652.
  6. Burggraaf J, Kamerling IMC, Gordon PB, et al. Detection of colorectal polyps in humans using an intravenously administered fluorescent peptide targeted against c-Met. Nature Medicine. Aug 2015; 21(8):955-61.
  7. de Vries HM, Bekers E, van Oosterom MN, et al. c-MET receptor-targeted fluorescence on the road to image-guided surgery in penile squamous cell carcinoma patients. 36th Annual EAU Congress (Online) [Accessed 30/07/2021]
  8. Peng M, Xiao D, Bu Y, et al. Novel Combination Therapies for the Treatment of Bladder CancerFrontiers in Oncology. 27 January 2021; 10:539527. Published 2021 Jan 27; 10:3163
  9. Eklund M, Jäderling F, Discacciati A, et al. MRI-Targeted or Standard Biopsy in Prostate Cancer Screening. New England Journal of Medicine. 9 Jul 2021; DOI: 10.1056/NEJMoa2100852

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