Feasibility and cost-effectiveness of genetic counselling for all patients with newly diagnosed ovarian cancer: a single-centre retrospective study.

BACKGROUND AND AIMS OF THE STUDY: Due to its importance for treatment and potential prevention in family members, germline testing for BRCA1/2 in patients with newly diagnosed ovarian cancer is decisive and considered a standard of care. Maintenance therapy with poly(ADP-ribose) polymerase (PARP) inhibitors substantially improves progression-free survival in patients with BRCA mutations and homologous recombination-deficient tumours by inducing synthetic lethality. In Switzerland, they are licensed only for these patients. Therefore, it is crucial to test patients early while they are receiving adjuvant chemotherapy. This study aimed to determine whether genetic counselling followed by homologous recombination deficiency testing is feasible for initialising maintenance therapy within eight weeks and cost-effective in daily practice in Switzerland compared to somatic tumour analysis of all patients at diagnosis. METHODS: This single-centre retrospective study included 44 patients with newly diagnosed high-grade serous ovarian cancer of a Federation of Gynaecology and Obstetrics (FIGO) stage of IIIA-IVB diagnosed between 12/2020 and 12/2022. It collected the outcomes of genetic counselling, germline testing, and somatic Geneva test for homologous recombination deficiency. Delays in initiating maintenance therapy, total testing costs per patient, and progression-free survival were examined to assess feasibility and cost-effectiveness in clinical practice. RESULTS: Thirty-seven of 44 patients (84%) with newly diagnosed ovarian cancer received counselling, of which 34 (77%) were tested for germline BRCA and other homologous recombination repair gene mutations. Five (15%) BRCA and three (9%) other homologous recombination deficiency mutations were identified. Eleven of the remaining 26 patients (42%) had tumours with somatic homologous recombination deficiency. The mean time to the initiation of maintenance therapy of 5.2 weeks was not longer than in studies for market authorisation (SOLO1, PAOLA, and PRIMA). The mean testing costs per patient were 3880 Swiss Franks (CHF), compared to 5624 CHF if all patients were tested at diagnosis with the myChoice CDx test (p <0.0001). CONCLUSION: Using genetic counselling to consent patients with newly diagnosed ovarian cancer for germline testing fulfils the international gold standard. Subsequent somatic homologous recombination deficiency analysis complements testing and identifies more patients who will benefit from PARP inhibitor maintenance therapy. Contrary to previous health cost model studies, the procedure does not increase testing costs in the Swiss population and does not delay maintenance therapy. Therefore, all patients should be offered a primary germline analysis. The challenge for the future will be to ensure sufficient resources for prompt genetic counselling and germline testing.

Cost-Effectiveness Analysis of HRD Testing for Previously Treated Patients with Advanced Ovarian Cancer in Italy.

INTRODUCTION: Ovarian cancer (OC) is the eighth most common cancer among women, and homologous recombination deficiency (HRD) is present in approximately 50% of these patients. For this group, poly(ADP-ribose) polymerase (PARP) inhibitors are more likely to be effective. The aim of the study was to investigate the cost-effectiveness of HRD testing versus BRCA testing (which identifies mutations present only in 25% of patients) in Italy to optimize the treatment management, possibly with PARP inhibitors. METHODS: A cost-effectiveness partition survival model was developed to estimate the expected costs and outcomes (life years, LYs; quality-adjusted life years, QALYs) with lifetime horizon of HRD testing versus BRCA testing alone in women with high-grade serous or endometrioid advanced ovarian cancer. The option to perform the tests in sequence, that is, the BRCA test followed by the HRD test, in patients with BRCA-negative test was also considered, and the model accounted for the National Healthcare Service (NHS) perspective in Italy. The treatments represented the best available options according to the initial test results and according to PARP inhibitors available in Italy. A 3% discount rate was applied. Both deterministic and probabilistic sensitivity analyses were performed to test the robustness of the model results. RESULTS: HRD testing was shown to be a cost-effective strategy compared to BRCA testing (incremental cost-utility ratio 22,610€/QALY) and a cost-saving strategy compared to the sequence of tests. The probabilistic sensitivity analysis showed that the HRD test is cost-effective compared to BRCA testing in 98.5% of model simulations considering a willingness-to-pay threshold of 50,000€/QALY. CONCLUSION: The identification of genetic anomalies in patients with advanced OC is a costly process. Regardless, HRD upfront testing compared to BRCA testing had a cost-effective profile, allowing the efficient use of healthcare resources and better life expectancy and quality of life for patients.

Ovarian cancer has been the most lethal gynecological tumor for years. Recently, there have been notable advances due to the introduction of poly(adenosine diphosphate-ribose polymerase) (PARP) inhibitor drugs, which have significantly increased the survival rates of women affected by advanced-stage disease. At least 50% of ovarian tumors have a defect in the DNA repair mechanism, known as homologous recombination deficiency, and the mechanism of action of these drugs involves blocking the DNA repair mechanisms implemented by neoplastic cells. The identification of patients with homologous recombination deficiency through a genetic test, with consequent optimized treatment management, possibly with PARP inhibitors, resulted in better life expectancy, even when adjusted for the quality of life, than the management of patients starting from BRCA testing alone. The homologous recombination deficiency testing strategy can be considered cost-effective from the National Healthcare Service perspective in Italy. These findings provide evidence of the value of a new diagnostic option for clinicians and payers to optimize the management of women with high-grade serous or endometrioid advanced ovarian cancer.

Poor Concordance Between Cancer Antigen-125 and RECIST Assessment for Progression in Patients With Platinum-Sensitive Relapsed Ovarian Cancer on Maintenance Therapy With a Poly(ADP-ribose) Polymerase Inhibitor.

