Addressing Unmet Needs in Advanced Prostate Cancer With PARP Inhibitors

Discover the critical unmet needs in patients with BRCA-mutated metastatic castration-resistant prostate cancer.

Watch video 2 here and video 3 here. 

Transcript:

Hi, I’m Dr Tanya Dorff, a medical oncologist and the division chief of the Genitourinary Cancer Program at City of Hope in Duarte, California. 

This video series examines the importance of poly (ADP-ribose) polymerase, or PARP, inhibitors in elevating the treatment of advanced prostate cancer. 

In this initial video, we will discuss the unmet needs in advanced prostate cancer and investigate how PARP inhibitors may benefit advanced prostate cancer patients with homologous recombination repair mutations. 

Prostate cancer is the most frequently diagnosed cancer in US men and the second-leading cause of cancer-related deaths, comprising about 10% of cancer deaths in men.¹  

Men of African descent are more likely to develop prostate cancer in their lifetime and are twice as likely to die after being diagnosed with the disease.¹  

However, in a controlled setting such as clinical trials, treatments are similarly effective in both Black and White men, emphasizing the importance of addressing socioeconomic barriers and other factors that may hinder access to screening and care.^2-4  

Prognosis is particularly poor for metastatic castration-resistant prostate cancer, or mCRPC, which has a median overall survival of only about 2 years from the time of diagnosis.^5,6 

Metastatic prostate cancer is often characterized by mutations in several biologic pathways. In a retrospective analysis of veterans, actionable genomic alterations were identified in approximately 14% to 16% of individuals with prostate cancer.⁷  

Cancer evolves with the gradual accumulation of somatic mutations over time.⁸ In particular, mutations in DNA damage repair pathways can lead to genetic instability and drive tumor growth.⁹  

As an example in prostate cancer, the homologous recombination repair, or HRR, mutations BRCA1 and BRCA2 are more frequently seen in advanced stages and are twice as likely to be associated with more aggressive disease.^10-12 

The prevalence of HRR deficiencies (including BRCA1, BRCA2, and ATM) has been found to be as high as 20% to 30% in patients with mCRPC, a significantly higher rate than that in patients with localized disease.^11,13-16  

Not only do HRR mutations tend to correlate with advanced and aggressive disease, they are also associated with inferior responses to conventional first-line androgen receptor-directed therapies.^17,18  

However, the presence of 1 or more of these mutations also confers the possibility of response to PARP inhibitors, which synergistically impair DNA repair targeted at cells with inherent HRR deficiency.^9,19-21 

Given the recent increase in treatments targeting genomic alterations for patients with advanced prostate cancer, companion diagnostics using next-generation sequencing, or NGS, are becoming more prevalent in this patient population.²²  

This strategy aligns with the current National Comprehensive Cancer Network’s recommendation of pursuing germline and somatic testing for HRR genes in patients with mCRPC to guide the selection of targeted therapy.^23,24  

However, there is still a need to improve the implementation of testing. 

A large cohort study of US patients with metastatic prostate cancer found that fewer than 30% of patients underwent NGS testing.²⁵ 

In another large, multi-institutional cohort study, somatic molecular testing was performed in over 80% of both Black and White patients with mCRPC, but germline testing was performed in only 10.5% of Black patients and 16.3% of White patients.⁴  

As we know, genetic testing can provide critical data to inform the selection of antineoplastic drugs, including PARP inhibitors.²² 

For prostate cancer, several PARP inhibitors have received US FDA approval for use in patients with certain types of HRR mutations detected through sequencing of either circulating tumor DNA or tissue DNA.  

Olaparib received a monotherapy indication based on the phase 3 trial, PROfound, and rucaparib also received accelerated approval for monotherapy use in 2020 based on the phase 2 study, TRITON2.^26,27  

More recently, the PARP inhibitors niraparib, olaparib, and talazoparib received approvals to be used in combination with androgen receptor pathway inhibitors.^28-30 

Despite these advances in systemic therapy, the lack of treatment intensification remains a key clinical challenge in mCRPC. Real-world data shows that, among patients receiving treatment, more than half of the patients receive only 1 line of therapy.^5,6 Clearly, there is more to do in expanding education and access to these important medications.  

