“My cancer is very aggressive. I have PTEN loss and mutations in the RB1 and the TP53 genes. Those three together are known as tumor suppressor genes, and if you have any two out of three, that’s considered an aggressive variant. And I got three out of three. Lucky me.”
– Mike Yancey
“RB1 is one thing to look at and study, but we have to include PTEN and TP53, and look at the signaling pathways, and what drugs are available that can begin to impact them. A lot of the drugs that we’re going to look at today haven’t been tested in prostate cancer; they’ve been tested in other cancers and shown some benefits for some of these pathways. And of course, when we start mixing multiple drugs, we get back into the bigger issue of no clinical trials and no dosing information.”
– Mike Yancey
In this meeting, advanced prostate cancer patient Mike Yancey discussed (1) his medical history, (2) the treatment opportunities and challenges he is facing now, and (3) his testing and treatment strategy. Mike has an aggressive prostate cancer driven by some key mutations that he believes needs to be treated with an equally aggressive drug combination.
1. Medical History
Mike Yancey had been diligent in getting an annual physical and having his PSA tested. In July 2021 his PSA rose to 2.4, and he was diagnosed with metastatic prostate cancer. He had metastases in his bones, which made it difficult to walk. Because at diagnosis he was already metastatic, the standard of care treatment skipped surgical removal (a prostatectomy). Instead, he immediately started taking a male hormone (androgen) deprivation drug (Lupron) and a chemotherapy agent (docetaxel). He finished this line of treatment four months later (in November 2021). It caused his PSA to reach its lowest point (0.07). He also received pelvic radiation – not focused on a cure, but for his bone pain.
In February 2022 Mike and a doctor he was seeing discussed a study he had seen that showed that another hormone therapy drug (abiraterone) was effective after the chemotherapy he had taken (docetaxel). The doctor suggested Mike take it since it would not hurt anything, and in April 2022 he started taking it. He has not seen a lot of impact from it, but his current oncologist confirmed that he should continue taking it because she felt that it might be doing some good. (Brian McCloskey challenged that advice since patients with one of Mike’s mutations – RB1 – are known to be resistant to abiraterone, and it is likely to have a low or no response. “This is the definition of a lack of precision medicine, and the flip side is that there are consequences of taking any drug.”)
In March 2022 Mike’s PSA began to increase slowly. He was concerned, but his local oncologists told him not to worry since the PSA increase was small and under 1.0.
In May 2022, still concerned and feeling a recurrence of bone pain, this time in his shoulders, he consulted with a new oncologist in Houston who determined that his cancer was a very aggressive type. Testing revealed mutations in three key “tumor suppressor genes” (PTEN loss, and RB1 and TP53 mutations). If someone has mutations in any two of these three genes, then the cancer is designated as “Aggressive Variant Prostate Cancer”. In his case, he had mutations in all three, which only 1% of prostate cancer patients have. Patients with this profile do not respond as well to many of the standard prostate cancer drugs, such as the ones he had received. Usually the cancer is held back for up to two years, but in his case it was only four months. He also learned that his cancer does not express much PSA, another common trait of this aggressive form, which is why they didn’t catch his prostate cancer earlier.
Mike got a scan that looks for a protein (Prostate Specific Membrane Antigen – PSMA) found on the surface of prostate cancer cells. It lights up throughout the body where it finds the protein, which confirmed his cancer had spread from his pelvis, spine, and right femur into his shoulders. He had an unusually high expression of PSMA (30 to 40 standardized uptake value vs. a median of 8.8, ranging from 2.1 to 62.4), which indicated he would be a good candidate for a newly approved therapy that combines a radioisotope that binds to PSMA to deliver radiation directly to the cancer (Pluvicto). Due to production issues with this new therapy, initial treatment was delayed a month; during this time his bone pain got so bad that he was prescribed a steroid. When he finally got Pluvicto in early August, it eliminated all bone pain, and he was able to resume his daily regimen of walking. He completed his second treatment round in mid-September 2022. His PSA had crept up again between July and early September. He is scheduled to have a new PSMA-PET scan in late October to see what impact the Pluvicto is having.
Mike has had a liquid biopsy, which showed two additional minor mutations in addition to the six that his bone biopsy report showed and were part of the input provided to the companies offering treatment option information. His plan is to have a liquid biopsy every six months to see what, if any, new mutations appear. He has never had a tissue biopsy of his prostate. His oncologist does not feel that the infection risk and discomfort is worth the benefit. (The meeting participants pushed for a biopsy of his prostate, given the potential information benefit.)
2. Current Treatment Opportunities and Challenges
The primary purpose of our conversation was to figure out what Mike should do after he completes his current line of therapy with Pluvicto.
Since cancer is heterogeneous, Mike wonders how much of his cancer does not express PSMA, and therefore will not be impacted by Pluvicto. And since his aggressive type of cancer had a relatively brief response to his previous line of therapy, how long will it be before the cancer comes roaring back this time.
Besides the recommendations from his medical team, Mike has received information on treatment options from Foundation Medicine, which did his gene sequencing; Massive Bio, which identified several clinical trials; and CureMatch, which provided several three- and two-drug combinations of FDA-approved drugs. He has a total of 17 treatment options to consider, of which he has ranked 8 on a short list. (Please see his spreadsheet and discussion for more on his treatment options.)
The only standard treatment option is the use of another chemotherapy (cabazitaxel and carboplatin), which would take about four months for the treatment cycle, and assuming the durability is equal to the four months experienced with his other chemotherapy (docetaxel), in eight months he will be out of options. He obviously needs other options.
3. Testing and Treatment Strategy
Mike plans to have a PSMA-PET scan done in the next few weeks, prior to his third round of treatment with Pluvicto, and then do them again prior to the fifth round of treatment, and a final set of scans after he has completed the Pluvicto treatment course (the sixth round of treatment). If Mike is not having much success, which he doesn’t expect, he may discuss whether to continue with Pluvicto. He knows that some people have taken Pluvicto and had very little response, and they’ve stopped.
Mike’s treatment strategy depends on understanding the signaling pathways associated with his key mutations, and what drugs are available that can impact them. A lot of the drugs that are on Mike’s list of treatment options have been tested with other cancers and shown some benefits, but haven’t been tested in prostate cancer. Some of these drugs are pretty toxic.
Mike’s research has convinced him that his unique aggressive combination of genomic mutations (PTEN loss, RB1, and TP53) calls for multiple therapies at the same time to attack multiple signaling pathways, rather than the traditional application of single agents, or serial application of single agents. Therefore, the drug combination treatment recommendations from CureMatch are at the top of his list. However, he is facing the challenge of convincing his treating physician, or finding a new one, to prescribe personalized, novel treatment combinations that are off-label, overcoming concerns about toxicity, reimbursement, and liability, when there are no randomized clinical trials that have tested these combinations.