PURPOSE: Cancer antigen-125 (CA-125) is recommended by treatment guidelines and widely used to diagnose ovarian cancer recurrence. The value of CA-125 as a surrogate for disease progression (PD) and its concordance with radiologic progression are unclear, particularly for women with platinum-sensitive relapsed ovarian cancer (PSROC) who have responded to chemotherapy and treated with maintenance poly(ADP-ribose) polymerase inhibitor (PARPi). METHODS: In this pooled analysis of four randomized trials of maintenance PARPi or placebo (Study 19, SOLO2, ARIEL3, and NOVA), we extracted data on CA-125 PD as defined by Gynecologic Cancer InterGroup criteria and RECIST v1.1. We evaluated the concordance between CA-125 and RECIST PD and reported on the negative predictive value (NPV) and positive predictive value (PPV). RESULTS: Of 1,262 participants (n = 818 PARPi, n = 444 placebo), 403 (32%) had CA-125 PD, and of these, 366 had concordant RECIST PD (PPV, 91% [95% CI, 88 to 93]). However, of 859 (68%) without CA-125 PD, 382 also did not have RECIST PD (NPV, 44% [95% CI, 41 to 48]). Within the treatment arms, PPV remained high (PARPi, 91% [95% CI, 86 to 94]; placebo, 91% [95% CI, 86 to 95]) but NPV was lower on placebo (PARPi, 53% [95% CI, 49 to 57]; placebo, 25% [95% CI, 20 to 31]). Of 477 with RECIST-only PD, most (95%) had a normal CA-125 at the start of maintenance therapy and the majority (n = 304, 64%) had CA-125 that remained within normal range. Solid organ recurrence without peritoneal disease was more common in those with RECIST-only PD than in those with CA-125 and RECIST PD (36% v 24%; P < .001). CONCLUSION: In patients with PSROC treated with maintenance PARPi, almost half with RECIST PD did not have CA-125 PD, challenging current guidelines. Periodic computed tomography imaging should be considered as part of surveillance, particularly in those with a normal CA-125 at the start of maintenance therapy and on treatment.

Homologous Recombination Deficiency Testing to Inform Patient Decisions About Niraparib Maintenance Therapy for High-Grade Serous or Endometrioid Epithelial Ovarian Cancer: A Health Technology Assessment.

Background: Ovarian cancer affects the cells of the ovaries, and epithelial cancer is the most common type of malignant ovarian cancer. The homologous recombination repair pathway enables error-free repair of DNA double-strand breaks. Damage of key genes associated with this pathway leads to homologous recombination deficiency (HRD), which results in unrepaired DNA and can lead to cancer. Tumours with HRD are believed to be sensitive to treatment with poly-adenosine diphosphate (ADP)-ribose polymerase (PARP) inhibitors, such as niraparib. We conducted a health technology assessment to evaluate the clinical utility and cost-effectiveness of HRD testing to inform patient decisions about the use of niraparib maintenance therapy for patients with high-grade serous or endometrioid epithelial ovarian cancer. We also evaluated the efficacy and safety of niraparib maintenance therapy in patients with HRD or homologous recombination proficiency (HRP), the cost-effectiveness of HRD testing, the budget impact of publicly funding HRD testing, and patient preferences and values. Methods: We performed a systematic literature search of the clinical evidence. We assessed the risk of bias of each included study using the Cochrane risk-of-bias tool for randomized trials version 2, and the quality of the body of evidence according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group criteria. We performed a systematic economic literature search and conducted a cost-utility analysis with a 5-year time horizon from a public payer perspective. We also analyzed the budget impact of publicly funding HRD testing in people with ovarian cancer in Ontario. We performed a literature search for quantitative evidence of patient and provider preferences with respect to HRD testing and maintenance therapy with PARP inhibitors. To contextualize the potential value of HRD testing, we spoke with people with ovarian cancer. Results: The clinical evidence review included two studies in high-grade epithelial ovarian cancer (one in patients with newly diagnosed advanced cases and one in patients with recurrent cancer). The studies evaluated niraparib maintenance therapy compared with no maintenance therapy and used HRD testing to group patients according to HRD status. Compared to placebo, niraparib maintenance therapy improved progression-free survival in patients with newly diagnosed and recurrent ovarian cancer, and in tumours with HRD or HRP (GRADE: High), but the studies did not compare the results between the HRD and HRP groups. The frequency of adverse events was higher in the niraparib group. We identified no studies that evaluated the clinical utility of HRD testing.We conducted a primary economic evaluation to evaluate the cost-effectiveness of HRD testing for people with newly diagnosed ovarian cancer in an Ontario setting. Our analysis used a 5-year time horizon. HRD testing (for all eligible people or only for people with BRCA wild type) resulted in a lower proportion of patients receiving niraparib maintenance therapy, leading to lower costs and fewer quality-adjusted life-years (QALYs). The average total cost per patient was $131,375 for no HRD testing, $126,867 for HRD testing only in people with BRCA wild type, and $127,746 for HRD testing in all eligible people. The average total QALYs per patient were 2.087 for no HRD testing, 1.971 for HRD testing only in people with BRCA wild type, and 1.971 for HRD testing in all eligible people. Our budget impact analysis suggested that assuming a high uptake rate, publicly funding HRD testing for people with newly diagnosed ovarian cancer would lead to a total saving of $9.00 million (if HRD testing were funded for all) to $12.67 million (if HRD testing were funded for people with BRCA wild type) over the next 5 years. Publicly funding HRD testing for people with recurrent cancer would lead to a total saving of $16.31 million (if HRD testing were funded for all) to $21.67 million (if HRD testing were funded for people with BRCA wild type) over the next 5 years.We identified no studies that evaluated quantitative preferences for HRD testing. Based on two studies that evaluated patients and oncologists' preferences for maintenance therapy with a PARP inhibitor in the recurrent setting, a decrease in moderate to severe adverse events was more important for patients than an improvement in progression-free survival; however, improvement in progression-free survival was more important for oncologists. Both patients and oncologists accepted some trade-offs between efficacy and safety. The people with ovarian cancer we spoke with demonstrated a shared value for access to information, prevention of cancer recurrence, and overall survival with minimal adverse effects. This was consistent with findings from another survey in patients with ovarian cancer and at least one episode of recurrence, which suggest that patients prioritize treatment benefit over some treatment adverse events in the context of niraparib maintenance therapy. Interviewees also emphasized the importance of the patient-doctor partnership, access to local health care services, and patient education. Conclusions: In patients with newly diagnosed (advanced) or recurrent high-grade serous or endometrioid ovarian cancer, niraparib maintenance therapy improved progression-free survival compared with no maintenance therapy in tumours with HRD or HRP (GRADE: High). Because we identified no studies on the clinical utility of HRD testing, we cannot comment on how it would affect patient decisions and clinical outcomes.Over a 5-year time horizon, HRD testing for people with BRCA wild type could save $4,509 per person and lead to a loss of 0.116 QALY. The findings of our economic analyses are dependent on assumptions about the use of niraparib following HRD testing. We estimate that publicly funding HRD testing would lead to a total saving of $9 million to $12.67 million for newly diagnosed cancer, and a total saving of $16.31 million to $21.67 million for recurrent cancer over 5 years, assuming the use of niraparib maintenance therapy would be reduced following HRD testing.Patients prioritized decreasing the risk of moderate to severe adverse events of maintenance therapy with PARP inhibitors over improving progression-free survival, and oncologists prioritized improving progression-free survival over decreasing the risk of moderate to severe adverse events. However, both patients and oncologists were open to accepting certain trade-offs between treatment efficacy and toxicity. The people we interviewed, who had lived experience with ovarian cancer and genetic testing, valued the potential clinical benefits of HRD testing for themselves and their family members. They emphasized patient education as an important consideration for public funding in Ontario.

