First PARP inhibitor to demonstrate clinical
benefit in combination with a new hormonal agent irrespective of
homologous recombination repair (HRR) gene mutations
AstraZeneca’s supplemental New Drug Application (sNDA) for
LYNPARZA® (olaparib) in combination with abiraterone and
prednisone or prednisolone has been accepted and granted Priority
Review in the US for the treatment of adult patients with
metastatic castration-resistant prostate cancer (mCRPC).
LYNPARZA is being jointly developed and commercialized by
AstraZeneca and Merck & Co., Inc., known as MSD outside the US
and Canada.
The Food and Drug Administration (FDA) grants Priority Review to
applications for medicines that offer significant advantages over
available options by demonstrating safety or efficacy improvements,
preventing serious conditions, or enhancing patient compliance.1
The Prescription Drug User Fee Act date, the FDA action date for
their regulatory decision, is anticipated during the fourth quarter
of 2022.
In the US, prostate cancer is the second most common cancer in
male patients and is projected to cause approximately 35,000 deaths
in 2022.2 Overall survival for patients with mCRPC is approximately
three years in clinical trial settings, and even shorter in the
real world.3-6 Approximately half of patients with mCRPC may
receive only one line of active treatment, with diminishing benefit
of subsequent therapies.6-11
Susan Galbraith, Executive Vice President, Oncology R&D,
AstraZeneca, said: “There remains a critical unmet need among
patients diagnosed with metastatic castration-resistant prostate
cancer, where the prognosis remains poor and treatment options are
limited. Today’s news is another step towards bringing forward a
new, much needed treatment option in this setting. If approved,
LYNPARZA with abiraterone will become the first combination of a
PARP inhibitor and a new hormonal agent for patients with this
disease.”
Dr. Eliav Barr, Senior Vice President, Head of Global Clinical
Development and Chief Medical Officer, Merck Research Laboratories,
said: “Merck is committed to developing new treatment options for
patients with metastatic castration-resistant prostate cancer, a
complex disease that urgently needs more therapies. We look forward
to working with the FDA towards the goal of bringing a new option
to patients with mCRPC with or without HRR gene mutations.”
The sNDA was based on results from the PROpel Phase III trial
presented at the 2022 American Society of Clinical Oncology (ASCO)
Genitourinary Cancers Symposium and later published in NEJM
Evidence.
These results showed LYNPARZA in combination with abiraterone
reduced the risk of disease progression or death by 34% versus
abiraterone alone (based on a hazard ratio [HR] of 0.66; 95%
confidence interval [CI] 0.54-0.81; p<0.0001). Median
radiographic progression-free survival (rPFS) was 24.8 months for
LYNPARZA plus abiraterone versus 16.6 for abiraterone alone. The
safety and tolerability of LYNPARZA in combination with abiraterone
was in line with that observed in prior clinical trials and the
known profiles of the individual medicines.12
LYNPARZA is approved in the US for patients with HRR
gene-mutated mCRPC (BRCA-mutated and other HRR gene mutations) who
have progressed following prior treatment with enzalutamide or
abiraterone; and in the EU, Japan and China for patients with
BRCA-mutated mCRPC who have progressed following prior therapy that
included a new hormonal agent. These approvals were based on the
data from the PROfound Phase III trial.
IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS
There are no contraindications for LYNPARZA.
WARNINGS AND PRECAUTIONS
Myelodysplastic Syndrome/Acute Myeloid Leukemia
(MDS/AML): Occurred in approximately 1.5% of patients exposed
to LYNPARZA monotherapy, and the majority of events had a fatal
outcome. The median duration of therapy in patients who developed
MDS/AML was 2 years (range: <6 months to >10 years). All of
these patients had previous chemotherapy with platinum agents
and/or other DNA-damaging agents, including radiotherapy.
Do not start LYNPARZA until patients have recovered from
hematological toxicity caused by previous chemotherapy (≤Grade 1).
Monitor complete blood count for cytopenia at baseline and monthly
thereafter for clinically significant changes during treatment. For
prolonged hematological toxicities, interrupt LYNPARZA and monitor
blood count weekly until recovery.
