Agents for Stage 4 Prostate Cancers

Since 2013 when 223Radium-dichloride was FDA approved, there has been some excitement in literature over its benefits in stage 4 prostate cancer. Conclusion of article was ” Ra also has demonstrated to increase overall survival in patients and to delay adverse skeletal events”. Biphophonates like Zoledronic acid and Denosumab can help with the pain of prostate bone cancer.

But the greatest excitement is with use of “225Ac-PSMA-617” – radioactive tagged prostate targetted compound that can induce remission of stage 4 prostate cancer. Sadly, availability may be lacking. Additionally, finding in subjects with oligomets(few metastastes) high dose radiation can induce blood changes similar to a vaccination and bring 1/2 of cases into remission for past year of trial.

Am J Clin Oncol. 2018 Sep 10. doi: 10.1097/COC.0000000000000479.  in press
Nuclear Medicine Therapy With 223Radium-dichloride for Osseous Metastases in
Prostate Carcinoma.
Wale DJ et al
https://www.ncbi.nlm.nih.gov/pubmed/30204613

I was asked how long do subjects live – not long though:
Onco Targets Ther. 2018 Dec 17;12:9-13. doi: 10.2147/OTT.S174206.
Pain predicts overall survival in men with metastatic castration-resistant prostate cancer treated with radium-223.
Roviello G et al
https://www.ncbi.nlm.nih.gov/pubmed/30588025
12.6 months in the patients with VAS <4/10 pain
6.6 months in the patients with VAS ≥4 (P=0.03).

Other agents for bone pain relief:

For pain relief,  Bone modifying biphosphonates drugs = pamidronate or zoledronic acid (ZOL)-
and denosumab  –  an engineered “mab” monoclonal antibody against the cytokine RANKL which tumor cell migrates, mediates
and activates.
Cancer Manag Res. 2018 Dec 18;11:37-46. doi: 10.2147/CMAR.S174731.
The history of cancer pain and bone-targeted agents: 10 most commonly asked questions.
Vieira CMP et
https://www.ncbi.nlm.nih.gov/pubmed/30588109
“Zoledronic acid (ZOL), the third generation, which can be administered in a 15-minute infusion, has proved to be at least as effective as PAMidronate in preventing SREs in breast cancer and multiple myeloma in a direct comparison clinical trial.2,8,9 ZOL has an impact on bone pain in patients with breast and prostate cancer.6,10–12.  However, the potential for renal toxicity with ZOL may limit its use.”
“Although studies of BTAs have not been designed to assess the speed of onset of pain relief, it is possible to note a significant effect on pain scores as early as 1–4 weeks after initial treatment.20,31 ZOL has been proved to be highly effective in patients with bone metastases from prostate cancer, with statistically significant reductions in skeletal morbidity, including bone pain.1,24”
“Denosumab has also demonstrated efficacy in relation to pain palliation. In patients with bone metastases, the analyses of data from three Phase III studies showed that denosumab delayed the onset of moderate/severe pain by a median of 1.8 months (95% CI 0.76–0.92; P<0.001) when compared to ZOL”


 

New Exciting Option though probably not yet available: 225Ac-PSMA-617

The latest excitement however has been over Actinium-225 tagged prostate-specific membrane antigen (PSMA). It latches on to cancer cells and the radioactivity kills the cell.  In stage 4 prostate cancers, it can bring about up to several years remission:
Sathekge, Mike, et al.
225 Ac-PSMA-617 in chemotherapy-naive patients with advanced prostate cancer: a pilot study.
European journal of nuclear medicine and molecular imaging 46.1 (2019): 129-138.
https://link.springer.com/article/10.1007/s00259-018-4167-0
17 cases advanced ca prostate had 2-3 courses this agent
15/17 have >50% decline in tumors
11 had complete resolution remaining in remission at 1 year.
(Other studies has found relapse by 3 years)
dry mouth from destruction salivary glands can be a limiting factor

The latest excitement is over high dose radiation inducing an immune response and remission in oliometastatic cases:
Primary outcoms of a phase II randomized Trial of Observation versus Stereotactic Ablative Radiation of Oligometastatic Prostate Cancer (ORIOLE)
Ryan Philips
Astro Annual Meeting Sept. 2019
https://www.astro.org/News-and-Publications/News-and-Media-Center/News-Releases/2019/Trial-reports-randomized-evidence-high-dose-radiat

 

  • stereotactic ablative radiotherapy (SABR)= “a form of high-precision cancer therapy that delivers substantially higher doses of radiation to the tumor site in just one or a few treatment sessions”.
  • ” Six months later, just 19% of patients treated with SABR saw their disease progress, compared to 61% of those in the observation arm (p=0.005). The median progression-free survival (PFS) time for those in the observation arm was 5.8 months (HR 0.30, p=0.002), whereas more than half of the patients in the SABR-treated arm were still progression-free more than a year after treatment.”
  • Blood analysis of radiation group showed immune changes similar to those seen in a vaccination setting.

 

 

Comment – when I originally wrote this article I said “there are new things coming up all the time so say tuned..” – it didn’t take long. The radiotherapy looks exciting while availability may be difficult for the radioactive component. However, we are uniquely situated with a Cylotron in Saskatoon and Chalk River nuclear research station in Ontario. Going to have to ask our oncologists…

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