Tanya Dorff, MD1; Joelle Hamilton, MD2; Jason M. Hafron, MD3; Benjamin Lowentritt, MD, FACS4
1Department of Medical Oncology & Therapeutics Research, City of Hope, Duarte, California
2Division of Hematology and Oncology, University of Alabama, Birmingham
3Michigan Institute of Urology, West Bloomfield
4Prostate Cancer Care Program, Chesapeake Urology, Towson, Maryland
KEYWORDS:
Prostatic neoplasms; poly(ADP-ribose) polymerase inhibitors; anemia
Abstract
Background: Anemia is a common adverse event (AE) in metastatic castration-resistant prostate cancer (mCRPC). Hematologic toxicities are well documented with poly(ADP-ribose) polymerase (PARP) inhibitors as single agents or in combination with androgen receptor pathway inhibitors in patients with mCRPC.
Methods: This review proposes anemia management guidelines to minimize dose modifications and discontinua-tions, maintain quality of life, and improve disease outcomes.
Results: Across phase 3 studies of PARP inhibitors, anemia was among the most common treatment-emergent AEs and the most common treatment-emergent AE of grade 3 or higher. Management of anemia was based on severity; patients received dose interruptions or reductions when supportive care alone did not adequately control anemia. A relatively small population discontinued treatment, indicating that anemia is generally manageable. Guidelines for prostate and other cancers recommend iron, vitamin B12, and folate screening at baseline, with regular monitoring; transfusion or erythropoiesis-stimulating agents; and dose interruptions, reductions, or discontinuations to manage anemia. This article recommends reserving transfusion for grade 3 or higher (hemoglobin ≤8 g/dL) or symptomatic anemia. Dose interruptions are recommended for grade 2 or higher (hemoglobin 8-10 g/dL) anemia, with treatment resumed when hemoglobin reaches above 9 g/dL, at the same or reduced dose in grade 2 anemia or a reduced dose in grade 3 or higher anemia.
Conclusions: This guidance enables patients with mCRPC to remain on PARP inhibitor therapy for as long as they derive clinical benefit. Clinicians should be aware of the risk of anemia and associated management strate-gies as PARP inhibitor use is expected to increase for mCRPC.
Prostate cancer is one of the most commonly diagnosed cancers in men in the United States.1 Within 5 years following prostate cancer diagnosis, approximately 10% to 20% of patients experience disease progression to metastatic castration-resistant prostate cancer (mCRPC), which is associated with poor prognosis.1 Despite the variety of treatment options, including androgen receptor pathway inhibitors (ARPIs) such as abiraterone and enzalutamide, median overall survival in patients with mCRPC is less than 2 years in clinical practice.1 In addition, patients with mCRPC have often received prior treatment with radiation, and more than 90% of these patients have radiologic evidence of bone metastases, a major cause of death, disability, and decreased health-related quality of life (QOL) and a risk factor for the development of anemia as a result of decreased bone marrow function.1,2 To fully realize survival extension with the expanding list of therapeutic agents for mCRPC, optimization of supportive strategies is required.
Poly(ADP-ribose) polymerase (PARP) inhibitors are anticancer agents approved for use in patients with ovarian, breast, pancreatic, and prostate cancers. In clinical trials, PARP inhibitors have demonstrated efficacy benefits in patients with mCRPC.3-7 As these agents become more commonly prescribed at earlier phases of disease and applied over a longer period, however, adequate management of adverse events (AEs) will be required to reduce the impact on patient health-related QOL, treatment efficacy, and continuation, potentially affecting disease outcomes. Anemia poses particular challenges in the community setting, where transfusion access may be limited or present a greater burden to patients.8,9
Anemia is common among patients with mCRPC and has many causes, such as progressive bone metastasis; prior marrow-suppressing therapy, including pelvic radiation; and chemical castration.8,9 Patients are also often pretreated with chemotherapy or other anticancer therapies, of which anemia is a common AE.8,9 In multiple systematic reviews and meta-analyses, PARP inhibitors have been demonstrated to increase the risk of hematologic toxicities in prostate, breast, and other cancers, both as single agents and in combination with ARPIs.8,10-14 Although erythropoiesis-stimulating agents (ESAs), with or without granulocyte-stimulating factor support, remain an option in the setting of chemotherapy-induced anemia, their application in the setting of treatment with PARP inhibitors is less well defined.
Exploratory analyses have been conducted in mCRPC studies to determine patient characteristics potentially associated with a higher risk of anemia.15,16 More information, however, is required regarding the prediction, monitoring, and management of anemia in patients with mCRPC.
This review article aims to raise awareness of the occurrence and management of anemia during treat-ment with PARP inhibitors and to provide further practical guidance on the management of anemia in patients with mCRPC, drawing on experience from other tumor types, to allow PARP inhibitor therapy to continue for as long as patients derive clinical benefit.
