Incredible Responses to Immunotherapy - 054
Advanced prostate cancer, especially metastatic castrate-resistant prostate cancer (mCRPC), is considered incurable by prostate cancer experts. But, as I've discussed previously, the term incurable can be a misnomer.
In the last newsletter, I said that immunotherapy of all types is ineffective in the majority of men with advanced prostate cancer. But, for certain men with specific genetic mutations, immunotherapy can be a godsend.
Pembrolizumab (Keytruda)
Pembrolizumab (Keytruda), a checkpoint inhibitor, is an immunotherapy drug used in two of these case studies. It's FDA-approved for treating men with mCRPC whose tumors have specific genetic mutations and have progressed following prior treatment and for whom there are no satisfactory alternative treatment options.
Pembrolizumab blocks a protein on the cell surface of the immune system's T-cells called PD-1. Blocking this protein takes the brakes off the T-cells, allowing them to attack cancer cells better.
Prostate cancer mutations that respond best to immunotherapy
The reason immunotherapy doesn't work for most men with prostate cancer is that the types of mutations and combinations of mutations that respond well to it are rare. The types of genetic mutations in prostate cancer that respond the best to immunotherapy are:
MSI-H (Microsatellite Instability - High)
dMMR (deficient MisMatch Repair)
BRCA2 (BReast CAncer gene 2)
High tumor mutational burden (TMB)
MSI-H (Microsatellite Instability - High)
Imagine DNA as a long string of beads, and some parts of the string have repeating patterns, such as red-green-red-green.
In MSI-H cancers, these repetitive patterns, called microsatellites, get messed up like red-green-red-red-green-green.
This results in a high number of unstable microsatellites.
This high number of microsatellites makes the cancer cells appear more foreign to the immune system, so they are recognized more easily.
dMMR (deficient MisMatch Repair)
Our body has unique proofreader proteins that fix mistakes in DNA.
In dMMR mutations, these proofreaders don't work well.
It's like having a spell-checker that doesn't catch typos.
Having dMMR mutations results in an inability to correct errors during DNA replication.
An accumulation of these mutations results in formation of cancer cells.
dMMR mutations in prostate cancer include:
mutL homolog 1 (MLH1)
mutS homolog 2 (MSH2)
mutS homolog 6 (MSH6)
postmeiotic segregation increased 2 (PMS2)
Having dMMR results in MSI-H, so they are interrelated. Cancer cells with MSI-H/dMMR make many mistakes when copying their DNA, making them look very different from normal cells. Our immune system is better at spotting and fighting these different-looking cancer cells.
BRCA2 Mutations
BRCA2 mutations lead to DNA repair defects, creating additional proteins the immune system can recognize as foreign.
The combination of BRCA2 mutations with MSI-H status significantly enhances immune recognition.
High TMB (tumor mutational burden)
High tumor mutational burden creates numerous altered proteins.
These altered proteins make the tumor appear more foreign to the immune cells.
Most dMMR tumors have very high TMB; however, not all TMB-high tumors have dMMR. Tumors with high TMB, especially in the setting of dMMR, are more responsive to checkpoint inhibitors like pembrolizumab.
So, the recurring theme with these mutations is that they result in better recognition by the immune system. When immunotherapy drugs take the brakes off T-cells, this better recognition goes into high gear.
Prevalence of these mutations
Now that I've given you a primer on immunotherapy let's move on to the three case studies involving metastatic castrate-resistant prostate cancer that had a dramatic and complete response to immunotherapy. I don't know the current status of these men, but at the time of the publication of their cases, they were in complete remission.
Case Study 1
The first case is from Prostapedia's November - December 2022 Immunotherapy quarterly magazine.
James Gulley, M.D., PhD. discusses the first case. Dr. Gulley is a Senior Investigator at the National Cancer Institute's Center for Immuno-Oncology. He specializes in studying immunotherapy for advanced prostate cancer.
In the spring of 2017, Dr. Gulley evaluated a retired army surgeon with metastatic castrate-resistant prostate cancer who had a PSA doubling time of less than one month despite androgen deprivation therapy.
Dr. Gulley entered the patient into a clinical trial studying the combination of PROSTVAC and nivolumab. PROSTVAC is a prostate cancer vaccine targeting prostate-specific antigen (PSA), and nivolumab (Opdivo) is a monoclonal antibody immunotherapy drug that enhances the body's immune response against cancer cells.
Dr. Gulley started the PROSTVAC vaccine and added nivolumab in week two. Two weeks after starting treatment, the patient said, "I feel a million times better." He began treatment with a PSA in the high 50s, and by week thirty-five, his PSA was undetectable.
