Some men with advanced prostate cancer who have exhausted all other treatment options could live for two years or more on immunotherapy, a major clinical trial has shown.
Researchers found that a small proportion of men were ‘super responders’ and were alive and well even after the trial had ended despite having had a very poor prognosis before treatment.
The study found that one in 20 men with end-stage prostate cancer responded to the immunotherapy pembrolizumab – but although the number who benefited was small, these patients sometimes gained years of extra life.
The most dramatic responses came in patients whose tumours had mutations in genes involved in repairing DNA, and the researchers are investigating whether this group might especially benefit from immunotherapy.
The phase II clinical trial was led globally by a team at The Institute of Cancer Research, London, and The Royal Marsden Foundation Trust, and involved 258 men with advanced prostate cancer who had previously been treated and become resistant to androgen deprivation therapy and docetaxel chemotherapy.
The study is published today (Wednesday) in the Journal of Clinical Oncology and was funded by the drug’s manufacturer Merck, Sharpe & Dohme.
Overall, 5 per cent of men treated with pembrolizumab saw their tumours actually shrink or disappear, while a larger group of 19 per cent had some evidence of tumour response with a decrease in prostate-specific antigen (PSA) level.
Among a group of 166 patients with particularly advanced disease and high levels of PSA, the average length of survival was 8.1 months with pembrolizumab.
Nine of these patients saw their disease disappear or partly disappear on scans. And of these, four were super-responders who remained on treatment at the end of study follow-up, with responses lasting for at least 22 months.
A second group of patients whose PSA levels were lower but whose disease had spread to the bone lived for an average of 14.1 months on pembrolizumab.
New larger trials are now under way to test whether men with DNA repair gene mutations in their tumours, or those whose cancer has spread to the bone, should receive pembrolizumab as part of their care.
The study also compared the effectiveness of pembrolizumab in men whose tumours had a protein called PD-L1 on the surface of their cancer cells and those whose tumours did not. Targeting PD-L1 activity with pembrolizumab takes the ‘brakes’ off the immune system, setting it free to attack cancer cells.
But the study found that testing for PD-L1 was not sufficient to tell which patients would respond to treatment. Men with PD-L1 in their tumours survived 9.5 months compared with 7.9 months for patients without PD-L1 in their tumours.
Identifying better tests to pick out who will respond best will be critical if pembrolizumab is to become a standard part of prostate cancer treatment.
Pembrolizumab was well tolerated, with 60 per cent of patients reporting any side effects and only 15 per cent of patients experiencing grade 3-5 side effects.
Professor Johann de Bono, Regius Professor of Cancer Research at The Institute of Cancer Research, London, and Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust, said:
“Our study has shown that a small proportion of men with very advanced prostate cancer are super responders to immunotherapy and could live for at least two years and possibly considerably longer.
“We don’t see much activity from the immune system in prostate tumours, so many oncologists thought immunotherapy wouldn’t work for this cancer type. But our study shows that a small proportion of men with end-stage cancer do respond, and crucially that some of these men do very well indeed.
“We found that men with mutations in DNA repair genes respond especially well to immunotherapy, including two of my own patients who have now been on the drug for more than two years. I am now leading a larger-scale trial specifically for this group of patients and am excited to see the results.”
Professor Paul Workman, Chief Executive of The Institute of Cancer Research, London, said:
“Immunotherapy has had tremendous benefits for some cancer patients and it’s fantastic news that even in prostate cancer, where we don’t see much immune activity, a proportion of men are responding well to treatment.
“A limitation with immunotherapy is that there’s no good test to pick out those who are most likely to respond. It’s encouraging to see testing for DNA repair mutations may identify some patients who are more likely to respond, and I’m keen to see how the new, larger trial in this group of patients plays out.”
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pjoshea13
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I had a very good initial response when I was on one of the checkmate trials involving nivolumab + rucaparib. The oncologist told me it was basically the parp ( rucaparib) that I had the response to as I had a BRCA mutation in the tumor. Would it be right in saying all cancers have a DNA mutation of some sort ?
The oncologist also told me I have basically used up my treatment options regarding parp inhibitors and immunotherapy drugs ,- as far as being accepted on a trial that is.