Assessment of Homologous Recombination Deficiency in Ovarian Cancer.

Accurately assessing homologous recombination deficiency (HRD) to use as a predictive biomarker is an area of intense research in ovarian cancer. Validated assays have demonstrated utility in determining maintenance therapy following platinum sensitive chemotherapy. Novel functional assays promise the potential to reflect HRD in real time and predict response to PARP inhibitors. See related articles by Pikkusaari et al., p. 3110 and Blanc-Durand et al., p. 3124.

Cost-Effectiveness Analysis of Biomarker Testing to Guide First-Line PARP Inhibitor Maintenance for Patients with Advanced Ovarian Cancer After Response to First-Line Platinum Chemotherapy in the USA.

BACKGROUND: Poly(ADP-ribose) polymerase inhibitor maintenance treatments are available for platinum-sensitive advanced ovarian cancer. Olaparib (O) is available for BRCA mutation patients or in combination with bevacizumab (O+B) for patients with homologous recombination deficiency (HRD+); niraparib (N) is available for all patients. OBJECTIVE: This study aimed to evaluate the cost effectiveness of biomarker testing and maintenance treatments (mTx) with poly(ADP-ribose) polymerase inhibitor in platinum-sensitive advanced ovarian cancer in the USA. PATIENTS AND METHODS: Ten strategies were evaluated (S1-S10), representing biomarker testing (none, BRCA or HRD), and mTx (O, O+B, N or B). PAOLA-1 data were used to build a model estimating progression-free survival (PFS), second PFS (PFS2) and overall survival for O+B. PFS was modelled through mixture cure models; PFS2 and overall survival were modelled by standard parametric models. Hazard ratios of PFS for O+B versus B, N and O were obtained from the literature to estimate PFS for B, N and O. PFS2 and OS for B, N and O were informed by PFS benefits. RESULTS: S2 (no testing, B) had the lowest cost while S10 (HRD testing, O+B for HRD+ and B for HRD-) had the highest quality-adjusted life-years (QALYs). All niraparib strategies were dominated. S2, S4 (BRCA testing, O for BRCA+ and B for BRCA-), S6 (BRCA testing, olaparib plus bevacizumab for BRCA+ and bevacizumab for BRCA-) and S10 were the non-dominated strategies with an incremental cost-effectiveness ratio of $29,095/QALY, $33,786/QALY and $52,948/QALY for S4 versus S2, S6 versus S4 and S10 versus S6, respectively. CONCLUSIONS: Homologous recombination deficiency testing followed by O+B for HRD+ and B for HRD- is a highly cost-effective strategy for patients with platinum-sensitive advanced ovarian cancer. A HRD biomarker-guided approach provides most QALYs with good economic value.

Nationwide Trends and Determinants of Germline BRCA1/2 Testing in Patients With Breast and Ovarian Cancer.

BACKGROUND: Germline genetic testing (GT) for BRCA1/2 is instrumental in identifying patients with breast and ovarian cancers who are eligible for PARP inhibitors (PARPi). Little is known about recent trends and determinants of GT since PARPi were approved for these patients. PATIENTS AND METHODS: We performed a retrospective cohort study of patients in a nationwide electronic health record (EHR)-derived oncology-specific database with the following GT eligibility criteria: breast cancer diagnosed at age ≤45 years, triple-negative breast cancer diagnosed at age ≤60 years, male breast cancer, or ovarian cancer. GT within 1 year of diagnosis was assessed and stratified by tumor type. Multivariable log-binomial regressions estimated adjusted relative risks (RRs) of GT by patient and tumor characteristics. RESULTS: Among 2,982 eligible patients with breast cancer, 56.4% underwent GT between January 2011 and March 2020, with a significant increase in GT over time (RR, 1.08; 95% CI, 1.05-1.11, for each year), independent of when PARPi were approved for BRCA1/2-mutated metastatic breast cancer in January 2018. In multivariable analyses, older age (RR, 0.93; 95% CI, 0.90-0.96, for every 5 years) and Medicare coverage (RR, 0.69; 95% CI, 0.49-0.96 vs commercial insurance) were associated with less GT. Among 5,563 eligible patients with ovarian cancer, 35.4% underwent GT between January 2011 and March 2020, with a significant increase in GT over time (RR, 1.11; 95% CI, 1.07-1.14, for each year) that accelerated after approval of PARPi for BRCA1/2-mutated, chemotherapy-refractory ovarian cancer in December 2014 (RR, 1.42; 95% CI, 1.19-1.70). Older age (RR, 0.95; 95% CI, 0.93-0.97, for every 5 years) and Black or African American race (RR, 0.80; 95% CI, 0.65-0.98 vs White race) were associated with less GT. CONCLUSIONS: GT remains underutilized nationwide among patients with breast and ovarian cancers. Although GT has increased over time, significant disparities by age, race, and insurance status persist. Additional work is needed to design, implement, and evaluate strategies to ensure that all eligible patients receive GT.

Patient Assessment and Therapy Planning Based on Homologous Recombination Repair Deficiency.

Defects in genes involved in the DNA damage response cause homologous recombination repair deficiency (HRD). HRD is found in a subgroup of cancer patients for several tumor types, and it has a clinical relevance to cancer prevention and therapies. Accumulating evidence has identified HRD as a biomarker for assessing the therapeutic response of tumor cells to poly(ADP-ribose) polymerase inhibitors and platinum-based chemotherapies. Nevertheless, the biology of HRD is complex, and its applications and the benefits of different HRD biomarker assays are controversial. This is primarily due to inconsistencies in HRD assessments and definitions (gene-level tests, genomic scars, mutational signatures, or a combination of these methods) and difficulties in assessing the contribution of each genomic event. Therefore, we aim to review the biological rationale and clinical evidence of HRD as a biomarker. This review provides a blueprint for the standardization and harmonization of HRD assessments.