In summary, we have established that the use of PARP inhibitors, both alone and in combination with other therapies, are indicated for certain patients with mCRPC. In order to identify eligible patients earlier in the treatment paradigm, genetic and somatic DNA testing must be accessible to all patients with advanced prostate cancer. 

Thank you for joining me today! To learn more, please watch the other videos in the series.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

There are no contraindications for LYNPARZA.

WARNINGS AND PRECAUTIONS

Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): Occurred in approximately 1.2% of patients with various BRCAm, gBRCAm, HRR gene-mutated or HRD-positive cancers who received LYNPARZA as a single agent or as part of a combination regimen, consistent with the approved indications, and the majority of events had a fatal outcome. The median duration of therapy in patients who developed MDS/AML was approximately 2 years (range: <6 months to >4 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.

Venous Thromboembolism (VTE): Including severe or fatal pulmonary embolism (PE) occurred in patients treated with LYNPARZA. In the combined data of two randomized, placebo-controlled clinical studies (PROfound and PROpel) in patients with metastatic castration-resistant prostate cancer (N=1180), VTE occurred in 8% of patients who received LYNPARZA, including pulmonary embolism in 6%. In the control arms, VTE occurred in 2.5%, including pulmonary embolism in 1.5%. 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.

Embryo-Fetal Toxicity: Based on its mechanism of action and findings in animals, LYNPARZA can cause fetal harm. Verify pregnancy status in 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.

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%).

ADVERSE REACTIONS—Metastatic Castration-Resistant Prostate Cancer in Combination with Abiraterone and Prednisone or Prednisolone

Most common adverse reactions (Grades 1-4) in ≥10% of patients who received LYNPARZA/abiraterone with a difference of ≥5% compared to placebo for PROpel were: anemia (48%), fatigue (including asthenia) (38%), nausea (30%), diarrhea (19%), decreased appetite (16%), lymphopenia (14%), dizziness (14%), and abdominal pain (13%).

Most common laboratory abnormalities (Grades 1-4) in ≥20% of patients who received LYNPARZA/abiraterone for PROpel were: decrease in hemoglobin (97%), decrease in lymphocytes (70%), decrease in platelets (23%), and decrease in absolute neutrophil count (23%).

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:

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.

BRCAm Metastatic Castration-Resistant Prostate Cancer in Combination with Abiraterone and Prednisone or Prednisolone

In combination with abiraterone and prednisone or prednisolone (abi/pred) for the treatment of adult patients with deleterious or suspected deleterious BRCA-mutated (BRCAm) metastatic castration-resistant prostate cancer (mCRPC). Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

Please see complete Prescribing Information, including Medication Guide.

References:

