Olaparib (Lynparza) w leczeniu mCRPC z mutacją BRCA

[wiatger]

30 września 2019 na kongresie ESMO zostały przedstawione wyniki ciekawego badania:


New Precision Medicine Treatment Could Benefit Many Men with Treatment-Resistant Metastatic Prostate Cancer

Phase 3 clinical trial results demonstrate significant efficacy of the PARP-inhibitor olaparib in advanced prostate cancer patients with specific tumor mutations
October 01, 2019 | By ANDREA K. MIYAHIRA, PHD

A study presented yesterday at the 2019 European Society for Medical Oncology (ESMO) Congress reported positive results from a Phase 3 clinical trial testing the PARP-inhibitor olaparib (Lynparza) in patients with metastatic castration-resistant prostate cancer (mCRPC) who have alterations  in certain DNA damage repair (DDR) genes; a result which will likely lead to a new FDA-approval. 
Roughly 20-30% of mCRPC patients harbor these DDR gene mutations in their tumors and thus may benefit from PARP-inhibition.
This trial of olaparib is the first positive Phase 3 “precision medicine” clinical trial testing a targeted therapy in men with advanced prostate cancer with specific mutations.

PARP-inhibitors, including olaparib, are a new class of therapies that are FDA-approved for the treatment of breast and ovarian cancers with mutations in the BRCA1 and BRCA2 genes.  BRCA1 and BRCA2 are critical DNA damage repair (DDR) genes – genes that act to mend any damaged DNA.
Mutations in BRCA genes render cells highly susceptible to acquiring other mutations and developing into cancer.  However, in order to survive, cancer cells that have lost BRCA1, BRCA2 or many other DNA repair genes become dependent on the function of a protein called PARP to maintain sufficient integrity of their DNA.  Thus, cancer cells with mutations in BRCA1/2 are highly sensitive to PARP-inhibiting drugs, with this being an Achilles’ heel and vulnerability for these tumor cells.
The BRCA1/2 genes first became infamous for their association with breast and ovarian cancer, as mutations in these genes are major drivers of these women’s cancers.  Germline (inherited) mutations in BRCA1 or BRCA2 significantly increase a woman’s risk for developing these cancers sometime in their lives. PARP-inhibitors were first FDA-approved as treatments for BRCA1/2-deficient breast and ovarian cancer in 2014.  However, Prostate Cancer Foundation (PCF)-funded studies demonstrated that BRCA1/2 and PARP are also important in prostate cancer.

Early data that PARP may be an important treatment target in prostate cancer came from a PCF-funded team led by Dr. Karen Knudsen, of Thomas Jefferson University.  This team provided preclinical evidence that PARP is a critical driver of prostate cancer and that PARP-inhibitors can suppress prostate tumor growth and progression to CRPC.

In 2015, the PCF International Prostate Cancer Dream Team published a landmark study demonstrating that up to a third of mCRPC cases have mutations in BRCA1, BRCA2, and a number of other DDR genes, such as ATM. 
This study was momentous, as it provided rationale for testing PARP-inhibitors as a precision medicine treatment in prostate cancer with DDR gene mutations.  Moreover, the PCF Dream Team found that ~12% of men with metastatic prostate cancer had germline mutations in DDR genes (most frequently in BRCA2) which likely drove the development of their cancer – a finding that rapidly changed NCCN guidelines for prostate cancer germline genetic testing, and has significant implications for cancer screening and risk in both male and female family members of men who carry these genes.

Led by Dr. Johann de Bono, of the Institute of Cancer Research and Royal Marsden NHS Foundation Trust in the UK, and colleagues, the PCF International Dream Team quickly applied all of these findings in the clinic. The team initiated a Phase 2 clinical trial, TOPARP, which demonstrated that olaparib had anti-tumor activity in mCRPC patients with DDR gene alterations.  These findings resulted in olaparib receiving a FDA “Breakthrough Therapy Designation” for the treatment of mCRPC with BRCA1/2 or ATM gene mutations.
“Support from the PCF was critically important to making this academic research trial serving this patient population happen, at a time when the pharmaceutical industry was not interested in studying these drugs for men suffering from prostate cancer,” said de Bono.