The patient had a complete response radiographically. He was able to stop intermittent self-catheterization due to the resolution of a large tumor mass obstructing his bladder. Dr. Gulley then biopsied the base of his bladder where the tumor mass used to be, and the results showed no tumor.
At the time of the quarterly magazine report, it had been over five years, and the patient had no evidence of disease with an undetectable PSA. Once his PSA became undetectable, so did his circulating tumor DNA. Dr. Gulley stopped his nivolumab at year three, and the patient continued to receive the vaccine every three months.
Dr. Gulley says,
That's a reminder that the immune system can be amazingly powerful, can eradicate tumor, even in men who have symptomatic disease and metastatic disease.
Ironically, PROSTVAC is not FDA-approved to treat prostate cancer, as phase 3 clinical trials showed no improvement in overall survival. Nivolumab is a monoclonal antibody that is still being studied in prostate cancer but has not yet attained FDA approval.
Case Study 2
The second case, published in The Oncologist in April 2019, is about a 64-year-old man diagnosed with aggressive prostate cancer (Gleason score 9) in 2015, with metastases to pelvic and abdominal lymph nodes.
He started androgen deprivation therapy (ADT), which initially reduced his prostate-specific antigen (PSA) levels. However, within months, his cancer became resistant to treatment, and PSA levels began to rise.
In 2016, the patient was treated with abiraterone and prednisone, followed by chemotherapy with docetaxel after disease progression. During this time, he also underwent surgery for low-grade bladder cancer.
Genetic testing showed he had a rare mutation associated with Lynch syndrome, a genetic condition linked to several cancers. Analysis of his prostate tumor showed high microsatellite instability (MSI-high) and loss of the MSH2 protein, both markers of mismatch repair deficiency (dMMR). These findings indicated the cancer might respond well to immunotherapy.
In 2017 the patient started pembrolizumab, an immunotherapy drug approved for MSI-high cancers. Remarkably, his PSA dropped rapidly, and imaging showed a complete response. After twelve cycles of pembrolizumab, treatment was stopped, and complete remission was persisting as of October 2018.
This case shows the potential of genetic testing and immunotherapy for patients with advanced prostate cancer, especially those with MSI-high or dMMR tumors.
Case Study 3
The third case was published in The Oncologist in August 2024 and is about an 81-year-old man diagnosed in 2021 with advanced prostate cancer that had spread to his bones. His prostate-specific antigen (PSA) was 30.8 ng/mL at the time.
He initially began Zoladex and bicalutamide, which initially reduced his PSA to 2.9 ng/mL. Five months later, his cancer worsened, with more bone metastases, rising PSA levels, and severe bone pain. Radiation therapy helped reduce his bone pain.
Genetic testing showed MSI-high, which means the tumor has trouble repairing DNA mistakes. Testing also showed the loss of a vital DNA repair gene called MSH6. This finding is significant because patients with MSI-high tumors often respond well to immunotherapy, with response rates up to 45%.
Testing also found a BRCA2 mutation. This gene also helps repair DNA damage, and cancer cells can grow more aggressively when not working correctly.
Testing also showed the patient's tumor mutational burden (TMB) of 109 mutations per megabase was very high. A high TMB (above 10) often means the cancer might respond better to immunotherapy treatments.
The patient started immunotherapy with pembrolizumab and enzalutamide, an advanced antiandrogen medication that blocks testosterone's effect on prostate cancer cells.
After one cycle of treatment, his PSA dropped by 50%. After two cycles, it decreased by over 95%, and his PSA became undetectable after three cycles.
Pembrolizumab was stopped, and the patient continued androgen deprivation therapy and enzalutamide for another 14 months, eventually stopping enzalutamide in June 2023. As of March 2024, he remains in remission, with undetectable PSA levels and improved bone scan results.
This case demonstrates how genetic testing and personalized treatments, including immunotherapy, can lead to remarkable outcomes in advanced prostate cancer.
Conclusion
These men shared one critical factor - uncommon genetic mutations identified through advanced genetic testing. Their stories underscore a vital message for men with advanced prostate cancer, especially those with metastatic castrate-resistant disease.
Unlike the average urologist in a non-academic setting, these specialized centers have the expertise, tools, and resources to identify rare genetic mutations and apply cutting-edge treatments tailored to individual cases. They also give you access to clinical trials like the one discussed in the first case study.
Until the next newsletter, stay healthy.
Much love,
Keith