Cost-effectiveness of poly-(ADP-ribose) polymerase (PARP)-inhibitors for the maintenance treatment after responding to first- and second-line chemotherapy in advanced ovarian cancer.

The introduction of inhibitors of poly-(ADP-ribose) polymerase (PARP) for the treatment of women with epithelial ovarian cancers (EOC) has radically changed the treatment in maintenance setting after responding to first- and second-line chemotherapy. The aim of this paper was to assess the pharmacological costs of PARP inhibitors (olaparib, niraparib, rucaparib and veliparib) in maintenance treatment after responding to first-line chemotherapy in EOC. Incremental cost-effectiveness ratio (ICER) was calculated as the ratio between the difference of the costs in the intervention and in the control groups (pharmacy costs) and the difference between the effect in the intervention and in the control groups (progression-free survival (PFS)). We have considered the pivotal phase III randomized controlled trials (RCTs). Three different populations were considered: the overall population, patients with germline BRCA mutation (gBRCA) and homologous recombination deficiency (HRD) patients non-gBRCA mutation. Three thousand four hundred and twenty patients and 1209 patients were considered in maintenance treatment after responding to first- and second-line chemotherapy in EOC, respectively. At the actual price, the treatment with PARP inhibitors is not cost-effective in maintenance treatment after responding to first-line and second-line chemotherapy in EOC. A reduction in pharmacological costs is mandatory.

Quantifying the Value of the Molecular Tumor Board: Discordance Recommendation Rate and Drug Cost Avoidance.

PURPOSE: Molecular tumor boards (MTBs) provide interventions that assist the patient's primary oncologist's interpretation and application of precision oncology and avoid clinical and financial toxicities of prescribing inappropriate targeted therapy. In this article, we describe a novel method for illustrating MTBs value and recommendation discordance rate and report associated drug cost avoidance data. METHODS: From January 1, 2021, to December 31, 2021, patients assessed by our program's MTB were retrospectively evaluated. Recommendation discordance was defined as any disagreement between MTB therapeutic recommendations and those provided in the next-generation sequencing vendor's report. RESULTS: In 2021, our program processed 1,119 next-generation sequencing orders via external vendors for 1,029 unique patients with a variety of solid tumor and hematologic malignancies. During this period, 962 patients were reviewed through our MTB process. MTB recommendation discordance rate was high (229 of 502; 45.6%) and varied across test vendors. Rationales for discordance included the following: low level of evidence (88% of patients), alternative standard of care available (60%), and tolerability concerns (42%), among others. Discordance was highest for Vendor C (30%), followed by Vendor A (24%) and Vendor B (8%). The most common drug classes not supported were mTOR, PARP, MEK, and PIK3CA inhibitors when recommended by vendors in off-label settings. MTB interventions accounted for $3,209,070 in US dollars in potential drug cost avoidance. CONCLUSION: Therapeutic recommendation discordance rates can provide quantitative insight into the benefit of MTB. Discordance-associated drug cost avoidance further demonstrates MTB's financial value. These measures may be used as part of the justification for this service line within a cancer care program.

Preclinical Assessment of the Combination of PSMA-Targeting Radionuclide Therapy with PARP Inhibitors for Prostate Cancer Treatment.

Prostate specific membrane antigen targeted radionuclide therapy (PSMA-TRT) is a promising novel treatment for prostate cancer (PCa) patients. However, PSMA-TRT cannot be used for curative intent yet, thus additional research on how to improve the therapeutic efficacy is warranted. A potential way of achieving this, is combining TRT with poly ADP-ribosylation inhibitors (PARPi), which has shown promising results for TRT of neuroendocrine tumor cells. Currently, several clinical trials have been initiated for this combination for PCa, however so far, no evidence of synergism is available for PCa. Therefore, we evaluated the combination of PSMA-TRT with three classes of PARPi in preclinical PCa models. In vitro viability and survival assays were performed using PSMA-expressing PCa cell lines PC3-PIP and LNCaP to assess the effect of increasing concentrations of PARPi veliparib, olaparib or talazoparib in combination with PSMA-TRT compared to single PARPi treatment. Next, DNA damage analyses were performed by quantifying the number of DNA breaks by immunofluorescent stainings. Lastly, the potential of the combination treatments was studied in vivo in mice bearing PC3-PIP xenografts. Our results show that combining PSMA-TRT with PARPi did not synergistically affect the in vitro clonogenic survival or cell viability. DNA-damage analysis revealed only a significant increase in DNA breaks when combining PSMA-TRT with veliparib and not in the other combination treatments. Moreover, PSMA-TRT with PARPi treatment did not improve tumor control compared to PSMA-TRT monotherapy. Overall, the data presented do not support the assumption that combining PSMA-TRT with PARPi leads to a synergistic antitumor effect in PCa. These results underline that extensive preclinical research using various PCa models is imperative to validate the applicability of the combination strategy for PCa, as it is for other cancer types.

Olaparib en mantenimiento de cáncer de ovario epitelial / Olaparib in cancer maintenance ovarian epithelial