If the levels have not recovered to Grade 1 or less after 4
weeks, refer the patient to a hematologist for further
investigations, including bone marrow analysis and blood sample for
cytogenetics. Discontinue LYNPARZA if MDS/AML is confirmed.
Pneumonitis: Occurred in 0.8% of patients exposed to
LYNPARZA monotherapy, and some cases were fatal. If patients
present with new or worsening respiratory symptoms such as dyspnea,
cough, and fever, or a radiological abnormality occurs, interrupt
LYNPARZA treatment and initiate prompt investigation. Discontinue
LYNPARZA if pneumonitis is confirmed and treat patient
appropriately.
Embryo-Fetal Toxicity: Based on its mechanism of action
and findings in animals, LYNPARZA can cause fetal harm. A pregnancy
test is recommended for females of reproductive potential prior to
initiating treatment.
Females Advise females of reproductive potential of the
potential risk to a fetus and to use effective contraception during
treatment and for 6 months following the last dose.
Males Advise male patients with female partners of reproductive
potential or who are pregnant to use effective contraception during
treatment and for 3 months following the last dose of LYNPARZA and
to not donate sperm during this time.
Venous Thromboembolic Events: Including pulmonary
embolism, occurred in 7% of patients with metastatic
castration-resistant prostate cancer who received LYNPARZA plus
androgen deprivation therapy (ADT) compared to 3.1% of patients
receiving enzalutamide or abiraterone plus ADT in the PROfound
study. Patients receiving LYNPARZA and ADT had a 6% incidence of
pulmonary embolism compared to 0.8% of patients treated with ADT
plus either enzalutamide or abiraterone. Monitor patients for signs
and symptoms of venous thrombosis and pulmonary embolism, and treat
as medically appropriate, which may include long-term
anticoagulation as clinically indicated.
ADVERSE REACTIONS—First-Line Maintenance BRCAm Advanced
Ovarian Cancer
Most common adverse reactions (Grades 1-4) in ≥10% of patients
who received LYNPARZA in the first-line maintenance setting
for SOLO-1 were: nausea (77%), fatigue (67%), abdominal pain
(45%), vomiting (40%), anemia (38%), diarrhea (37%), constipation
(28%), upper respiratory tract
infection/influenza/nasopharyngitis/bronchitis (28%), dysgeusia
(26%), decreased appetite (20%), dizziness (20%), neutropenia
(17%), dyspepsia (17%), dyspnea (15%), leukopenia (13%), urinary
tract infection (13%), thrombocytopenia (11%), and stomatitis
(11%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of
patients who received LYNPARZA in the first-line maintenance
setting for SOLO-1 were: decrease in hemoglobin (87%),
increase in mean corpuscular volume (87%), decrease in leukocytes
(70%), decrease in lymphocytes (67%), decrease in absolute
neutrophil count (51%), decrease in platelets (35%), and increase
in serum creatinine (34%).
ADVERSE REACTIONS—First-Line Maintenance Advanced Ovarian
Cancer in Combination with Bevacizumab
Most common adverse reactions (Grades 1-4) in ≥10% of patients
treated with LYNPARZA/bevacizumab compared to a ≥5% frequency for
placebo/bevacizumab in the first-line maintenance setting
for PAOLA-1 were: nausea (53%), fatigue (including asthenia)
(53%), anemia (41%), lymphopenia (24%), vomiting (22%), and
leukopenia (18%). In addition, the most common adverse reactions
(≥10%) for patients receiving LYNPARZA/bevacizumab irrespective of
the frequency compared with the placebo/bevacizumab arm were:
diarrhea (18%), neutropenia (18%), urinary tract infection (15%),
and headache (14%).
In addition, venous thromboembolic events occurred more commonly
in patients receiving LYNPARZA/bevacizumab (5%) than in those
receiving placebo/bevacizumab (1.9%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of
patients for LYNPARZA in combination with bevacizumab in the
first-line maintenance setting for PAOLA-1 were:
decrease in hemoglobin (79%), decrease in lymphocytes (63%),
increase in serum creatinine (61%), decrease in leukocytes (59%),
decrease in absolute neutrophil count (35%), and decrease in
platelets (35%).