Multiple clinical trials have led to regulatory approval of PARP inhibitors in patients with mCRPC (Table 1). The phase 3 TRITON3 study (ClinicalTrials.gov identifier NCT02975934) investigated rucaparib mono-therapy vs the investigator’s choice of control (docetaxel or ARPI) in patients with mCRPC with a BRCA1, BRCA2, or ATM mutation who experienced disease progression after ARPI therapy.17 The primary end point of radiographic progression-free survival (PFS) was significantly longer with rucaparib than for the control in the intention-to-treat population (median radiographic PFS for rucaparib, 10.2 months vs 6.4 months for control; hazard ratio [HR], 0.61 [95% CI, 0.47-0.80]; P < .001) and in the subgroup of participants with BRCA1/2 alterations (median radiographic PFS for rucaparib, 11.2 months vs 6.4 months for control; HR, 0.50 [95% CI, 0.36-0.69]; P < .001).
The phase 3 PROfound study (ClinicalTrials.gov identifier NCT02987543) evaluated olaparib monotherapy vs physician’s choice of abiraterone or enzalutamide in patients with mCRPC and alterations in at least 1 of 15 genes with a role in homologous recombination repair (HRR) whose disease had progressed during ARPI treatment.7 The primary end point of radio-graphic PFS in cohort A (patients with alterations in BRCA1, BRCA2, or ATM genes) was significantly longer in the olaparib arm (median radiographic PFS, 7.4 months) than in the control arm (median radiographic PFS, 3.6 months; HR, 0.34 [95% CI, 0.25-0.47]; P < .001). Improvements in overall survival with olaparib were significant (HR, 0.64 [95% CI, 0.43-0.97]; P = .02). A significant radiographic PFS benefit with olaparib was also seen in the overall population (cohorts A and B [patients with mutations in any of 12 prespecified genes with roles in HRR]); improvements in overall survival with olaparib in the overall population were greater but not statistically significant.
The combination of olaparib plus abiraterone was investigated in the first-line setting in the phase 3 PROpel study (ClinicalTrials.gov identifier NCT03732820) of patients with mCRPC.6 At primary analysis, radiographic PFS was significantly longer with olaparib plus abiraterone and prednisone or prednisolone (median radiographic PFS, 24.8 months) than it was with placebo plus abiraterone and prednisone or prednisolone (median radiographic PFS, 16.6 months; HR, 0.66 [95% CI, 0.54-0.81]; P < .001).
The phase 3 MAGNITUDE study (ClinicalTrials.gov ID NCT03748641) evaluated niraparib plus abiraterone and prednisone vs placebo plus abiraterone and prednisone in patients with mCRPC with and without HRR-associated gene alterations.5 Radiographic PFS was significantly longer with the addition of niraparib in participants with HRR-associated gene alterations (median radiographic PFS for niraparib, 16.5 months vs 13.7 months for placebo; HR, 0.73 [95% CI, 0.56-0.96]; P = .022) and participants with BRCA1/2 alterations (median radiographic PFS for niraparib, 16.6 months vs 10.9 months for placebo; HR, 0.53 [95% CI, 0.36-0.79]; P = .001). Futility analysis in participants without HRR-associated gene alterations, however, did not demonstrate clinical benefit, so further enrollment into this cohort was stopped.
TALAPRO-2 (ClinicalTrials.gov ID NCT03395197) was a phase 3 study of talazoparib plus enzalutamide vs placebo plus enzalutamide as first-line therapy in patients with mCRPC.4 At the primary analysis, radiographic PFS was significantly longer with talazoparib plus enzalutamide (median radiographic PFS not reached) than with placebo plus enzalutamide (median radiographic PFS, 21.9 months; HR, 0.63 [95% CI, 0.51-0.78]; P < .001).
The clinical trial experience of PARP inhibitors for the treatment of mCRPC does not include head-to-head trials, and crosstrial comparisons are therefore challenging, with patient populations differing with regard to biomarker status, symptomatic status according to Brief Pain Inventory–Short Form score, and line of treatment (eg, first-line vs second-line post-ARPI treatment of mCRPC). Treatments were also given as monotherapy or in combination with ARPIs. In addition, hemoglobin (Hb) entry requirements differed between studies, making direct comparisons of anemia occurrence challenging. When considered together, however, this clinical trial experience provides key information about trends and practices in the treatment of mCRPC.