At the 2019 ESMO Congress Presidential Session, PCF-funded investigator and PCF Dream Team member Dr. Maha Hussain,  Deputy Director, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, presented results from the randomized Phase 3 PROfound trial, which tested olaparib versus physician’s choice of either abiraterone (Zytiga) + prednisone or enzalutamide (Xtandi) in men with mCRPC who failed prior treatment with abiraterone + prednisone or enzalutamide, and who were found to have a mutation in a DDR gene. 

Because BRCA1, BRCA2, and ATM mutations were the best characterized genes at the time of the study design, this trial prospectively grouped patients into
those with BRCA1, BRCA2, or ATM mutations (cohort A), and
those with mutations in any of 12 other predetermined DDR genes (cohort B; BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D or RAD54L).

Overall, 4,425 men were pre-screened internationally for DDR gene alterations in their tumors, and 387 were enrolled onto the trial:
245 in Cohort A and 142 in Cohort B. 
In each cohort, patients were randomized 2:1 to receive olaparib vs. physician’s choice of abiraterone or enzalutamide. 

The patients on this trial had been heavily pretreated: all had been treated with either abiraterone (40%), enzalutamide (41%) or both (19%), and 66% had previously been treated with taxane chemotherapy (docetaxel, cabazitaxel, or both).

Olaparib significantly delayed the time to radiographic disease progression (tumors growing on scans) or death (whichever came first) compared with abiraterone or enzalutamide,
by an average of 3.84 months (7.39 months vs. 3.55 months) in Cohort A (BRCA1, BRCA2, or ATM mutations),  and
by an average of 2.3 months (5.82 months vs. 3.52 months) in Cohorts A+B combined (mutations in any qualifying DDR gene).  
This represents a reduction in risk of metastatic disease progression or death by 66% in Cohort A, and by 51% in Cohorts A+B.

At 12-months post-enrollment, 40% of men in Cohort A who received olaparib had no radiographic disease progression vs 11% of men who had received abiraterone or enzalutamide.

Response rates, a measure of tumor shrinkage on scans, could be determined for men who had metastatic sites considered measurable at the start of treatment.  Overall, in men with measurable disease in Cohort A, 33.3% who received olaparib responded, while only 2.3% who received abiraterone or enzalutamide responded.
In men with measurable disease in Cohorts A+B, 21.7% who received olaparib responded and 4.5% who received abiraterone or enzalutamide responded.

Olaparib prolonged overall survival by an average of 3.39 months (18.5 vs 15.11 months) in Cohort A (36% reduction in risk of death), and by 3.25 months (17.51 vs 14.26 months) in Cohorts A+B (33%   reduction in risk of death), despite 80% of the men in the control arm crossing over to receive olaparib as soon as they progressed on abiraterone or enzalutamide.
However, the data from the trial is still not mature enough to definitively conclude whether olaparib prolongs overall survival.

Olaparib also significantly delayed the average time to pain progression by 56% in Cohort A, and by 36% in Cohorts A+B.

Across both cohorts A and B, adverse events were more common in patients receiving olaparib vs abiraterone or enzalutamide (95.3% vs. 87.7% for adverse events of any grade; 50.8% vs 37.7% for grade 3 adverse events).  However, patients on olaparib received treatment for a longer time (an average of 7.4 vs. 3.9 months), which may have contributed to higher rates of side effects.
Grade 3 adverse events occurring in patients who received olaparib included anemia (21.5%), fatigue and physical weakness (2.7%), vomiting (2.3%), difficult or labored breathing (2.3%), urinary tract infection (1.6%), nausea (1.2%), and decreased appetite (1.2%). 
4.3% of patients who received olaparib experienced a non-fatal pulmonary embolism (vs. 0.8% who received abiraterone or enzalutamide).
Overall, physicians considered olaparib to be well-tolerated.