ADVERSE REACTIONS—Maintenance Recurrent Ovarian
Cancer
Most common adverse reactions (Grades 1-4) in ≥20% of patients
who received LYNPARZA in the maintenance setting for
SOLO-2 were: nausea (76%), fatigue (including asthenia)
(66%), anemia (44%), vomiting (37%), nasopharyngitis/upper
respiratory tract infection (URI)/influenza (36%), diarrhea (33%),
arthralgia/myalgia (30%), dysgeusia (27%), headache (26%),
decreased appetite (22%), and stomatitis (20%).
Study 19: nausea (71%), fatigue (including asthenia)
(63%), vomiting (35%), diarrhea (28%), anemia (23%), respiratory
tract infection (22%), constipation (22%), headache (21%),
decreased appetite (21%), and dyspepsia (20%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of
patients who received LYNPARZA in the maintenance setting
(SOLO-2/Study 19) were: increase in mean corpuscular volume
(89%/82%), decrease in hemoglobin (83%/82%), decrease in leukocytes
(69%/58%), decrease in lymphocytes (67%/52%), decrease in absolute
neutrophil count (51%/47%), increase in serum creatinine (44%/45%),
and decrease in platelets (42%/36%).
ADVERSE REACTIONS—Advanced gBRCAm Ovarian Cancer After 3 or
More Lines of Chemotherapy
Most common adverse reactions (Grades 1-4) in ≥20% of patients
who received LYNPARZA for advanced gBRCAm ovarian cancer after 3
or more lines of chemotherapy (pooled from 6 studies) were:
fatigue/asthenia (66%), nausea (64%), vomiting (43%), anemia (34%),
diarrhea (31%), nasopharyngitis/upper respiratory tract infection
(URI) (26%), dyspepsia (25%), myalgia (22%), decreased appetite
(22%), and arthralgia/musculoskeletal pain (21%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of
patients who received LYNPARZA for advanced gBRCAm ovarian
cancer (pooled from 6 studies) were: decrease in hemoglobin
(90%), mean corpuscular volume elevation (57%), decrease in
lymphocytes (56%), increase in serum creatinine (30%), decrease in
platelets (30%), and decrease in absolute neutrophil count
(25%).
ADVERSE REACTIONS—Adjuvant Treatment of gBRCAm,
HER2-Negative, High-Risk Early Breast Cancer
Most common adverse reactions (Grades 1-4) in ≥10% of patients
who received LYNPARZA in the adjuvant setting for
OlympiA were: nausea (57%), fatigue (including asthenia)
(42%), anemia (24%), vomiting (23%), headache (20%), diarrhea
(18%), leukopenia (17%), neutropenia (16%), decreased appetite
(13%), dysgeusia (12%), dizziness (11%), and stomatitis (10%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of
patients who received LYNPARZA in the adjuvant setting for
OlympiA were: decrease in lymphocytes (77%), increase in
mean corpuscular volume (67%), decrease in hemoglobin (65%),
decrease in leukocytes (64%), and decrease in absolute neutrophil
count (39%).
ADVERSE REACTIONS—gBRCAm, HER2-Negative Metastatic Breast
Cancer
Most common adverse reactions (Grades 1-4) in ≥20% of patients
who received LYNPARZA in the metastatic setting for
OlympiAD were: nausea (58%), anemia (40%), fatigue
(including asthenia) (37%), vomiting (30%), neutropenia (27%),
respiratory tract infection (27%), leukopenia (25%), diarrhea
(21%), and headache (20%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of
patients who received LYNPARZA in the metastatic setting for
OlympiAD were: decrease in hemoglobin (82%), decrease in
lymphocytes (73%), decrease in leukocytes (71%), increase in mean
corpuscular volume (71%), decrease in absolute neutrophil count
(46%), and decrease in platelets (33%).