In TRITON3 (rucaparib monotherapy), participants were required to have adequate organ function for at least 14 days before their first treatment dose, with adequate Hb levels defined as at least 10.0 g/dL independent of transfusion in the past 14 days (Table 1).3 In PROfound (olaparib monotherapy) and PROpel (olaparib plus abiraterone), patients were required to have normal organ and bone marrow function for at least 28 days before random assignment, with adequate Hb levels defined as at least 10.0 g/dL and no blood transfusions in the past 28 days.6,7,18 In MAGNITUDE (niraparib plus abiraterone), all participants met the screening criteria for Hb level (>9.0 g/dL).5 In TALAPRO-2 (talazoparib plus enzalutamide), patients were required to have adequate bone marrow function, including an Hb level of at least 9.0 g/dL4; at baseline, 49% of participants in the talazoparib arm had Hb lower than 10.0 g/dL.19
Across clinical trials, anemia severity was graded according to the Common Terminology Criteria for Adverse Events (Table 2). At grade 3 or higher, Common Terminology Criteria for Adverse Events indicate interventions, including transfusions, for the normalization of Hb levels.
Despite differences in study design, population, and treatment regimens, anemia was the most common treatment-emergent AE (TEAE) of grade 3 or higher reported in each clinical trial; occurrence of grade 3 or higher anemia ranged between 15.1% with olaparib plus abiraterone in PROpel and 46% with talazoparib plus enzalutamide in TALAPRO-2 (Figure 1).4-7,17
In MAGNITUDE, anemia (defined as a preferred term per the Medical Dictionary for Regulatory Activities) was the most common TEAE of any grade (occurring in 46.2% [98/212] of participants) and TEAEs of grade 3 or higher (occurring in 29.7% [63/212] of participants) in the niraparib plus abiraterone arm.5 In TALAPRO-2, the preferred term anemia was also the most common AE of any grade (occurring in 66% [262/398] of participants) and AE of grade 3 or higher (occurring in 46% [185/398] of participants) in the talazoparib plus enzalutamide arm.4
In PROpel, the grouped term anemia (comprising anemia, decreased Hb level, decreased red blood cell count, decreased hematocrit level, erythropenia, macrocytic anemia, normochromic anemia, normochromic normocytic anemia, and normocytic anemia) of grade 3 or higher was reported in 15.1% (60/398) of participants in the olaparib plus abiraterone arm vs 3.3% (13/396) of participants in the placebo plus abiraterone arm.6 In PROfound, 23% (58/256) of participants in the olaparib arm and 5% (7/130) of participants in the control arm reported the grouped term anemia of grade 3 or higher.7 In both studies, anemia was the most common all-grade TEAE in the olaparib treatment arm (46% [183/398] and 50% [127/256], respectively).
In TRITON3, the preferred term anemia and decreased Hb, both of grade 3 or higher, were reported in 24% (64/270) of participants in the rucaparib arm and 1% (1/130) of participants in the control arm.17 Any-grade anemia was the third-most common any-grade AE and was reported in 47% (126/270) of participants in the rucaparib arm and 18% (23/130) of participants in the control arm.
Data regarding the time to onset of anemia or decline in Hb levels are available for the PROfound, PROpel, and TALAPRO-2 trials (Figure 2).18,20,21 In additional safety analyses of both PROfound and PROpel, the reported time to onset was 1.9 months. The median duration of anemia was 3.9 months in PROfound and 4.2 months in PROpel. In TALAPRO-2, the median time to onset of first grade 3 or higher anemia was 3.3 months; in an analysis of Hb levels, the greatest reduction in levels was limited to the first 13 weeks of treatment.21 Together, these data highlight that the onset of anemia is most likely to occur during the initial months of PARP inhibitor treatment irrespective of line of therapy, a point that emphasizes the importance of regularly monitoring patients in the first months of treatment.