So how many patients may benefit from this new precision therapy?
In a separate ESMO presentation, de Bono, who co-led the PROfound trial with Hussain, reported on the prevalence of DDR mutations among the patients pre-screened for enrollment onto the PROfound trial.  Of 4,426 mCRPC patients who were initially screened, genomic testing of primary or metastatic tumor samples was performed in 4,047 patients. Testing was successful and could be interpreted in 2,792 patients (69%).   Overall, 17.1% of successfully tested patients had a Cohort A mutation (BRCA2, BRCA1, ATM), and 28% had a mutation in any one of the 15 DDR genes being tested for (Cohort A+B). 
The most commonly mutated DDR gene was BRCA2 (8.7%) — and patients with BRCA2 mutations were also the most likely to benefit from treatment with olaparib. 
More studies are needed to better define which mutations in which genes are most likely to render prostate cancer sensitive to treatment with olaparib.
In addition to olaparib, three other PARP-inhibitor drugs are currently in Phase 3 clinical trials in prostate cancer: rucaparib (Rubraca), talazoparib (Talzenna), and niraparib (Zejula). 
Trials are also testing PARP-inhibitors in all prostate cancer patients (regardless of the presence or absence of DDR gene mutations) and in combination with other treatments, including immunotherapies and radionuclide therapies.

The Prostate Cancer Foundation is proud to have funded the foundational studies that provided the biologic and clinical rationale for this clinical trial.  These practice-changing findings will result in a new precision medicine treatment option for many men with advanced prostate cancer.  A significant proportion of the PCF research portfolio is dedicated to funding research into new precision medicines, such that all men with advanced disease will have additional effective treatment options.
https://www.pcf.org/news/new-precision- ... te-cancer/

[zosia bluszcz]

O olaparibie (Lynparza) pisałam tydzien temu (post z 23.09.2019) w wątku adarka:

Proszę powiedzieć, jeśli ktoś wie, czy badania genetyczne służą jedynie przyszłym męskim pokoleniom?
Bo chyba samemu choremu nic w leczeniu nie pomogą.

Mogą pomóc choremu na CaP jeśli znaleziono u niego mutację BRCA.
Z kolei męscy potomkowie obciążeni tą mutacja, zwlaszcza BRCA2, mają znacznie zwiekszone ryzyko zachorowania na raka prostaty w związku z czym powinni zacząc monitorowac PSA w mlodszym wieku.
Nie nalezy zapominac o corkach i ich zwiekszonym ryzyku zachorownia na raka piersi i jajnikow.
Ryzyko zachorowania na raka piersi dotyczy rowniez męzczyzn z mutacją BRCA.

Czy są jakieś poważne, powtarzam, poważne procedury leczenia CaP na podstawie badań genetycznych?
Tu chyba jednak trzeba by zbadać DNA samego nowotworu a nie DNA chorego?

Olaparib czyli Lynparza, lek stosowany od jakiegos czasu w leczeniu raka jajnikow u pacjentek z mutacją BRCA, dziala rowniez w przypadku chorych na CaP z tą wlasnie mutacją.




2019 ASCO: TOPARP-B Finds Olaparib Shows Efficacy in Men With BRCA-Mutant Prostate Cancer

Key Points

Overall, 47% of men with DNA repair defects in their tumors responded to olaparib, and the drug delayed progression for a median of 5.5 months.
80% of men with BRCA1/2-mutated prostate cancer responded to olaparib.
57% of patients with mutations in the PALB2 gene responded to olaparib.
https://www.ascopost.com/News/60138



Drug Effective in 80% of Men With BRCA-mutant Prostate Cancer
https://www.technologynetworks.com/canc ... cer-320348



PARP Inhibitor - Lynparza Effective in Men with BRCA-Mutant Prostate Cancer
https://news.cancerconnect.com/prostate ... 7jPGn4V5Q/

BRCA2 and Other DDR Genes in Prostate Cancer.pdf

[bela71]

Są też wyniki wskazujące na to, że bipolar androgen therapy (BAT) może być najbardziej skuteczna u pacjentów z wymienianymi w tym wątku mutacjami:


Genomic determinants of sensitivity to bipolar androgen therapy (BAT) in castrate-resistant prostate cancer (CRPC).

Background:
BAT is a promising treatment for CRPC and preclinical work has shown that its effects may be mediated by inducing DNA damage or cell cycle arrest. We sought to evaluate if mutations in DNA damage repair (DDR) genes or cell cycle regulators were associated with improved outcomes.

Methods:
Biospecimens from CRPC patients enrolled to studies testing BAT underwent germline or somatic next-generation sequencing (NGS). Samples tested included plasma (i.e. cell-free DNA) (N = 79), tumor tissue (N = 21) and saliva (N = 10). A variety of clinical grade NGS platforms were generally used. Given the concern for false negatives, we excluded cases if plasma NGS did not reveal a somatic alteration. Absence of a germline alteration was not assumed to indicate absence of somatic alterations. Comparative analyses to assess candidate biomarkers of BAT efficacy were performed.