ADVERSE REACTIONS—First-Line Maintenance gBRCAm Metastatic
Pancreatic Adenocarcinoma
Most common adverse reactions (Grades 1-4) in ≥10% of patients
who received LYNPARZA in the first-line maintenance setting
for POLO were: fatigue (60%), nausea (45%), abdominal pain
(34%), diarrhea (29%), anemia (27%), decreased appetite (25%),
constipation (23%), vomiting (20%), back pain (19%), arthralgia
(15%), rash (15%), thrombocytopenia (14%), dyspnea (13%),
neutropenia (12%), nasopharyngitis (12%), dysgeusia (11%), and
stomatitis (10%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of
patients who received LYNPARZA in the first-line maintenance
setting for POLO were: increase in serum creatinine
(99%), decrease in hemoglobin (86%), increase in mean corpuscular
volume (71%), decrease in lymphocytes (61%), decrease in platelets
(56%), decrease in leukocytes (50%), and decrease in absolute
neutrophil count (25%).
ADVERSE REACTIONS—HRR Gene-mutated Metastatic
Castration-Resistant Prostate Cancer
Most common adverse reactions (Grades 1-4) in ≥10% of patients
who received LYNPARZA for PROfound were: anemia (46%),
fatigue (including asthenia) (41%), nausea (41%), decreased
appetite (30%), diarrhea (21%), vomiting (18%), thrombocytopenia
(12%), cough (11%), and dyspnea (10%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of
patients who received LYNPARZA for PROfound were: decrease
in hemoglobin (98%), decrease in lymphocytes (62%), decrease in
leukocytes (53%), and decrease in absolute neutrophil count
(34%).
DRUG INTERACTIONS
Anticancer Agents: Clinical studies of LYNPARZA with
other myelosuppressive anticancer agents, including DNA-damaging
agents, indicate a potentiation and prolongation of
myelosuppressive toxicity.
CYP3A Inhibitors: Avoid coadministration of strong or
moderate CYP3A inhibitors when using LYNPARZA. If a strong or
moderate CYP3A inhibitor must be coadministered, reduce the dose of
LYNPARZA. Advise patients to avoid grapefruit, grapefruit juice,
Seville oranges, and Seville orange juice during LYNPARZA
treatment.
CYP3A Inducers: Avoid coadministration of strong or
moderate CYP3A inducers when using LYNPARZA.
USE IN SPECIFIC POPULATIONS
Lactation: No data are available regarding the presence
of olaparib in human milk, its effects on the breastfed infant or
on milk production. Because of the potential for serious adverse
reactions in the breastfed infant, advise a lactating woman not to
breastfeed during treatment with LYNPARZA and for 1 month after
receiving the final dose.
Pediatric Use: The safety and efficacy of LYNPARZA have
not been established in pediatric patients.
Hepatic Impairment: No adjustment to the starting dose is
required in patients with mild or moderate hepatic impairment
(Child-Pugh classification A and B). There are no data in patients
with severe hepatic impairment (Child-Pugh classification C).
Renal Impairment: No dosage modification is recommended
in patients with mild renal impairment (CLcr 51-80 mL/min estimated
by Cockcroft-Gault). In patients with moderate renal impairment
(CLcr 31-50 mL/min), reduce the dose of LYNPARZA to 200 mg twice
daily. There are no data in patients with severe renal impairment
or end-stage renal disease (CLcr ≤30 mL/min).
INDICATIONS
LYNPARZA is a poly (ADP-ribose) polymerase (PARP) inhibitor
indicated:
First-Line Maintenance BRCAm Advanced Ovarian Cancer For
the maintenance treatment of adult patients with deleterious or
suspected deleterious germline or somatic BRCA-mutated (gBRCAm or
sBRCAm) advanced epithelial ovarian, fallopian tube, or primary
peritoneal cancer who are in complete or partial response to
first-line platinum-based chemotherapy. Select patients for therapy
based on an FDA-approved companion diagnostic for LYNPARZA.