Concerning the management of anemia in the clinical trial setting, although not available during the primary analysis of MAGNITUDE, a subsequent analysis showed that 27.4% of participants in the niraparib plus abiraterone arm required transfusion support for anemia, with 16.8% of participants requiring only 1 transfusion.22 After hematologic toxicities requiring transfusion, the prescribing information for niraparib recommends resumption of niraparib treatment at a reduced dose.23 Anemia was therefore the most common cause of dose reduction of niraparib in 13.2% of patients, while only 2.4% of patients discontinued niraparib as a result of anemia.5
In the talazoparib plus enzalutamide arm of TALAPRO-2, 43.2% of participants had anemia leading to dose reduction, while 8.3% of participants discontinued talazoparib as a result of anemia.21 Overall, 39.2% of participants in the talazoparib arm required a blood transfusion, including 22% of participants who required multiple transfusions; 8.3% of participants received ESAs, 7.5% received granulocyte-stimulating factors, and 1.5% received platelet-stimulating factors. These proportions are in line with guidance from the talazoparib prescribing information, which recommends withholding talazoparib until adequate recovery from hematologic toxicity and discontinuation of treatment should the toxicity not resolve within 28 days.24
In the olaparib plus abiraterone arm of PROpel, anemia resulted in treatment interruptions in 16% of patients, dose reductions in 11% of patients, and discontinuation in 4% of participants.18 Supportive therapies for the management of anemia included blood transfusions (15.6% of participants in the olaparib plus abiraterone arm) and the use of ESAs at the discretion of the investigators, in line with local guidance (0.5% of the olaparib plus abiraterone arm). In PROfound, for most participants with anemia in the olaparib arm, anemia was similarly managed with supportive therapy (30% [78/256]), followed by dose interruptions (26% [67/256]) and dose reductions (16% [42/256]); anemia was resolved in 20% (50/256) of participants reporting the AE, whereas 8% of participants discontinued olaparib treatment as a result of anemia.20 Supportive therapies for patients reporting anemia included 66 of 127 (52%) participants receiving blood transfusions (red blood cell products and whole-blood transfusions) and 13 of 127 (10%) receiving an ESA. In addition, the prescribing information for olaparib recommends monitoring hematologic toxicities, with treatment interruption and weekly complete blood cell counts (CBCs) recommended for prolonged hematologic toxicities, followed by referral to a hematologist if the hematologic toxicity was not recovered to grade 1 or lower within 4 weeks.25
In TRITON3, rucaparib monotherapy dose interruptions or reductions were permitted for grade 3 or higher toxicities or grade 2 toxicities not adequately controlled by concomitant medications or supportive care.17 In participants with grade 3 or higher anemia, dose interruption was recommended until the event resolved to grade 2 or lower, after which dosing could resume. If grade 3 or higher anemia continued for more than 14 days despite dose interruption, treatment discontinuation was recommended. In contrast to the management process used in the study, the rucaparib prescribing information recommends dose interruption or reduction after more than 4 weeks of hematologic toxicity.
Despite the prevalence of anemia as a TEAE among clinical trials in mCRPC, the proportion of participants who discontinued treatment as a result of anemia was comparatively low (2.4%-8.3% across studies), indicating that anemia is a largely manageable AE.17,18,20-22
In the event of anemia in patients with prostate cancer, a multidisciplinary team that includes patients, caregivers, and prescribing physicians can lead to more effective management of the AE. Treatment guidelines recommend a multidisciplinary approach, including the use of CBC monitoring, nutritional supplementation, blood transfusion, ESAs, and dose interruptions or reductions.26,27
National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines) and European Society for Medical Oncology treatment guidelines both recommend regular screening and monitoring of Hb levels and iron status in patients with prostate cancer.26,27 The causes of anemia include disturbed iron homeostasis as well as deficiencies in vitamin B12 and folate; however, the latter are considered relatively rare causes of anemia in patients with cancer.26 Vitamin B12 and/or folate supplementation is recommended for patients with Hb levels of 8 g/dL to 11 g/dL and low serum B12 or folate; for patients with iron deficiency, iron repletion is recommended. In the NCCN Guidelines, iron supplementation is recommended for patients presenting with ferritin levels lower than 30 ng/mL and transferrin saturation less than 20%. Intravenous iron supplementation with erythropoietic therapy is recommended when ferritin levels are between 30 ng/mL and 500 ng/mL and transferrin saturation is less than 50%.27
In more severe cases of anemia (Table 2), blood transfusions may be required.26 Because of potential transfusion reactions, thrombotic events, and pathogen transmission associated with transfusion, European Society for Medical Oncology guidelines recommend that blood transfusions be reserved for patients with severe or symptomatic anemia.26 To preempt transfusion, guidelines recommend optimizing patients’ endogenous erythrocyte mass, minimizing blood loss, and evaluating the physiologic tolerance of anemia.
Erythropoiesis-stimulating agents have been demonstrated to increase Hb levels in patients with cancer and anemia and therefore reduce the need for blood transfusions.26,28 In a meta-analysis of QOL results in patients treated with ESAs vs control intervention, there was a statistically significant improvement in anemia-related symptoms.29 Guidelines, however, recommend stopping ESA treatment if patients do not respond within 4 to 8 weeks because evidence does not suggest improvements with dose escalation or differing ESAs. Compared with blood transfusions, ESAs present an increased risk of thrombotic events, anemia progression, and red blood cell aplasia, but they carry less risk of infection and transfusion reactions.26,30 Because of concerns raised in trials involving radiation and the use of ESAs to increase Hb levels to 12 g/dL, ESAs have been generally limited in recent years to patients with cancer who are receiving cytotoxic chemotherapy with noncurative intent.31 Therefore, safety data for the use of ESAs in combination with PARP inhibitors are limited.
In cases of more severe anemia (grade ≥3), dose interruptions or reductions are recommended to allow Hb levels to recover. In the multidisciplinary setting, discussion among the multidisciplinary team may facilitate designation of the Hb level at which to resume treatment.