Results:
Most patients received BAT following one or more next generation hormonal therapy, while 6 received BAT as first-line CRPC therapy.
Of 65 cases where a germline or somatic pathogenic alteration in any gene was detected, 30 (46%) had evidence of homologous recombination deficiency (HRD), with mutations found in BRCA2 (N = 10), ATM (N = 8), CHEK2 (N = 5), PALB2 (N = 4), CDK12 (N = 3), CHD1 (N = 2), FANCA (N = 1), FANCD2 (N = 1) and BRCA1 (N = 1). TP53 alterations were also common (27/65; 42%).
HRD mutations associated with increased PSA50 responses, with a trend toward improved PSA50 responses in TP53 mutated cases too (Table).
In a combined analysis, men with HRD and/or TP53 mutations had improved PSA50 responses and near-significant improvement in progression free survival (PFS).

Conclusions:
These preliminary data suggest that BAT may be most efficacious in cancers harboring mutations in genes involved in DDR and/or cell cycle regulation.
These results require prospective confirmation.
https://ascopubs.org/doi/abs/10.1200/JC ... _suppl.200





University of Washington prowadzi badanie fazy II nad łączeniem BAT z olaparibem u pacjentow z CRPC:


Testosterone and Olaparib in Treating Participants With Castration-Resistant Prostate Cancer
(NCT03516812)

Brief Summary:
This phase II trial studies how well testosterone (enanthate or cypionate) and olaparib work in treating participants with prostate cancer that has progressed despite hormonal therapy.
Hormonal therapy, such as leuprolide, may lessen the amount of male sex hormones made by the body.
In patients that have developed progressive cancer in spite of standard hormonal treatment (i.e. castration-resistant prostate cancer), administering testosterone may result in regression of tumors by causing DNA damage in cancer cells that have adapted to low testosterone conditions.
Olaparib may stop the growth of tumor cells by blocking some of the enzymes involved in repairing DNA damage. Therefore, giving testosterone and olaparib together may work better in treating castration-resistant prostate cancer by generating DNA damage that the cancer cell is unable to repair.


Condition or disease
=> Castration Levels of Testosterone
=> Castration-Resistant Prostate Carcinoma
=> Prostate Adenocarcinoma
=> PSA Level Greater Than or Equal to One
=> PSA Progression
(...)
https://clinicaltrials.gov/ct2/show/NCT03516812

[kemoturf]

Jest rejestracja FDA. Nowa nadzieja dla wielu chorych, choć do PL szybko nie zawita w postaci refundowanej - około 3700$ na miesiąc.

Oral Tablet 100 mg
Lynparza oral tablet from $7,403.93 for 60 tablet


BREAKING NEWS: FDA Approves Olaparib For Treatment of Advanced Prostate Cancer
https://www.pcf.org/blog/breaking-news- ... te-cancer/

[zrebie]

ESMO Congress 2020

Wyniki badania klinicznego PROfound wskazują na dłuższe przeżycie (OS) mężczyzn z mCRPC z mutacją BRCA1, BRCA2 lub ATM i z progresją po leczeniu ADT drugiej generacji (enzalutamid, abirateron) leczonych Olaparibem w stosunku do mężczyzn leczonych wyłacznie ADT drugiej generacji.




Updated Findings Show Olaparib Prolongs OS in Men with mCRPC


Olaparib induced a significantly longer duration of overall survival, compared with enzalutamide or abiraterone plus prednisone, in men with metastatic castration-resistant prostate cancer who had tumors with at least 1 alteration in BRCA1, BRCA2, or ATM and whose disease had progressed during previous treatment with a next-generation hormonal agent.
(...)

“PROfound is the first positive phase 3 PARP inhibitor trial in metastatic castration-resistant prostate cancer, meeting its primary end point of prolonged radiographic progression-free survival for metastatic castration-resistant prostate cancer with alterations in BRCA1, BRCA2, or ATM progressing on prior next-generation hormonal agents and treated with olaparib versus with enzalutamide or abiraterone,” Mateo said, adding that these data supported the FDA’s approval of olaparib in this setting.

https://www.onclive.com/view/updated-fi ... with-mcrpc


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