First-Line Maintenance HRD-Positive Advanced Ovarian Cancer
in Combination with Bevacizumab In combination with bevacizumab
for the maintenance treatment of adult patients with advanced
epithelial ovarian, fallopian tube or primary peritoneal cancer who
are in complete or partial response to first-line platinum-based
chemotherapy and whose cancer is associated with homologous
recombination deficiency (HRD) positive status defined by
either:
- a deleterious or suspected deleterious BRCA mutation,
and/or
- genomic instability
Select patients for therapy based on an FDA-approved companion
diagnostic for LYNPARZA.
Maintenance Recurrent Ovarian Cancer For the maintenance
treatment of adult patients with recurrent epithelial ovarian,
fallopian tube, or primary peritoneal cancer, who are in complete
or partial response to platinum-based chemotherapy.
Advanced gBRCAm Ovarian Cancer For the treatment of adult
patients with deleterious or suspected deleterious germline
BRCA-mutated (gBRCAm) advanced ovarian cancer who have been treated
with 3 or more prior lines of chemotherapy. Select patients for
therapy based on an FDA-approved companion diagnostic for
LYNPARZA.
Adjuvant Treatment of gBRCAm, HER2-Negative, High-Risk Early
Breast Cancer For the adjuvant treatment of adult patients with
deleterious or suspected deleterious gBRCAm, human epidermal growth
factor receptor 2 (HER2)-negative high-risk early breast cancer who
have been treated with neoadjuvant or adjuvant chemotherapy. Select
patients for therapy based on an FDA-approved companion diagnostic
for LYNPARZA.
gBRCAm, HER2-Negative Metastatic Breast Cancer For the
treatment of adult patients with deleterious or suspected
deleterious gBRCAm, human epidermal growth factor receptor 2
(HER2)-negative metastatic breast cancer who have been treated with
chemotherapy in the neoadjuvant, adjuvant, or metastatic setting.
Patients with hormone receptor (HR)-positive breast cancer should
have been treated with a prior endocrine therapy or be considered
inappropriate for endocrine therapy. Select patients for therapy
based on an FDA-approved companion diagnostic for LYNPARZA.
First-Line Maintenance gBRCAm Metastatic Pancreatic
Cancer For the maintenance treatment of adult patients with
deleterious or suspected deleterious gBRCAm metastatic pancreatic
adenocarcinoma whose disease has not progressed on at least 16
weeks of a first-line platinum-based chemotherapy regimen. Select
patients for therapy based on an FDA-approved companion diagnostic
for LYNPARZA.
HRR Gene-mutated Metastatic Castration-Resistant Prostate
Cancer For the treatment of adult patients with deleterious or
suspected deleterious germline or somatic homologous recombination
repair (HRR) gene-mutated metastatic castration-resistant prostate
cancer (mCRPC) who have progressed following prior treatment with
enzalutamide or abiraterone. Select patients for therapy based on
an FDA-approved companion diagnostic for LYNPARZA.
Please see complete Prescribing Information,
including Medication Guide.
Notes
Metastatic castration-resistant prostate cancer
Metastatic prostate cancer is associated with a significant
mortality rate.13 Development of prostate cancer is often driven by
male sex hormones called androgens, including testosterone.14
In patients with mCRPC, their prostate cancer grows and spreads
to other parts of the body despite the use of androgen-deprivation
therapy to block the action of male sex hormones.7 Approximately
10-20% of men with advanced prostate cancer will develop
castration-resistant prostate cancer (CRPC) within five years, and
at least 84% of these men will have metastases at the time of CRPC
diagnosis.7 Of patients with no metastases at CRPC diagnosis, 33%
are likely to develop metastases within two years.6
Despite the advances in mCRPC treatment in the past decade with
taxane and new hormonal agent (NHA) treatment, there is high unmet
need in this population.7,9,10,15
PROpel PROpel is a randomized, double-blind, multi-center
Phase III trial testing the efficacy, safety, and tolerability of
LYNPARZA versus placebo when given in addition to abiraterone in
men with mCRPC who had not received prior chemotherapy or NHAs in
the mCRPC setting.
