When to consider Keytruda as not working?

[dunde8889]

My dad is 4 weeks in after first keytruda (he got a second dose last week). So far there has been no response in terms of numbers. PSA has increased from 150 before first dose to 280. Bilirubin has increased to 16.

Biopsy showed MSI-H. Has liver and lung mets. Already failed Lupron, Zytiga, and Jevtana. Did not tolerate xtandi.

Is there any hope left with keytruda? Any alternatives or is this the end?

[Magnus1964]

Casodex has fewer side effects.

[j-o-h-n]

Only one comment which is that I receive Keytruda for my lung Melanoma and it's working. But I guess it's apples and oranges...

Good Luck, Good Health and Good Humor.

j-o-h-n Saturday 10/12/2019 9:02 PM DST

[GAdrummer]

Keytruda may not be working, or your body isn't strong enough to flush out the dead cancer cells, thus creating an initial PSA spike. My husband is an example of the variations of response to Keytruda. After four treatments, a PET scan showed: (1) the larger of the two enlarged lymph nodes had shrunk markedly and the sugar uptake value was below background, (2) the smaller lymph node had shrunk slightly and the sugar uptake value had more than doubled in the past four months, and (3) the cyst on the pancreatic tail which had been benign has increased its sugar uptake above background indicating a possibility of a new malignancy. Over this time interval, the PSA value dropped from 42 to 0.4 with no initial spike like those he experienced on other treatments. The treatments appear to have eliminated one mutation but not another and may have stimulated a different, worse kind of cancer. Whack-A-Mole

Interesting how the PET scan report gives the patient all the good news first, saving the really bad news to the last line.

Good luck

[dunde8889 in reply to GAdrummer]

Thanks for sharing. Hopefully your cyst is benign inflammation.

I’m hoping my dads psa spike is the inability to flush cancer cells but he’s getting weaker with less appetite which worries me that it may mean keytruda is not working.

[AlanLawrenson]

MSI- H men are usually responsive to Keytruda. Hang in there, it might just need time. An alternative is Lutetium-177, but only via clinical trials in USA. Paying customers are done in Germany, Australia and South Africa (Pretoria University). This therapy would probably reduce the PCa load in the lungs and liver. Note it is ineffective in 15% of men. (A PSMA PET scan tells whether it will likely work).

It may be possible to re-instate the efficacy of Zytiga. Other alternatives are darulutamide and Erleada. Zejula (niraparib) is helping men with mismatch repair genes.

Hope this helps.

Alan

[dunde8889 in reply to AlanLawrenson]

I’m hoping keytruda will soon show signs of working but so far no signs it has even helped a bit. How would we reinstate the efficacy of Zytiga?

[AlanLawrenson]

Mol Cancer Ther. 2017 Jan;16(1):35-44. doi: 10.1158/1535-7163.MCT-16-0186. Epub 2016 Oct 28.

Inhibition of AKR1C3 Activation Overcomes Resistance to Abiraterone in Advanced Prostate Cancer.

Liu C1, Armstrong CM1, Lou W1, Lombard A1, Evans CP1,2, Gao AC3,2,4.

Author information

1

Department of Urology, University of California, Davis, Davis, California.

2

UC Davis Comprehensive Cancer Center, University of California, Davis, Davis, California.

3

Department of Urology, University of California, Davis, Davis, California. [e-mail].

4

VA Northern California Health Care System, Sacramento, California.

Abstract

Abiraterone suppresses intracrine androgen synthesis via inhibition of CYP17A1. However, clinical evidence suggests that androgen synthesis is not fully inhibited by abiraterone and the sustained androgen production may lead to disease relapse. In the present study, we identified AKR1C3, an important enzyme in the steroidogenesis pathway, as a critical mechanism driving resistance to abiraterone through increasing intracrine androgen synthesis and enhancing androgen signaling. We found that overexpression of AKR1C3 confers resistance to abiraterone while downregulation of AKR1C3 resensitizes resistant cells to abiraterone treatment. In abiraterone-resistant prostate cancer cells, AKR1C3 is overexpressed and the levels of intracrine androgens are elevated. In addition, AKR1C3 activation increases intracrine androgen synthesis and enhances androgen receptor (AR) signaling via activating AR transcriptional activity. Treatment of abiraterone-resistant cells with indomethacin, an AKR1C3 inhibitor, overcomes resistance and enhances abiraterone therapy both in vitro and in vivo by reducing the levels of intracrine androgens and diminishing AR transcriptional activity. These results demonstrate that AKR1C3 activation is a critical mechanism of resistance to abiraterone through increasing intracrine androgen synthesis and enhancing androgen signaling. Furthermore, this study provides a preclinical proof-of-principle for clinical trials investigating the combination of targeting AKR1C3 using indomethacin with abiraterone for advanced prostate cancer. Mol Cancer Ther; 16(1); 35-44.

Dexamethasone might also help. I came across these when researching my new book An ABC of Prostate Cancer Today - 3rd Edition which is due out next month on Amazon. I have on file newer published papers on overcoming resistance to Zytiga and Xtandi, but just can't find them at present. I'll keep looking. Few MO are aware that resistance to these drugs can, in some instances, be achieved. Maybe the manufacturers of these therapies could give you more details as to overcoming Zytiga resistance. If you find out anything positive there, let me know at [e-mail].

Best wishes

Alan Lawrenson