I would also like your opinion on similar drugs made by different manufacturers e.g the one I mentioned nivolumab (opdivo) and keytruda for instance. There both "checkpoint inhibitors" I believe, that target PDL1. I've read where keytruda has had some success in recent trials and if I go on what my oncologist has stated then I will probably never be in a position to know whether keytruda could possibly work for me ?
You asked: "Would it be right in saying all cancers have a DNA mutation of some sort ?"
Most of the mutations found in CRPC cells are treatment-emergent. Palliative treatments select against "normal" PCa cells. The stronger the treatment, the greater the difficulty to manage when resistance occurs.
Before treatment, abnormalities seem largely to be epigenetic. i.e. changes have occurred above the gene. These changes can theoretically be reversed. Genes are not altered by epigenetic changes.
A common issue is silencing of the promoter region for tumor-suppressor genes via hypermethylation. A demethylation drug might reverse the silencing.
Another ploy by PCa is to upregulate histone deacetylase [HDAC], which prevents access to anti-cancer DNA instructions. HDAC inhibitors might reverse that.
The years go by & we continue to be be fixated on the androgen receptor axis.
Thanks Patrick, when you mention demethylation drugs and HDAC inhibitors where do they sit as treatment definitions ? Would they be described as gene therapies and is there a spot somewhere for stem cells in all of this or " has the bird already flown" ?
Also when you mention the androgen receptor axis are you referring to PD1 and PDL1 etc.
and would there focus be better suited to pre castrate types ?
Too many questions and I thank you very much for your valuable insights.
Epigenetic cancer drugs do not alter DNA, but reverse the silencing of genes. If given early, I imagine that lesser cancers would be cured. But, in any context, reactivation of antitumor genes has to be a good thing.
***
There is an old HDAC Inhibitor [HDACI]: Valproic Acid:
"primarily used to treat epilepsy and bipolar disorder and to prevent migraine headaches" [1]
It has often been used in PCa cell studies [2].
The Wiki page for HDACIs is a little light [3].
"A number of structurally diverse histone deacetylase inhibitors have shown potent antitumor efficacy with little toxicity in vivo in animal models."
***
For more about DNA methylation [4]:
"In many disease processes, such as cancer, gene promoter CpG islands acquire abnormal hypermethylation, which results in transcriptional silencing that can be inherited by daughter cells following cell division.[38] Alterations of DNA methylation have been recognized as an important component of cancer development."
"Generally, in progression to cancer, hundreds of genes are silenced or activated. Although silencing of some genes in cancers occurs by mutation, a large proportion of carcinogenic gene silencing is a result of altered DNA methylation".
For "DNA methylation in cancer": [5].
Genistein may help reverse hypermethylation.
For an example of PCa research:
"Selected drugs that inhibit DNA methylation can preferentially kill p53 deficient cells" [6].
***
Drugs that target the "androgen receptor axis" inhibit androgen production or inhibit the binding of androgen to the AR.
I’ve been on a trial sponsored by Pfizer consisting of
Avelumab (checkpoint-I) combined with Talazoparib (PARP-I). Disease progression so far has been stopped, since about April.
I’m BRCA2, so I don’t know if the benefits are from one of the drugs or the combination
Before that, SOC didn’t work for me (taxotere, abiraterone). I’m afraid that once you’ve taken a PARP-I you won’t qualify for trials using a different brand...
What about previous immunotherapy ? I've had thus far nivolumab and atezolizimab.
What are my chances of getting on a phase 3 trial (hypothetically) for keytruda, given that it has been somewhat successful for a subset of patients in the Keynote trial ?
J Clin Oncol. 2019 Nov 27:JCO1901638. doi: 10.1200/JCO.19.01638. [Epub ahead of print]
Pembrolizumab for Treatment-Refractory Metastatic Castration-Resistant Prostate Cancer: Multicohort, Open-Label Phase II KEYNOTE-199 Study.
Antonarakis ES1, Piulats JM2, Gross-Goupil M3, Goh J4,5, Ojamaa K6, Hoimes CJ7, Vaishampayan U8, Berger R9, Sezer A10, Alanko T11, de Wit R12, Li C13, Omlin A14, Procopio G15, Fukasawa S16, Tabata KI17, Park SH18, Feyerabend S19, Drake CG20, Wu H21, Qiu P22, Kim J22, Poehlein C22, de Bono JS23.