Men in both treatment groups will also receive either prednisone
or prednisolone twice daily. The primary endpoint is rPFS and
secondary endpoints include overall survival, time to secondary
progression or death, and time to first subsequent therapy.
For more information about the trial please visit
ClinicalTrials.gov.
LYNPARZA LYNPARZA (olaparib) is a first-in-class PARP
inhibitor and the first targeted treatment to block DNA damage
response (DDR) in cells/tumors harboring a deficiency in HRR, such
as those with mutations in BRCA1 and/or BRCA2, or those where
deficiency is induced by other agents (such as NHAs).
Inhibition of PARP with LYNPARZA leads to the trapping of PARP
bound to DNA single-strand breaks, stalling of replication forks,
their collapse and the generation of DNA double-strand breaks and
cancer cell death. In the PROpel Phase III trial, LYNPARZA is
combined with abiraterone, an NHA which targets the androgen
receptor (AR) pathway.
Androgen receptor signaling engages a transcriptional program
that is critical for tumor cell growth & survival in prostate
cancer.16,17 Preclinical models have identified interactions
between PARP signaling and the AR pathway which support the
observation of a combined anti-tumor effect of LYNPARZA and NHAs,
like abiraterone, in both HRR deficient and HRR proficient prostate
cancer.18,19,20
The PARP1 protein has been reported to be required for the
transcriptional activity of androgen receptors; therefore
inhibiting PARP with LYNPARZA may impair the expression of androgen
receptor target genes and enhance the activity of NHAs.16,19,21
Additionally, it is thought that abiraterone may alter/inhibit the
transcription of some HRR genes which may induce HRR deficiency and
increase sensitivity to PARP inhibition.18,20,22,23
LYNPARZA is currently approved in a number of countries across
PARP-dependent tumor types with defects and dependencies in the DDR
pathway including maintenance treatment of platinum-sensitive
relapsed ovarian cancer and as both monotherapy and in combination
with bevacizumab for the 1st-line maintenance treatment of
BRCA-mutated (BRCAm) and homologous recombination repair deficient
(HRD)-positive advanced ovarian cancer, respectively; for germline
BRCAm (gBRCAm) HER2-negative metastatic breast cancer (in the EU
and Japan this includes locally advanced breast cancer); for
gBRCAm, HER2-negative high-risk early breast cancer; for gBRCAm
metastatic pancreatic cancer; and HRR gene-mutated metastatic
castration-resistant prostate cancer (BRCAm only in the EU and
Japan).
LYNPARZA, which is being jointly developed and commercialized by
AstraZeneca and Merck, is the foundation of AstraZeneca's
industry-leading portfolio of potential new medicines.
The AstraZeneca and Merck strategic oncology
collaboration In July 2017, AstraZeneca and Merck & Co.,
Inc., Kenilworth, NJ, US, known as MSD outside the US and Canada,
announced a global strategic oncology collaboration to co-develop
and co-commercialize LYNPARZA, the world’s first PARP inhibitor,
and selumetinib, a mitogen-activated protein kinase (MEK)
inhibitor, for multiple cancer types.
Working together, the companies will develop LYNPARZA and
selumetinib and other potential new medicines as monotherapies. The
companies will also develop LYNPARZA and selumetinib in combination
with their respective PD-L1 and PD-1 medicines independently.
AstraZeneca in oncology AstraZeneca is leading a
revolution in oncology with the ambition to provide cures for
cancer in every form, following the science to understand cancer
and all its complexities to discover, develop and deliver
life-changing medicines to patients.
The Company's focus is on some of the most challenging cancers.
It is through persistent innovation that AstraZeneca has built one
of the most diverse portfolios and pipelines in the industry, with
the potential to catalyze changes in the practice of medicine and
transform the patient experience.
AstraZeneca has the vision to redefine cancer care and, one day,
eliminate cancer as a cause of death.