INTRODUCCIÓN: En mujeres las neoplasias malignas de origen epitelial ovárico, de las trompas de Falopio y el peritoneo presentan características clínicas y comportamiento similares.1 Debido a esto, suelen combinarse estas entidades y se definen conjuntamente como cáncer de ovario epitelial (COE). El cáncer de ovario seroso de alto grado (COSAG) representa aproximadamente entre el 75% y 90% de todos los COE. Aproximadamente el 17% de los cánceres de ovario son atribuibles a mutaciones germinales deletéreas de los genes BRCA 1 y 2 (gBRCAm). A su vez, se presentan mutaciones somáticas de estos genes hasta en un 7%, y hasta un 50% muestran deficiencia de la recombinación homóloga que afecta los mecanismos de reparación y replicación del ADN. Los síntomas más comunes de la patología son molestias gastrointestinales y ascitis, aunque también pueden presentarse otros síntomas al inicio de la patología como la distención abdominal, dolor abdominal o pélvico, y fatiga. Debido a que los síntomas suelen aparecer tardíamente o ser atribuidos a otras enfermedades, aproximadamente el 75% de los COE son diagnosticados en estadios avanzados (III y IV), siendo en estos casos la sobrevida a 5 años del diagnóstico de aproximadamente 46%. OBJETIVO: El objetivo del presente informe será evaluar la eficacia, seguridad y el impacto presupuestario de olaparib como terapia de mantenimiento en pacientes con cáncer de ovario epitelia. METODOLOGÍA: Se buscó en los sitios públicos de Pubmed, LILACS, BRISA/REDETSA-, CRD (del inglés, Centre for Reviews and Dissemination- University of York), Cochrane; en "buscadores genéricos de internet" y sociedades científicas. En lo que respecta a agencias de ETS, se buscó́ en: Base de datos internacional para las ETS de INHATA (su sigla del inglés, International Network of Agencies for Health Technology Assessment), Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA), NICE (del inglés, National Institute for Health and Clinical Excellence) del Reino Unido; PBAC (del inglés, The Pharmaceutical Benefits Advisory Committee) de Australia; CADTH (del inglés, Canadian Agency for Drugs and Technologies in Health) de Canadá y CONITEC (del portugués, Comissão Nacional de Incorporação de Tecnologías no SUS) de Brasil. RESULTADOS: Con la estrategia de búsqueda mencionada, se identificaron tres ensayos clínicos controlados y aleatorizados (siete registros) y tres revisiones sistemáticas (RS) que evaluaron la efectividad de olaparib en cáncer de ovario. También fueron incluidos cinco informes de evaluación de tecnologías sanitarias (ETS), tres guías de práctica clínica (GPC), 12 políticas de cobertura y siete evaluaciones económicas. CONCLUSIONES: En pacientes con COE avanzado seroso o endometroide de alto grado con respuesta completa o parcial tras una primera línea de quimioterapia en base a platino, y sean portadoras de mutaciones en los genes BRCA 1/2, evidencia de moderada calidad sugiere que olaparib como terapia de mantenimiento frente al cuidado estándar no modificaría la sobrevida global o la calidad de vida, mientras que evidencia de alta calidad muestra que produce un beneficio mayor en la sobrevida libre de progresión. Su utilización también produciría una mayor cantidad de efectos adversos severos y graves. En mujeres recaídas cuya enfermedad se haya manifestado como sensible a la quimioterapia en base a platino, evidencia de alta calidad muestra que olaparib como terapia de mantenimiento, genera un impacto mayor en la sobrevida global y libre de progresión con una mayor cantidad de efectos adversos severos y graves, respecto al estándar de cuidado. Los beneficios clínicos parecen estar limitados aquellas pacientes portadoras de mutaciones deletéreas en los genes BRCA 1/2. Evidencia de muy baja calidad proveniente de comparaciones indirectas, no permite concluir sobre la eficacia y seguridad comparativa de olaparib frente a niraparib. No se hallaron evaluaciones económicas para nuestro país o Latinoamérica. Estudios realizados para Singapur y Estados Unidos mostraron que la tecnología es costoefectiva tras la primera línea de tratamiento, pero no en el tratamiento de pacientes platino sensible recurrentes. Dos análisis de impacto presupuestario realizados en España y Estados Unidos sugieren que el impacto de la tecnología seria moderado. Para Argentina el impacto presupuestario estimado fue alto para la implementación de olaparib como terapia de mantenimiento luego de la primera línea de quimioterapia, al igual que en pacientes platino sensibles recaídas. Guías de práctica clínica de Argentina, Estados Unidos y la Red Nacional Integral del Cáncer recomiendan el uso de olaparib como terapia de mantenimiento tanto en pacientes platino sensible recurrentes como tras una primera línea de tratamiento. De las políticas de cobertura relevadas Alemania, Estados Unidos, Francia y el Reino Unido cubren olaparib como terapia de mantenimiento luego de la primera línea de tratamiento, mientras que países como Argentina, Australia, Brasil, Canadá, Chile, Colombia y Uruguay no mencionan su cobertura. En el caso de pacientes platino sensible, Brasil, Canadá y Francia contemplan su cobertura en pacientes con mutación BRCA, mientras que Estados Unidos y Reino Unido consideran su cobertura sin discriminar el estado de la mutación.

Monitoramento do horizonte tecnológico: Medicamentos para tratamento de primeira linha do câncer de próstata metastático resistente à castração / Monitoring the technology horizon: Drugs for first-line treatment of metastatic castration-resistant prostate cancer

A DOENÇA: O câncer de próstata (CP) é uma doença heterogênea com diversos subtipos, que acomete a glândula próstata. A função dessa glândula é a produção do líquido prostático e do líquido seminal, que juntos são capazes de nutrir os espermatozoides e auxiliá-los na sua mobilidade. No adulto jovem a próstata possui o tamanho aproximado de uma ameixa, e pode de modo fisiológico aumentar de tamanho, de acordo com o envelhecimento. Na maioria dos casos o CP apresenta evolução silenciosa, podendo não apresentar sinais e sintomas em sua fase inicial. Entretanto, as manifestações clínicas mais comuns são: dificuldade de urinar, demora em iniciar ou finalizar o jato urinário, diminuição do jato urinário, necessidade de urinar mais vezes durante o dia ou a noite e presença de sangue na urina. Como esses sinais e sintomas são inespecíficos é necessário a avaliação médica para fins de diagnóstico diferencial. TRATAMENTOS SISTÊMICOS DE PRIMEIRA LINHA DISPONÍVEIS: As Diretrizes Diagnósticas e Terapêuticas (DDT) do adenocarcinoma de próstata, publicadas em 2016, estão em processo de atualização no momento. Para pacientes assintomáticos ou pouco sintomáticos é recomendado como tratamento de primeira linha a utilização de novos agentes inibidores do eixo de sinalização androgênica, preferencialmente, abiraterona ou enzalutamida (nível de evidência 1 e força de recomendação A). Para pacientes sintomáticos é recomendado como tratamento de primeira linha a quimioterapia com docetaxel e o radiofármaco Radium-223 (nível de evidência 1 e força de recomendação A). ESTRATÉGIA DE BUSCA: Os medicamentos em fase de desenvolvimento para o tratamento de primeira linha de pacientes com câncer de próstata metastático