Management recommendations for anemia during PARP inhibitor therapy in ovarian cancer are similar to those seen in PARP inhibitor therapy for mCRPC.32-35 In a review of clinical trial and real-world data regarding patients with ovarian cancer, the authors recommended workup investigations to exclude other causes of anemia and to consider dose interruptions in the case of lower-grade anemia symptoms or initial management (Table 3).32 For high-grade, symptomatic, or recurrent anemia, the authors recommended dose interruption when Hb levels are lower than 8 g/dL, with blood transfusions recommended when Hb levels are lower than 7 g/dL or symptomatic or when clinically significant comorbidities are present.32 Once recovered, however, patients may resume PARP inhibitor treatment at the same or a reduced dosage.
In an Italian real-world study of experience managing olaparib toxicities in patients with ovarian cancer, CBC testing was similarly recommended before treatment and every month for the first year of treatment to monitor patients, followed by regular blood tests after the first year.33 In an algorithm developed for the management of hematologic toxicities during PARP inhibitor treatment, non-pharmacologic interventions were recommended for grade 1 anemia (Table 2), including the consideration of early iron and folic acid supplementation. For anemia of grades 2 and 3, both dose interruptions and reductions were recom-mended, with olaparib treatment resuming if the toxicity resolved within 28 days.
In practical guidance for the management of side effects of rucaparib in ovarian cancer, supplementary vitamin B12 and folates were recommended as an initial measure; blood transfusions and the use of ESAs were also recommended to allow continuation of the same dose of rucaparib once iron, vitamin B12, and folate deficiencies had been excluded.34 For recurrent anemia, dose reduction or interruption should be considered.
In the American Society of Clinical Oncology guide-lines for the use of PARP inhibitors to treat ovarian cancer, the authors recommended monitoring patients who require blood transfusions for anemia symptom relief and/or Hb levels less than 8 g/dL.35 In the case of recurrent anemia, the authors recommended reducing the PARP inhibitor dose to avoid the need for multiple transfusions. For progressive anemia, patients may be offered growth factor per American Society of Clinical Oncology guidelines and physician and patient comfort levels.
Considering the evidence and discussion earlier in this review, we propose select recommendations for the management of anemia during PARP inhibitor treatment (Figure 3).
The authors recommend assessments of iron, vitamin B12, and folate levels for all patients with anemia at baseline, with the aim to reach grade 1 levels before the initiation of PARP inhibitor treatment, because deficiencies are more common in patients with prostate cancer than generally stated in the literature.26 Following this assessment, for all patients receiving PARP inhibitor therapy, the authors recommend regular blood monitoring through CBC panels every 2 to 4 weeks in the first 3 to 4 months of treatment and every 4 to 6 weeks after that. Adjustment may be required to align with the prescribing information for specific PARP inhibitors. For patients with grade 1 anemia whose Hb levels have dropped by approx-imately 2 g/dL between assessments (eg, from Hb ≤13 g/dL to ≤11 g/dL), the authors recommend increasing the frequency of CBC monitoring.
Incorporating patients into the shared decision-making process may also increase the prediction and monitoring of anemia during treatment. Informing patients of the key symptoms of anemia, including fatigue, dyspnea with exertion or altered exercise tolerance, and headache, may assist in the early detection of anemia and earlier intervention before the development of higher-grade AEs. Recording symptoms in patient diaries is an effective approach to monitoring AEs.
A proposed algorithm for the management of anemia provides recommendations based on anemia severity (Figure 3). Similar to existing management guidelines, the authors recommend reserving blood transfusion for anemia of grades 3 and 4 (where Hb ≤8 g/dL) or symptomatic or recurrent anemia of grades 2 and 3 (where Hb <9 g/dL) in need of rapid Hb improvement.26 Following transfusion, patients should be monitored weekly or every 2 weeks depending on whether the patient is frail or has cardiovascular disease or another comorbidity. Despite the inclusion of ESA use in current practice guidelines for the treatment of anemia in certain patients with cancer, the authors do not recommend concomitant use of ESAs with PARP inhibitors in patients with mCRPC because of a lack of prospective safety and efficacy data.
Dose interruption or reduction is recommended in grade 2 or higher anemia, when Hb levels are 8 g/dL to 10 g/dL; earlier dose interruption at a higher Hb level is preferable to late interruption to preempt the development of more severe anemia. Following a dose interruption, the frequency of patient monitoring may be dependent on several factors; however, a CBC panel should be conducted weekly or every 2 weeks. PARP inhibitor treatment may be resumed at the same or a reduced dose when Hb levels are higher than 9 g/dL; in the case of anemia of grade 3 or higher or a second occurrence of anemia, PARP inhibitor treatment should be resumed only at a reduced dose.