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2. Dess RT, Hartman HE, Mahal BA, et al. Association of Black race with prostate cancer-specific and other-cause mortality. JAMA Oncol. 2019;5(7):975-983. doi:10.1001/jamaoncol.2019.0826  
3. George DJ, Halabi S, Heath EI, et al. A prospective trial of abiraterone acetate plus prednisone in Black and White men with metastatic castrate-resistant prostate cancer. Cancer. 2021;127(16):2954-2965. doi:10.1002/cncr.33589  
4. Hwang C, Henderson NC, Chu SC, et al. Biomarker-directed therapy in Black and White men with metastatic castration-resistant prostate cancer. JAMA Netw Open. 2023;6(9):e2334208. doi:10.1001/jamanetworkopen.2023.34208   
5. George DJ, Sartor O, Miller K, 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. Clin Genitourin Cancer. 2020;18(4):284-294. doi:10.1016/j.clgc.2019.12.019  
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7. Valle LF, Nickols NG, Hausler R, et al. Actionable genomic alterations in prostate cancer among Black and White United States veterans. Oncologist. 2023;28(6):e473-e477. doi:10.1093/oncolo/oyad042   
8. Jolly C, Van Loo P. Timing somatic events in the evolution of cancer. Genome Biol. 2018;19(1):95. doi:10.1186/s13059-018-1476-3  
9. O'Connor MJ. Targeting the DNA damage response in cancer. Mol Cell. 2015;60(4):547-560. doi:10.1016/j.molcel.2015.10.040  
10. Castro E, Goh C, Olmos D, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 2013;31(14):1748-1757. doi:10.1200/JCO.2012.43.1882  
11. Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med. 2016;375(5):443-453. doi:10.1056/NEJMoa1603144  
12. Robinson D, Van Allen EM, Wu YM, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161(5):1215-1228. doi:10.1016/j.cell.2015.05.001  
13. Abida W, Armenia J, Gopalan A, et al. Prospective genomic profiling of prostate cancer across disease states reveals germline and somatic alterations that may affect clinical decision making. JCO Precis Oncol. 2017;2017:PO.17.00029. doi:10.1200/PO.17.00029  
14. Chung JH, Dewal N, Sokol E, et al. Prospective comprehensive genomic profiling of primary and metastatic prostate tumors. JCO Precis Oncol. 2019;3:PO.18.00283. doi:10.1200/PO.18.00283  
15. de Bono J, Fizazi K, Saad F, et al. Central, prospective detection of homologous recombination repair gene mutations (HRRm) in tumour tissue from >4000 men with metastatic castration-resistant prostate cancer (mCRPC) screened for the PROfound study. Presented at: ESMO; September 29, 2019; Barcelona, Spain.  
16. de Bono J, Mateo J, Fizazi K, et al. Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med. 2020;382(22):2091-2102. doi:10.1056/NEJMoa1911440   
17. Annala M, Struss WJ, Warner EW, et al. Treatment outcomes and tumor loss of heterozygosity in germline DNA repair-deficient prostate cancer. Eur Urol. 2017;72(1):34-42. doi:10.1016/j.eururo.2017.02.023  
18. Annala M, Vandekerkhove G, Khalaf D, et al. Circulating tumor DNA genomics correlate with resistance to abiraterone and enzalutamide in prostate cancer. Cancer Discov. 2018;8(4):444-457. doi:10.1158/2159-8290.CD-17-0937  
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23. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer V.1.2025. ©National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed December 11, 2024. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way. 
24. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate V.2.2025. ©National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed January 30, 2025. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way. 
25. Hage Chehade C, Jo Y, Gebrael G, et al. Trends and disparities in next-generation sequencing in metastatic prostate and urothelial cancers. JAMA Netw Open. 2024;7(7):e2423186. doi:10.1001/jamanetworkopen.2024.23186  
26. US Food & Drug Administration. FDA approves olaparib for HRR gene-mutated metastatic castration-resistant prostate cancer. Published May 20, 2020. Accessed July 9, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-olaparib-hrr-gene-mutated-metastatic-castration-resistant-prostate-cancer  
27. US Food & Drug Administration. FDA grants accelerated approval to rucaparib for BRCA-mutated metastatic castration-resistant prostate cancer. Published May 15, 2020. Accessed July 9, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-rucaparib-brca-mutated-metastatic-castration-resistant-prostate  
28. US Food & Drug Administration. FDA approves niraparib and abiraterone acetate plus prednisone for BRCA-mutated metastatic castration-resistant prostate cancer. Published August 11, 2020. Accessed July 9, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-niraparib-and-abiraterone-acetate-plus-prednisone-brca-mutated-metastatic-castration  
29. US Food & Drug Administration. FDA approves olaparib with abiraterone and prednisone (or prednisolone) for BRCA-mutated metastatic castration-resistant prostate cancer. Published May 31, 2023. Accessed July 9, 2024. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-olaparib-abiraterone-and-prednisone-or-prednisolone-brca-mutated-metastatic-castration  
30. US Food & Drug Administration. FDA approves talazoparib with enzalutamide for HRR gene-mutated metastatic castration-resistant prostate cancer. Published June 20, 2023. Accessed July 9, 2024. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-talazoparib-enzalutamide-hrr-gene-mutated-metastatic-castration-resistant-prostate   

US-97484  Last Updated 1/25