Eficacia y seguridad de olaparib como terapia de mantenimiento en pacientes con cáncer de ovario, de trompas de falopio, o peritoneal primario, recurrente, sensible a la quimioterapia basada en platino / Efficacy and safety of olaparib as maintenance therapy in patients with primary, recurrent ovarian, fallopian tube, or peritoneal cancer sensitive to platinum-based chemotherapy

ANTECEDENTES: En el marco de la metodología ad hoc para evaluar solicitudes de tecnologías sanitarias, aprobada mediante Resolución de Instituto de Evaluación de Tecnologías en Salud e Investigación N° 111-IETSI-ESSALUD-2021, se ha elaborado el presente dictamen, el que expone la evaluación de la eficacia y seguridad de olaparib como terapia de mantenimiento en pacientes con cáncer de ovario, de trompas de Falopio, o peritoneal primario, recurrente, sensible a la quimioterapia basada en platino. Así, el Dr. Miguel Ángel Ticona Castro, médico especialista en oncología del Servicio de Oncología del Hospital Nacional Edgardo Rebagliati Martins de la Red Prestacional Rebagliati, siguiendo la Directiva N° 003-IETSI-ESSALUD-2016, envió al Instituto de Evaluación de Tecnologías en Salud e Investigación ­ IETSI la solicitud de uso por fuera del petitorio del producto farmacéutico olaparib. ASPECTOS GENERALES: En el 2019, en Perú se diagnosticaron aproximadamente 1237 nuevos casos de cáncer de ovario, con 771 muertes atribuidas a la enfermedad (Institute for Health Metrics and Evaluation 2022). El cáncer de ovario epitelial seroso es la histología que se encuentra con más frecuencia en los cánceres de ovario avanzados, y entre 20 % y 30 % de los cánceres de ovario serosos de alto grado tienen la mutación del gen del cáncer de mama 1 o 2 (BRCA 1/2). El tratamiento estándar para el cáncer de ovario, de trompas de Falopio, o peritoneal primario (en lo sucesivo denominados colectivamente como cáncer de ovario) incluye la cirugía y la quimioterapia basada en platino. A pesar de las altas tasas de respuesta esperadas (75 % al 85 %), la recurrencia es probable en la mayoría de las mujeres. Si esta recurrencia ocurre seis meses o más después de la última quimioterapia basada en platino, los pacientes se clasifican como sensibles al platino. Tras la respuesta a la quimioterapia basada en platino, la estrategia de tratamiento estándar actual a nivel internacional es "observar y esperar" si se vuelve a dar una progresión de la enfermedad (CADTH 2017; Ray-coquard et al. 2020). METODOLOGÍA: Se realizó una búsqueda sistemática utilizando las bases de datos PubMed, Cochrane Library y LILACS. Además, se realizó una búsqueda dentro de bases de datos pertenecientes a grupos que realizan evaluaciones de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC), incluyendo el Scottish Medicines Consortium (SMC), el National Institute for Health and Care Excellence (NICE), la Canadian Agency for Drugs and Technologies in Health (CADTH), la Haute Autorité de Santé (HAS), el Institute for Quality and Efficiency in Health Care (IQWiG), el Instituto de Evaluación Tecnológica en Salud de Colombia (IETS), la Comissáo Nacional de Incorporacáo de Tecnologias no Sistema Único de Saúde (CONITEC), entre otros. Asimismo, se revisó la Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA) y páginas web de sociedades especializadas en el manejo del cáncer como la National Comprehensive Cancer Network (NCCN), la European Society for Medical Oncology (ESMO), la American Society of Clinical Oncology (ASCO), y la Sociedad Española de Oncología Médica (SEOM). Adicionalmente, se hizo una búsqueda en las páginas web del registro de ensayos clínicos administrado por la Biblioteca Nacional de Medicina de los Estados Unidos (https://clinicaltrials.gov/) y de la International Clinical Trial Registry Platform (ICTRP) (https://apps.who.int/trialsearch/), para identificar ensayos clínicos en curso o cuyos resultados no hayan sido publicados. La búsqueda de literatura se limitó a GPC, ETS, revisiones sistemáticas con metaanálisis de ensayos clínicos aleatorizados (ECA) y ECA que abordaran la pregunta PICO del presente dictamen. Se incluyeron las publicaciones en inglés y español. Se excluyeron los ensayos clínicos no aleatorizados, los estudios observacionales, las series de casos, los reportes de casos, las cartas al editor, los comentarios, las editoriales y los resúmenes de congresos. Teniendo en cuenta que los datos finales de los estudios SOLO2 y Studyl9 (estudios pivotales de olaparib en cáncer de ovario recurrente) se publicaron recientemente, en marzo de 2021 y octubre de 2018, respectivamente, solo se incluyeron las revisiones sistemáticas con meta-análisis si incluían los datos finales de ambos estudios. En cuanto a las GPC, se priorizaron aquellas que utilizaron sistemas de gradación para el nivel de evidencia y el grado de las recomendaciones brindadas. RESULTADOS: La búsqueda de literatura permitió identificar 13 publicaciones que aportan información de relevancia para fines de la presente actualización: cuatro GPC realizadas por la NCCN (NCCN 2022), la SEOM (Redondo et al. 2021), la ASCO (Tew et al. 2020), y la ESMO (ESMO 2020); cinco ETS elaboradas por el NICE de Inglaterra y Gales (NICE 2020), el IQWiG de Alemania (IQWiG 2018), la CADTH de Canadá (CADTH 2017), el SMC de Escocia (SMC 2016), y la HAS de Francia (HAS 2015); y cuatro publicaciones de ECA: dos publicaciones del ECA de fase II Studyl9 (Ledermann et al. 2012; Friedlander et al. 2018) y dos publicaciones del ECA de fase III SOLO2 (Pujade-lauraine et al. 2017; Poveda et al. 2021). CONCLUSIÓN: Por todo lo expuesto, el IETSI no aprueba el uso de olaparib como terapia de mantenimiento para pacientes con cáncer de ovario, con o sin mutación BRCA, recurrente, sensible a la quimioterapia basada en platino, que hayan recibido al menos 2 líneas previas de quimioterapia basada en platino, con respuesta completa o parcial a su régimen más reciente.

Olaparib as first line in BRCA-mutated advanced ovarian carcinoma: Is it cost-effective in Spain?