If hematologic levels do not recover after dose interruption (eg, recovery to grade ≤1 within 4 weeks) (Table 1), the authors recommend referral to a hematologist for further investigation. Additional cases requiring referral to a hematologist include trilineage cytopenia and a second occurrence of anemia. Confirmation of myelodysplastic syndrome or acute myeloid leukemia requires discontinuation of PARP inhibitor treatment.
Along with these recommendations, consideration of patient preference and comfort is key to the management of anemia. As anticancer treatments including PARP inhibitors are associated with the development of anemia, multidisciplinary teams should set realistic expectations for treatment with PARP inhibitors, and pretreatment counseling should include information about the risk for anemia requiring blood transfusion. Patients should also be made aware that proactive anemia diagnosis, management, monitoring, and prompt treatment can reduce the severity of AEs and that dose modification is not known to adversely affect disease outcomes and treatment efficacy.
With increased clinical trial experience, approvals, and use of PARP inhibitors in mCRPC, practitioners need practical guidance for managing common AEs such as anemia. Anemia generally occurs early in the course of treatment; however, appropriate management strategies allow patients to remain on treatment. Clinicians should be aware of the risk for anemia and the management strategies available as a result of the expected increased use of PARP inhibitors in treating mCRPC. The guidance provided in this review is intended to support the community in the management of anemia during PARP inhibitor treatment of mCRPC, to maintain patient health-related QOL, and to avoid unnecessary dose adjustments and interruptions to allow patients to continue treatment for as long as they receive clinical benefit.
1. Shore ND, Laliberté F, Ionescu-Ittu R, 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(8):4520-4540. doi:10.1007/s12325-021-01823-6
2. Parker C, Nilsson S, Heinrich D, et al; ALSYMPCA Investigators. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-223.
3. Abida W, Patnaik A, Campbell D, et al. Rucaparib in men with metastatic castration-resistant prostate cancer har-boring a BRCA1 or BRCA2 gene alteration. J Clin Oncol. 2020;38(32):3763-3772. doi:10.1200/JCO.20.01035
4. Agarwal N, Azad AA, Carles J, et al. Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial. Lancet. Jun 2 2023;402(10398):291-303. doi:10.1016/S0140-6736(23)01055-3
5. Chi KN, Rathkopf D, Smith MR, et al; MAGNITUDE Principal Investigators. Niraparib and abiraterone acetate for met-astatic castration-resistant prostate cancer. J Clin Oncol. 2023;41(18):3339-3351. doi:10.1200/JCO.22.016496. Clarke NW, Armstrong AJ, Thiery-Vuillemin A, et al. Abi-raterone and olaparib for metastatic castration-resistant prostate cancer. NEJM Evid. 2022;1(9):EVIDoa2200043. doi:10.1056/EVIDoa2200043
7. 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
8. Maiorano BA, De Giorgi U, Verzoni E, et al; MeetURO group. Hematological toxicity of PARP inhibitors in metastatic prostate cancer patients with mutations of BRCA or HRR genes: a systematic review and safety meta-analysis. Target Oncol. 2024;19(1):1-11. doi:10.1007/s11523-023-01016-x
9. Dai D, Han S, Li L, et al. Anemia is associated with poor outcomes of metastatic castration-resistant prostate cancer, a systematic review and meta-analysis. Am J Transl Res. 2018;10(12):3877-3886.
