Aggressive Variant Prostate Cancer Treatment & Genomic Mutations

Brad Power and Mike Yancey September 28, 2022 “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.

” 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.

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.

Medical History Mike Yancey had been diligent in getting an annual physical and having his PSA tested. 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). 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. ”) In March 2022 Mike’s PSA began to increase slowly. 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. 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. 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 it will 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.

) 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.

Testing and Treatment Strategy Mike plans to have PSMA-PET scans 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. Treatment Options Walkthrough Please see Mike’s treatment options spreadsheet to accompany this discussion.

Mike has identified 17 treatment options, 8 of which he has ranked on his short list because they stood out as having a higher probability of success. His ranking builds on what he found out about the treatments, such as the use of Everolimus, recommended by Foundations Medicine. He has noted for each treatment the organization which recommended it. Most came from CureMatch, with a few from Massive Bio and from Foundations Medicine.

He also added a couple of clinical trials for Ipatasertib that were of interest to him that he found in doing some other research. Beginning at the top of his spreadsheet, the first two recommendations are from Foundation Medicine, which did somatic testing on his bone biopsy that was taken in July 2021. They recommended two possible monotherapy drugs, Everolimus and Temsirolimus.

Further research that Mike did revealed that these drugs, when used alone, have not provided much of a response, therefore these two were not ranked as part of his preferred options. These two drugs also are very toxic so significant caution is needed in their use.

As we get further down his list to some treatment combinations recommended by CureMatch, you will again see the drug Everolimus, but with their recommendation it is used in conjunction with one or two other drugs. The third treatment option on his list is a chemotherapy-based, “Standard of Care” option.

This treatment is a combination of Cabazitaxel along with Carboplatin, where the platinum element has shown to have some better benefit with Aggressive Variant Prostate Cancer. However, the durability is going to be short, probably three to four months in his case after you have finished the 18 week series of treatments.

So this is a decision of doing another chemotherapy with a relatively short durability along with the side effects, which he admits he is a little vain, but the hair loss for incremental benefit does not bring this high enough to rank. Next are the recommendations from Massive Bio. There are 3 clinical trials they suggest. The first is Bipolar Androgen Therapy (BAT) coupled with another radioactive treatment called Radium 223.

Radium 223 does nothing towards the primary cancer in the prostate, but impacts the bone mets. BAT holds interest to Mike, however the testosterone injections coupled with his very aggressive cancer and potentially having his cancer take off and grow very, very quickly, presents significant concerns, as it would take some time to minimize the testosterone in his body. As many have stated, it might be like “throwing gasoline on a fire”.

So, even though he does not have it ranked in his preferred list of possible treatments, there is still a lot of interest in this option. WIth respect to this treatment and Brian’s question as to whether Mike has AR copy number gain, Mike does not know. It definitely was not listed in his Foundations Medicine bone biopsy somatic testing report, nor the report for his liquid biopsy.

Brian understands that having the TP53 mutation along with AR copy number gain might point to potential benefit from BAT. Two additional clinical trial recommendations were made by Massive Bio, but based on a review meeting where Mike provided more clarification on his situation, it was determined he is not a candidate for either of these two trials.

One is a combination of Enzalutamide and Rucaparib, providing an AR inhibitor along with a PARP inhibitor, while the other is a combination of Cabozantinib and Atezolizumab which targets PD-L1 expression. Now we are down to the CureMatch treatment recommendations beginning with numbers 7 thru 9. At this point he has provided his ranking assessments. He has ranked the first CureMatch treatment as number 1.

When CureMatch provides possible treatment matches, they also give each treatment a match value or score. This first one has a match value of 67, which according to Ally Perlina of CureMatch is quite high. On average they find matches somewhere in a range around 33%. So this match is double the normal average, and based on their research and looking at Mike’s mutations, this drug combination may have a positive impact.

This treatment option is planned to target the AKT2 pathway via mTOR as well as the PTEN loss using the drug Everolimus, which we looked at a few minutes ago as a monotherapy recommended by Foundation Medicine. Also the drug Ponatinib is expected to target both Mike’s SRC mutation as well as TP53, using the FLT1 gene and KDR gene. Last is the use of Pembrolizumab targeting PDL1 overexpression via the PD-1 pathway.