OBJECTIVE: To estimate the cost-effectiveness of olaparib after being funded by the Spanish National Health Service (SNHS) as first-line monotherapy maintenance treatment in patients with advanced high-grade serous ovarian carcinoma (HGSOC) and BRCA mutations in Spain. METHODS: A semi-Markov model with one-month cycles was adapted to the Spanish healthcare setting, using the perspective of the SNHS, and a time horizon of 50 years. Two scenarios were compared: receiving olaparib vs. no maintenance treatment. The model comprised four health states and included the clinical results of the SOLO1 study, along with the direct healthcare costs associated with the use of first-line and subsequent treatment resources (2020 €). A discount rate of 3% was applied for future cost and quality-of-life outcomes. A probabilistic sensitivity analysis (PSA) was also carried out and a cost-effectiveness threshold of €25,000 per quality adjusted life year (QALY) was considered. RESULTS: The introduction of olaparib as a first-line maintenance treatment for advanced HGSOC patients with BRCA mutations implied a cost of €131,614.98 compared to €102,369.54 without olaparib (difference: €29,245.44), with an improvement of 2.00 QALYs (5.56 and 3.57, respectively). Therefore, olaparib is cost-effective for advanced HGSOC patients with BRCA mutations, with an incremental cost-effectiveness ratio of €14,653.2/QALY. The results from the PSA showed that 92.1% of the simulations fell below the €25,000/QALY threshold. The model showed that olaparib could improve the overall survival by 2 years, vs. no maintenance treatment. CONCLUSIONS: Olaparib as first-line maintenance treatment is cost-effective in advanced HGSOC patients with BRCA mutations in Spain.

Patients' and oncologists' preferences for second-line maintenance PARP inhibitor therapy in epithelial ovarian cancer.

Aim: To understand the preferences of US patients and oncologists for PARP inhibitors as second-line maintenance (2LM) for epithelial ovarian cancer. Methods: A discrete choice experiment was conducted to assess the preferences of treatment attributes. Results: The most valued attributes were risk of grade 3/4 adverse events (AEs; patients, n = 204) and progression-free survival (PFS; oncologists, n = 151). To accept a 37% increased risk of grade 3/4 AEs, PFS would need to increase by 27.9 months (patients) and 6.3 months (oncologists). The least valued attributes were dosing form/frequency (patients) and grade 3/4 anemia risk (oncologists). Conclusion: Patients' and oncologists' willingness to make benefit-risk trade-offs in the 2LM setting suggests that the PFS gains observed in selected studies of poly (ADP-ribose) polymerase inhibitors in BRCA-mutated disease are worth the toxicity risk.

Plain language summary Maintenance therapy is a treatment option intended to keep ovarian cancer from coming back or getting worse for as long as possible after responding to chemotherapy. PARP inhibitors are a new type of maintenance therapy for ovarian cancer. This study aimed to understand the patients' and physicians' preferences for the benefits and risks associated with different PARP inhibitors used as maintenance therapy for ovarian cancer. Participants were asked to compare various treatment options based on their different safety profiles, effectiveness and form of medication (e.g., three capsules by mouth once a day versus two tablets by mouth twice a day), and then choose the treatment they most preferred. Through this exercise, the treatment features that mattered most to patients and physicians were identified. The most important treatment feature for patients was decreasing the chance of experiencing a serious side effect that requires medical intervention or hospitalization. In contrast, physicians valued lengthening the time that a cancer remains stable and does not worsen. To accept a 37% higher chance of experiencing a side effect that requires medical intervention or hospitalization, patients expect their cancer to remain stable and not worsen for an additional 28 months. This was a large difference from the 6 months that the physicians would consider as acceptable. The least important treatment features for patients are the amount of pills required per dose, the form of the given medication (e.g., tablet vs capsule) and the schedule of taking the treatment. On the other hand, physicians were least concerned about lowering the risk of experiencing low blood counts that, requiring medical intervention.

Monitoramento do horizonte tecnológico: Medicamentos em desenvolvimento para tratamento do câncer de mama triplo negativo localmente avançado irressecável ou metastático / Monitoring the technological horizon: Drugs in development for the treatment of unresectable or metastatic locally advanced triple negative breast cancer