10. Bowling GC, Swargaloganathan P, Heintz C, et al. Hematological toxicities with PARP inhibitors in prostate cancer: a systematic review and meta-analysis of phase II/III randomized controlled trials. Cancers (Basel). 2023;15(19):4904. doi:10.3390/cancers15194904
11. Liu X, Wu K, Zheng D, et al. Efficacy and safety of PARP inhibitors in advanced or metastatic triple-negative breast cancer: a systematic review and meta-analysis. Front Oncol. 2021;11:742139. doi:10.3389/fonc.2021.742139
12. Jiang Y, Zhao J, Zhang L, et al. Evaluation of the efficacy and safety of PARP inhibitors in advanced-stage epithelial ovarian cancer. Front Oncol. 2020;10:954. doi:10.3389/fonc.2020.00954
13. Hao J, Liu Y, Zhang T, et al. Efficacy and safety of PARP inhibitors in the treatment of advanced ovarian cancer: an updated systematic review and meta-analysis of randomized controlled trials. Crit Rev Oncol Hematol. 2021;157:103145. doi:10.1016/j.critrevonc.2020.103145
14. Ruiz-Schutz VC, Gomes LM, Mariano RC, et al. Risk of fatigue and anemia in patients with advanced cancer treated with olaparib: a meta-analysis of randomized controlled trials. Crit Rev Oncol Hematol. 2019;141:163-173. doi:10.1016/j. critrevonc.2019.06.012
15. Azad AA, Wang Y, Hadigol M, et al. 1829P Exposure-safety analyses of talazoparib in combination of enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) in TALAPRO-2 trial. Ann Oncol. 2023;34(suppl2):S990. doi:10.1016/j.annonc.2023.09.2777
16. Armstrong AJ, Saad F, Oya M, et al. Association of baseline characteristics with adverse events (AEs) in the PROpel trial of olaparib (ola) plus abiraterone (abi) as first-line (1L) treatment for metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2024;42(16_suppl):e17030. doi:10.1200/JCO.2024.42.16_suppl.e17030
17. Fizazi K, Piulats JM, Reaume MN, et al; TRITON3 Investigators. Rucaparib or physician’s choice in metastatic prostate cancer. N Engl J Med. 2023;388(8):719-732. doi:10.1056/NEJMoa2214676
18. Saad F, Armstrong AJ, Oya M, et al. Tolerability of olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: further results from the phase 3 PROpel trial. Eur Urol Oncol. 2024;7(6):1394-1402. doi:10.1016/j.euo.2024.03.006
19. Messina C, Giunta EF, Signori A, et al. Combining PARP inhibitors and androgen receptor signalling inhibitors in metastatic prostate cancer: a quantitative synthesis and meta-analysis. Eur Urol Oncol. 2024;7(2):179-188. doi:10.1016/j. euo.2023.07.013
20. Roubaud G, Özgüroğlu M, Penel N, et al. Olaparib tolerability and common adverse-event management in patients with metastatic castration-resistant prostate cancer: further analyses from the PROfound study. Eur J Cancer. 2022;170:73-84. doi:10.1016/j.ejca.2022.04.016
21. Azad A, Fizazi K, Matsubara N, et al. Talazoparib (TALA) plus enzalutamide (ENZA) in metastatic castration-resistant prostate cancer (mCRPC): safety analyses from the randomized, placebo (PBO)-controlled, phase 3 TALAPRO-2 study. J Clin Oncol. 2023;41(16_suppl):5053. doi:10.1200/JCO.2023.41.16_suppl.5053
22. Chi KN, Sandhu S, Smith MR, et al. Niraparib plus abiraterone acetate with prednisone in patients with metastatic castration-resistant prostate cancer and homologous recombination repair gene alterations: second interim analysis of the randomized phase III MAGNITUDE trial. Ann Oncol. 2023;34(9):772-782. doi:10.1016/j.annonc.2023.06.009
23. Zejula. Prescribing information. GlaxoSmithKline; 2022. Accessed April 15, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/208447s026lbl.pdf
24. Talzenna. Prescribing information. Pfizer Inc; 2023. Accessed April 15, 2025. https://www.accessdata.fda.gov/drugsatf-da_docs/label/2023/211651s010lbl.pdf
25. Lynparza. Prescribing information. AstraZeneca Pharmaceuticals LP; 2020. Accessed April 15, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208558s014lbl.pdf
26. Aapro M, Beguin Y, Bokemeyer C, et al. Management of anaemia and iron deficiency in patients with cancer: ESMO Clinical Practice Guidelines. Ann Oncol. 2018;29(suppl4):iv271. doi:10.1093/annonc/mdy323
27. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for hematopoietic growth factors V1 2025. ©National Comprehensive Cancer Network, Inc. 2025. All rights reserved. Accessed April 15, 2025. To view the most recent and complete version of the guideline, go online to NCCN.org. Vol. 2025.
28. Hedenus M, Adriansson M, San Miguel J, et al; Darbepoetin Alfa 20000161 Study Group. Efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies: a randomized, double-blind, placebo-controlled study. Br J Haematol. 2003;122(3):394-403. doi:10.1046/j.1365-2141.2003.04448.x
29. Bohlius J, Tonia T, Nüesch E, et al. Effects of erythropoiesis-stimulating agents on fatigue- and anaemia-related symptoms in cancer patients: systematic review and meta-analyses of published and unpublished data. Br J Cancer. 2014;111(1):33-45. doi:10.1038/bjc.2014.171
30. Glaspy J, Crawford J, Vansteenkiste J, et al. Erythropoiesis-stimulating agents in oncology: a study-level meta-analysis of survival and other safety outcomes. Br J Cancer. 2010;102(2):301-315. doi:10.1038/sj.bjc.6605498
31. Heregger R, Greil R. Erythropoiesis-stimulating agents—benefits and harms in the treatment of anemia in cancer patients. Memo—Magazine of European Medical Oncology. 2023;16:259-262. doi:10.1007/s12254-023-00902-4
32. Friedlander M, Lee YC, Tew WP. Managing adverse effects associated with poly (ADP-ribose) polymerase inhibitors in ovarian cancer: a synthesis of clinical trial and real-world data. Am Soc Clin Oncol Educ Book. 2023;43:e390876. doi:10.1200/EDBK_390876
33. Lorusso D, Bologna A, Cecere SC, et al. Sharing real-world experiences to optimize the management of olaparib toxicities: a practical guidance from an Italian expert panel. Support Care Cancer. 2020;28(5):2435-2442. doi:10.1007/s00520-020-05320-4
34. Tookman L, Krell J, Nkolobe B, Burley L, McNeish IA. Practical guidance for the management of side effects during rucaparib therapy in a multidisciplinary UK setting. Ther Adv Med Oncol. 2020;12:1758835920921980. doi:10.1177/1758835920921980
35. Tew WP, Lacchetti C, Ellis A, et al. PARP inhibitors in the management of ovarian cancer: ASCO guideline. J Clin Oncol. 2020;38(30):3468-3493. doi:10.1200/JCO.20.01924
Published: June 23, 2025.