This is his top ranked treatment, but there is significant potential toxicity possibilities individually which is increased with the use of multiple drugs. So most likely it would require some slow experimentation to see what level of dosages a person can use safely. As Brad Power mentioned, this toxicity concern with drug combinations has been a recurring theme.

However, he has been introduced to a doctor at UCSD, Mina Nikanjam, who is a specialist in dosing strategies, which may help address this concern. The next CureMatch recommendation is number 8 on the list, and Mike’s ranking as the number 2 treatment of interest. This one also has a high CureMatch score of 65%, so once again a very high potential for benefit.

This drug combination is very similar to number 7, which we just looked at, but makes a slight change by using Bosutinib in place of Ponatinib. Where Ponatinib targeted both his SRC mutation as well as TP53 using the FLT1 gene and KDR gene, Bosutinib is targets only his SRC mutation. Based on some further research Mike did, and may not be entirely correct, Bosutinib has less significant toxicity as compared to Ponatinib.

So potentially an option to reduce some toxicity concerns but retain a high probability of benefit. The next treatment option is number 9, which Mike has ranked as number 3. Similar to option 8, this treatment option is the same as Option 7, but substitutes Ponatinib with Nintedanib and also carries a relatively high CureMatch score of 63%. Much like Option 7, Nintedanib targets the SRC mutation as well as TP53 using the FLT1 gene and KDR gene.

This treatment option also retains the use of Everoimus and Pembrolizumab. Mike has ranked these three drug treatment options (7, 8, and 9) as his top 1, 2, and 3 choices. Now we move to two-drug combinations recommended by CureMatch. Number 10, which Mike has ranked as his number 4, still carries a CureMatch score of 59%. It retains the Everolimus and Pembrolizumab that were part of the three drug options 7, 8, and 9.

This treatment option is planned to target the AKT2 pathway via mTOR as well as the PTEN loss using the drug Everolimus, and the use of Pembrolizumab targeting PDL1 overexpression via the PD-1 pathway. Next is number 11, which Mike has ranked as number 5 with a CureMatch score of 58%.

In comparison to number 10 which we just looked at, it retains Pembrolizumab while removing Everolimus and adding Ponatinib, which was part of option 7 for the three-drug combinations. Number 12, which Mike has ranked number 6, is also a two-drug combination with a CureMatch score of 56%. This mirrors number 11, which we just looked at, retaining Pembrolizumab while substituting Bosutinib in place of Ponatinib.

Next we have 3 one-drug treatment recommendations from CureMatch, numbers 13, 14, and 15. Mike did not rank these because once again he feels confident that with his particular aggressive cancer, the one-drug options are going to do very little; he feels strongly that any benefits will only be achieved with multi-drug treatment options, so his preference is for the three-drug recommendations.

Numbers 16 and 17, the last two on the list, are two clinical trials he found online while doing some research. These trials are testing the drug Ipatserib with number 16, which he has ranked at number 7, coupled with Abiraterone, and number 17, which he has ranked as number 8, coupled with Atezolizumab. 2 months using Abiraterone alone. This potential treatment is targeting the PTEN and AKT pathway.

The last one, number 17, which Mike has ranked number 8, uses Atezolizumab with Ipatserib targeting the AKT pathway. He does not know a lot about this trial other than the prime target is the AKT pathway.

Mike is expecting, but has not yet received any recommendations from Cancer Commons because Emma Shtivelman is in agreement that Pluvicto is the best treatment option at this time, and as we have already discussed, seems to be providing positive results. She wants to wait until Mike has completed Pluvicto and another round of tests, then provide some treatment options to use going forward.

Johnathan Starr asked whether stereotactic body radiotherapy (SBRT - precisely focused radiation beams) could address Mike’s bone metastases. Mike responded that he is completely covered with lesions, including his spine, pelvic region, right femur, and more recently left clavicle and right shoulder. ” So he knew he was in trouble. Jonathan Starr also asked whether Mike is considering Provenge as a treatment option.