A DOENÇA: O câncer de mama triplo negativo (CMTN) é definido pela ausência da expressão dos receptores de estrogênio (RE), receptores de progesterona (RP) e receptores do fator de crescimento epidermal humano (HER2 ­ human epidermal growth factor receptor 2), que são marcadores presentes na maioria dos tipos de câncer de mama e utilizados para a definição do tratamento. Em média, entre os casos de câncer de mama, 15 a 20% são definidos como CMTN e mais de 30% desses casos progridem para doença metastática. Diferente dos outros tipos de câncer de mama, sua frequência é maior entre mulheres jovens abaixo de 50 anos, com maior prevalência entre aquelas com 35 anos. Os pacientes com CMTN apresentam geralmente tumores em graus mais avançados e desfechos clínicos ruins em termos de sobrevida global e sobrevida livre de doença. As curvas de sobrevida no CMTN, diferentes de outros subtipos de câncer de mama, são caracterizadas por um aumento na recidiva e uma diminuição na sobrevida durante os primeiros três a cinco anos após o diagnóstico. Apesar de avanços substanciais nos resultados clínicos de novos tratamentos para o câncer de mama nos últimos anos, o subtipo de CMTN permanece uma área com necessidade clínica ainda não atendida. Como não apresentam expressão de RE, RP e HER2, os tratamentos com hormonioterapia e terapia anti-HER2 não estão indicados para esses pacientes, sendo adotada a estratégia de quimioterapia, além da cirurgia e radioterapia, conforme preconizado nas Diretrizes Diagnósticas e Terapêuticas do Carcinoma de Mama. TRATAMENTO DISPONÍVEL: As Diretrizes Diagnósticas e Terapêuticas do Carcinoma de Mama de 2019 não fazem recomendação específica para o tratamento dos pacientes com CMTN. Entretanto, entre os medicamentos utilizados para o tratamento dos tipos de câncer de mama é relatado que a associação do bevacizumabe ao paclitaxel nos pacientes com CMTN proporciona um aumento na taxa de resposta e na sobrevida livre de progressão de doença sem alterar a sobrevida mediana global. De acordo com as Diretrizes de Tratamentos Oncológicos recomendados pela Sociedade Brasileira de Oncologia Clínica (SBOC) de 2021 para o câncer de mama metastático, os pacientes com CMTN devem ser tratados com quimioterapia. O regime deve ser individualizado com base no tamanho, localização e características do tumor; e sintomas e preferências do paciente. Além disso, devem ser considerados a resposta e o intervalo sem progressão com os tratamentos anteriores. Os taxanos e antracíclicos são os medicamentos do tratamento padrão tanto em (neo) adjuvância como na primeira linha de doença metastática. A doxorrubicina e a epirrubicina são os antracíclicos mais comumente usados no tratamento do câncer de mama. A escolha entre os taxanos é determinada pelo tratamento prévio, podendo-se escolher entre o paclitaxel e o docetaxel, de acordo com o perfil de toxicidade e preferência do paciente. No caso de pacientes refratários a antracíclicos e taxanos, existe uma série de opções de tratamentos quimioterápicos, que podem ser utilizados em monoterapia e associados. Os principais medicamentos utilizados em monoterapia são: capecitabina, eribulina, vinorelbine e gemcitabina. As terapias com medicamentos associados mais comumente utilizados são paclitaxel com gencitabina, docetaxel com capecitabina e combinações com platinas6 . Além desses, a adição de bevacizumabe à quimioterapia, em primeira ou segunda linha, resultou em aumento modesto de resposta objetiva e sobrevida livre de progressão, sem aumento de sobrevida global. ESTRATÉGIA DE BUSCA: Os medicamentos em fase de pesquisa clínica para câncer de mama triplo negativo foram identificados, inicialmente, na base de pesquisa clínica Clinicatrials.gov em 19 de abril de 2021, com filtros para estudo de intervenção, em fase 3 de ensaio clínico e em andamento. Foram excluídos da análise os estudos cuja situação estava desatualizada a mais de um ano na base e os estudos cujo objetivo da tecnologia era atuar como adjuvante ou neoadjuvante. Além disso, foram consultados as bases eletrônicas MEDLINE (via PubMed) e EMBASE (via Periódicos Capes) em 19 de abril de 2021; e Cortellis15, da Clarivate Analytics, em 28 de abril de 2021, utilizando o termo "advanced triple negative breast cancer" e seus sinônimos, com filtro para tecnologias em desenvolvimento na fase 3 de ensaio clínico. TECNOLOGIAS EM DESENVOLVIMENTO: Foram identificados 55 ensaios clínicos de fase 3, com 10 tecnologias em desenvolvimento para a indicação estudada e que foram elegíveis para compor este informe20: sacituzumabe govitecan, olaparibe, carelizumabe, pembrolizumabe, toripalimabe, TQB2450, alpelisibe, capivasertibe, ipatasertibe, e bicalutamida. O quadro 1 apresenta essas tecnologias consideradas com informações sobre sua classe terapêutica e situação regulatória nas agências sanitárias FDA, EMA, Health Canada e Anvisa. Algumas tecnologias estão em estágios iniciais do ensaio clínico de fase 3 sem resultados parciais publicados, entretanto, suas características serão descritas nesta seção. São eles: carelizumabe, toripalimabe, TQB2450, alpelisibe, capivasertibe e bicalutamida. CONSIDERAÇÕES FINAIS: O câncer de mama triplo negativo localmente avançado irressecável ou metastático é uma doença heterogênea com um prognóstico ruim e atualmente com poucas opções de tratamento em uso. A aprovação do medicamento atezolizumabe no Brasil, para uso em combinação com nab-paclitaxel trouxe um avanço para o tratamento alvo-direcionado para essa população. Este informe apresentou o panorama das tecnologias mais promissoras em fase de desenvolvimento clínico para a doença. Algumas em vias de administração com maior comodidade posológica, como a via oral (olaparibe, alpelisibe, capivasertibe, ipatasertibe e bicalutamida). A identificação dessas tecnologias neste informe projeta uma expectativa sobre diferentes vias moleculares de combate a doença que podem impactar no prognóstico dos pacientes com câncer de mama triplo negativo localmente avançado irressecável ou metastático. Algumas dessas tecnologias estão em fases finais de pesquisa clínica com resultados publicados e já são autorizadas ou iniciaram seus pedidos nas agências sanitárias internacionais. Entre elas destacam-se o sacituzumabe govitecan e o pembrolizumabe, ambas com autorização de comercialização recente pela agência sanitária dos EUA para a indicação de CMTN. Mesmo sendo essa autorização em um contexto de aprovação acelerada, que necessita de acompanhamento dos resultados dos estudos em andamento, existe um avanço para o tratamento da doença que hoje ainda é considerada com uma necessidade não atendida. O sacituzumabe govitecan obteve bons resultados para os desfechos de sobrevida livre de progressão, sobrevida global e taxa de resposta objetiva. Os resultados com pembrolizumabe, apesar de não indicarem uma diferença grande em relação ao comparador nos desfechos de sobrevida livre de progressão, se mostraram consistentes ao longo do tempo e foram maiores conforme o aumento da expressão de PD-1, indicando que pode existir uma relação direta com esse marcador. As tecnologias em desenvolvimento identificadas estão direcionadas a alvos moleculares específicos do desenvolvimento da doença, de modo que a definição dos subtipos moleculares é essencial para o planejamento das estratégias de tratamento, que cada vez mais serão baseadas em medicina personalizada, como por exemplo, a quantificação da expressão do PD-1 como biomarcador preditivo de benefício para a escolha dos pacientes que devem fazer imunoterapia. Espera-se que a conclusão dos estudos em andamento possa trazer resultados clínicos robustos que possam aumentar as opções terapêuticas do tratamento e assim representar um melhor prognóstico da doença.

BRCA Mutations in Prostate Cancer: Assessment, Implications and Treatment Considerations.

Prostate cancer ranks fifth in cancer-related mortality in men worldwide. DNA damage is implicated in cancer and DNA damage response (DDR) pathways are in place against this to maintain genomic stability. Impaired DDR pathways play a role in prostate carcinogenesis and germline or somatic mutations in DDR genes have been found in both primary and metastatic prostate cancer. Among these, BRCA mutations have been found to be especially clinically relevant with a role for germline or somatic testing. Prostate cancer with DDR defects may be sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors which target proteins in a process called PARylation. Initially they were used to target BRCA-mutated tumor cells in a process of synthetic lethality. However, recent studies have found potential for PARP inhibitors in a variety of other genetic settings. In this review, we explore the mechanisms of DNA repair, potential for genomic analysis of prostate cancer and therapeutics of PARP inhibitors along with their safety profile.