Conflict of Interest Disclosures: Dr Dorff has served as a consultant for Astellas, AstraZeneca, Bayer, and Janssen. Her institution has received research funding from AbbVie, Amgen, Arvinas, AstraZeneca, Hookipa, and Xencor.
Dr Hamilton served as a consultant for Astellas, Bayer, Janssen, and Pfizer; has served as a speaker for Bayer and Janssen; and has served on advisory boards for Astellas, Janssen, and Pfizer. She has received research support from Bayer and Janssen. Dr Hamilton also serves as the vice president of the ConDUC scientific committee and as a board member of the Mike Slive Foundation.
Dr Hafron has been a meeting participant or lecturer for Amgen Inc; Astellas Pharma Inc; Bayer; Blue Earth Diagnostics; Dendreon Pharmaceuticals LLC; Jans-sen Biotech Inc; Lantheus; Merck & Co Inc; Myovant Sciences Inc; Myriad Genetics Inc; Pfizer Inc; PROCEPT Biorobotics Corp; Progenics Pharmaceuticals, Inc; Tolmar Pharmaceuticals, Inc; and UroGen Pharma. He is a consultant or adviser for Astellas Pharma; Dendreon Pharmaceuticals LLC; Eli Lilly and Company; Janssen Biotech Inc; Immunis.AI; Lipella Pharmaceuticals Inc; Lynx DX, Inc; Myovant Sciences Inc; Myriad Genetics Inc; Pfizer Inc; Photocure; Promaxo, Inc; Tolmar Pharmaceuticals, Inc; and UroGen Pharma. He has been involved in scientific studies and trials for Astellas Pharma Inc, Bayer, Dendreon Pharmaceuticals LLC, Immunis.AI, Janssen Biotech Inc, Lipella Pharmaceuticals Inc, Merck & Co Inc, miR Scientific, Myovant Sciences Inc, Myriad Genetics Inc, Nucleix, and Pfizer Inc.
Dr Lowentritt has received honoraria from Astellas Pharma Inc; AstraZeneca; Bayer AG; Dendreon Pharmaceuticals LLC; Janssen Pharmaceuticals Inc; Lantheus; Pfizer Inc; and Tolmar Pharmaceuticals, Inc. He is a consultant for Astellas Pharma Inc, AstraZeneca, Bayer AG, Blue Earth Diagnostics, Dendreon Pharmaceuticals LLC, Janssen Pharmaceuticals Inc, Myovant Sciences Inc, and Pfizer Inc. Research funding was supported by Bayer AG, Blue Earth Diagnostics, Janssen Pharmaceuticals Inc, and Myovant Sciences Inc.
Funding/Support: The manuscript was sponsored by AstraZeneca. The funder was not involved in the journal’s decision to publish the manuscript.
Author Contributions: Tanya Dorff, Joelle Hamilton, Jason Hafron, and Benjamin Lowentritt each made a substantial contribution to the conception and design of the work and performed a critical review of the work for important intellectual content. All authors provided final approval of the version to be published and agree to be accountable for all aspects of the work.
Data Availability Statement: None.
Acknowledgments: Medical writing assistance was provided by Rebecca Helson, PhD, and Andrew Briggs, MA, AMICULUM Business Services Ltd, funded by Astra-Zeneca.
Supplementary Material: Supplementary material is available at Reviews in Urology online.
Citation: Dorff T, Hamilton J, Hafron JM, Lowentritt B. Anemia management during PARP inhibitor therapy for metastatic castration-resistant prostate cancer. Rev Urol. 2025;24(2):e41-e56.
Corresponding author: Tanya Dorff, MD, City of Hope, 1500 E Duarte Rd, Duarte, CA 91010 (tdorff@coh.org)