About AstraZeneca AstraZeneca is a global, science-led
biopharmaceutical company that focuses on the discovery,
development, and commercialization of prescription medicines in
Oncology, Rare Diseases, and BioPharmaceuticals, including
Cardiovascular, Renal & Metabolism, and Respiratory &
Immunology. Based in Cambridge, UK, AstraZeneca operates in over
100 countries and its innovative medicines are used by millions of
patients worldwide. Please visit www.astrazeneca-us.com and follow
the Company on Twitter @AstraZenecaUS.
References
1. US Food and Drug Administration. Priority Review. Available
at:
https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/priority-review.
Accessed August 2022. 2. Cancer.org. Key Statistics for Prostate
Cancer. Available at
https://www.cancer.org/cancer/prostate-cancer/about/key-statistics.html.
Accessed August 2022. 3. Ng K, et al. Metastatic Hormone-Sensitive
Prostate Cancer (mHSPC): Advances and Treatment Strategies in the
First-Line Setting. Oncol Ther. 2020; 8:209–230. 4. Shore N, et al.
Real-World Treatment Patterns and Overall Survival of Patients with
Metastatic Castration-Resistant Prostate Cancer in the US Prior to
PARP Inhibitors. Adv Ther. 2021;38:4520–4540. 5. Wallis C, et al.
Real-World Use of Androgen-Deprivation Therapy: Intensification
Among Older Canadian Men With de Novo Metastatic Prostate Cancer.
JNCI Cancer Spectrum. 2021;5(6):pkab082. 6. George D, et al.
Treatment Patterns and Outcomes in Patients With Metastatic
Castration-resistant Prostate Cancer in a Real-world Clinical
Practice Setting in the United States. Clinical Genitourinary
Cancer. 2020 Aug;18(4):284-294. 7. Kirby, M, et al. Characterising
the castration-resistant prostate cancer population: a systematic
review. International Journal of Clinical Practice,
2021;65(11):1180-1192. 8. Smith MR, et al. Natural history of
rising serum prostate-specific antigen in men with castrate
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9. UroToday. What is Changing in Advanced Prostate Cancer?
Available at
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Accessed August 2022. 10. Liu J, et al. Second-line Hormonal
Therapy for the Management of Metastatic Castration-resistant
Prostate Cancer: a Real-World Data Study Using a Claims Database.
Scientific Report. 2020;10(4240):2020. 11. Mateo J, et al.
DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. N
Engl J Med. 2015; 373:1697-1708. 12. Clarke N, et al. Abiraterone
and Olaparib for Metastatic Castration-Resistant Prostate Cancer.
NEJM. 2022;1(7) 13. Chowdhury S, et al. Real-world outcomes in
first-line treatment of metastatic castration-resistant prostate
cancer: the prostate cancer registry. Target Oncol.
2020;15(3):301-15. 14. Cancer.Net. Treatment of metastatic
castration-resistant prostate cancer. Available at
www.cancer.net/research-and-advocacy/asco-care-and-treatment-recommendations-patients/treatment-metastatic-castration-resistant-prostate-cancer.
Accessed August 2022. 15. UroToday. Beyond First-line Treatment of
Metastatic Castrate-resistant Prostate Cancer. Available at
https://www.urotoday.com/library-resources/mcrpc-treatment/114592-beyond-first-line-treatment-of-metastatic-castrate-resistant-prostate-cancer.html.
Accessed August 2022. 16. Schiewer MJ, et al. Dual roles of PARP-1
promote cancer growth and progression. Cancer Discov.
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treat prostate cancer: novel AMPK activators emerge for cancer
therapy. EMBO Mol Med. 2014;6(4):439-441. 18. Li L, et al. Androgen
receptor inhibitor–induced “BRCAness” and PARP inhibition are
synthetically lethal for castration-resistant prostate cancer. Sci
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receptor signaling regulates DNA repair in prostate cancers. Cancer
Discov. 2013;3(11):1245-1253. 20. Asim M, et al. Synthetic
lethality between androgen receptor signalling and the PARP pathway
in prostate cancer. Nat Commun. 2017;374(8). 21. Ju B-G, et al. A
topoisomerase IIbeta-mediated dsDNA break required for regulated
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et al. A hormone-DNA repair circuit governs the response to
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US-67592 Last Updated 08/22
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