Author information
1
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD.
2
Catalan Cancer Institute, Bellvitge Biomedical Research Institute, Centro de Investigación Biomédica en Red de Cáncer, Hospitalet de Llobregat, Barcelona, Spain.
3
Institut Bergonié, Bordeaux, France.
4
Royal Brisbane and Women's Hospital, Herston, QLD, Australia.
5
University of Queensland, St Lucia, QLD, Australia.
6
East Tallinn Central Hospital, Tallinn, Estonia.
7
Case Comprehensive Cancer Center at University Hospitals Seidman Cancer Center, Cleveland, OH.
8
Karmanos Cancer Institute, Wayne State University, Detroit, MI.
9
Chaim Sheba Medical Center, Tel Hashomer, Israel.
10
Başkent University Hospital Adana, Adana, Turkey.
11
Docrates Cancer Center, Helsinki, Finland.
12
Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
13
Karolinska Institutet, Stockholm, Sweden.
14
Cantonal Hospital St Gallen, University of Bern, Bern, Switzerland.
15
Fondazione Istituto Nazionale Tumori, Milan, Italy.
16
Chiba Cancer Center, Chiba, Japan.
17
Kitasato University, Kanagawa, Japan.
18
Sungkyunkwan University, Samsung Medical Center, Seoul, South Korea.
19
Studienpraxis Urologie, Nürtingen, Germany.
20
New York Presbyterian/Columbia University Medical Center, New York, NY.
21
MSD China, Beijing, China.
22
Merck & Co, Kenilworth, NJ.
23
The Institute of Cancer Research and Royal Marsden Hospital, London, United Kingdom.
Abstract
PURPOSE:
Pembrolizumab has previously shown antitumor activity against programmed death ligand 1 (PD-L1)-positive metastatic castration-resistant prostate cancer (mCRPC). Here, we assessed the antitumor activity and safety of pembrolizumab in three parallel cohorts of a larger mCRPC population.
METHODS:
The phase II KEYNOTE-199 study included three cohorts of patients with mCRPC treated with docetaxel and one or more targeted endocrine therapies. Cohorts 1 and 2 enrolled patients with RECIST-measurable PD-L1-positive and PD-L1-negative disease, respectively. Cohort 3 enrolled patients with bone-predominant disease, regardless of PD-L1 expression. All patients received pembrolizumab 200 mg every 3 weeks for up to 35 cycles. The primary end point was objective response rate per RECIST v1.1 assessed by central review in cohorts 1 and 2. Secondary end points included disease control rate, duration of response, overall survival (OS), and safety.
RESULTS:
Two hundred fifty-eight patients were enrolled: 133 in cohort 1, 66 in cohort 2, and 59 in cohort 3. Objective response rate was 5% (95% CI, 2% to 11%) in cohort 1 and 3% (95% CI, < 1% to 11%) in cohort 2. Median duration of response was not reached (range, 1.9 to ≥ 21.8 months) and 10.6 months (range, 4.4 to 16.8 months), respectively. Disease control rate was 10% in cohort 1, 9% in cohort 2, and 22% in cohort 3. Median OS was 9.5 months in cohort 1, 7.9 months in cohort 2, and 14.1 months in cohort 3. Treatment-related adverse events occurred in 60% of patients, were of grade 3 to 5 severity in 15%, and led to discontinuation of treatment in 5%.
CONCLUSION:
Pembrolizumab monotherapy shows antitumor activity with an acceptable safety profile in a subset of patients with RECIST-measurable and bone-predominant mCRPC previously treated with docetaxel and targeted endocrine therapy. Observed responses seem to be durable, and OS estimates are encouraging.
Activity of durvalumab plus olaparib in metastatic castration-resistant prostate cancer in men with and without DNA damage repair mutations
"Durvalumab plus olaparib has acceptable toxicity, and the combination demonstrates efficacy, particularly in men with DDR {DNA damage repair} abnormalities."
There is also a French study in the works (not yet recruiting) described here:
Precision medicine phase II study evaluating the efficacy of a double immunotherapy by durvalumab and tremelimumab combined with olaparib in patients with solid cancers and carriers of homologous recombination repair genes mutation in response or stable after olaparib treatment
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Immunotherapy for prostate cancer continues to disappoint, but at least we are learning why
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