Abiraterone + olaparib in metastatic castration-resistant prostate cancer: tolerable, not toxic
PROpel was a randomised phase III trial comparing olaparib, a poly [adenosine diphosphate (ADP)-ribose] polymerase inhibitor (PARPi), plus abiraterone with placebo plus abiraterone in first-line metastatic castration-resistant prostate cancer (mCRPC) (1). The primary endpoint was reached, with a statistically significant increase in radiographic progression-free survival (rPFS) and numerical increase in overall survival (OS) in patients unselected for homologous recombination repair mutation (HRRm) status (1,2). Based on this data, olaparib and abiraterone received approval from the European Medicines Agency (EMA) in unselected mCRPC patients and from the Food and Drug Administration (FDA) in patients with BRCA-mutated mCRPC. Subsequent to the findings from PROpel, the randomised phase III TALAPRO-2 (3,4) and MAGNITUDE trials (5) led to FDA and EMA approval of talazoparib plus enzalutamide in HRRm-mCRPC and niraparib plus abiraterone in BRCA-mutated mCRPC as well.
Despite the positive results from these trials, concerns have been raised about the toxicity of PARPi, particularly in patients without HRRm who derive less benefit from the combination of an androgen receptor pathway inhibitor (ARPI) + PARPi. Saad et al. recently presented a detailed safety analysis from the PROpel trial to address these concerns (6) and reported adverse events (AEs) (all grades) that were more frequent in the olaparib plus abiraterone arm compared to the placebo plus abiraterone arm included anaemia (46.0% vs. 16.4%), nausea (28.1% vs. 12.6%), fatigue (27.9% vs. 18.9%) and venous thromboembolism (VTE) (7.3% vs. 3.3%). The toxicity profiles observed in the TALAPRO-2 and MAGNITUDE trials were broadly similar but with some key differences to PROpel (Table 1). Table 1 includes updated data for PROpel.
Table 1
| Variable | PROpel | TALAPRO-2 | MAGNITUDE | |||||
|---|---|---|---|---|---|---|---|---|
| Olaparib + abiraterone | Placebo + abiraterone | Talazoparib + enzalutamide | Placebo + enzalutamide | Niraparib + abiraterone | Placebo + abiraterone | |||
| TRAE grade ≥3 | 56% | 43% | 75% | 45% | 72% | 49% | ||
| SAE | 40% | 32% | 39% | 27% | 44% | 29% | ||
| Most common all-cause adverse events (≥30% patients) | ||||||||
| Anaemia | 50% | 18% | 66% | 17% | 50% | 23% | ||
| Fatigue | 39% | 30% | 34% | 29% | ||||
| Neutropenia | 36% | 7% | ||||||
| Hypertension | 33% | 22% | ||||||
| Nausea | 31% | 14% | ||||||
| Constipation | 33% | 16% | ||||||
| Thrombocytopenia | 25% | 3% | ||||||
| Most common grade 3–4 AE (≥10% patients) | ||||||||
| Anaemia | 16% | 3% | 46% | 4% | 30% | 9% | ||
| Neutropenia | 18% | 1% | ||||||
| Hypertension | 16% | 12% | ||||||
| Anaemia (all grade/≥3) | 50%/16% | 18%/3% | 66%/46% | 17%/4% | 50%/30% | 23%/9% | ||
| Requiring red blood cell transfusion/s | 18% | 4% | 39% | 27% | 5% | |||
| Neutropenia (all grade/≥3) | 8.3% | 4% | 36%/18% | 7%/1% | 15%/7% | 7%/2% | ||
| Thrombocytopenia (all grade/≥3) | 6% | 4% | 25%/7% | 3%/1% | 23%/8% | 10%/2% | ||
| Fatigue (all grade/≥3) | 39%/3% | 30%/2% | 34%/4% | 29%/2% | 30%/4% | 19%/5% | ||
| Nausea (all grade/≥3) | 31%/<1% | 14%/<1% | 21%/<1% | 12%/<1% | 25%/<1% | 15%/<1% | ||
| Anorexia (all grade/≥3) | 17%/1% | 8%/0% | 22%/1% | 16%/1% | 16%/1% | 7%/1% | ||
| Diarrhea (all grade/≥3) | 21%/1% | 11%/<1% | 14%/<1% | 14%/0% | ||||
| Constipation (all grade/≥3) | 19%/0% | 15%/<1% | 18%/<1% | 17%/<1% | 33%/<1% | 16%/0% | ||
| Hypertension (all grade/≥3) | 15%/4% | 19%/5% | 14%/5% | 15%/7% | 33%/16% | 22%/12% | ||
| MDS/AML | MDS <1% | 0 | MDS: <1%; AML: <1% | 0 | 0 | MDS/AML <1% | ||
| VTE | 7.3% | 3.3% | 4% | <1% | ||||
| PE | 7% | 7% | 3% | 2% | 1% | |||
| Dose interruptions due to AE | 49% | 28% | 62% talazoparib/39% enzalutamide | 21% placebo/19% enzalutamide | 49% | 28% | ||
| Dose reductions due to AE | 23% olaparib/3% abiraterone | 6% placebo/4% abiraterone | 53% talazoparib/15% enzalutamide | 7% placebo/8% enzalutamide | 20% | 4% | ||
| Discontinued due to AE | 14% | 8% | 19% talazoparib/11% enzalutamide | 12% talazoparib/11% placebo | 15% | 6% | ||
| Treatment related deaths | 7% | 5% | 3% | 4% | 9% | 4% | ||
| Treatment duration (median, months) | 18.5 (olaparib); 20.1 (abiraterone) | 15.7 (placebo); 15.7 (abiraterone) | 19.8 (talazoparib); 22.2 (enzalutamide) | 16.1 (placebo); 16.6 (enzalutamide) | 17.9 (niraparib and abiraterone) | 15.2 (placebo and abiraterone) | ||
AE, adverse event; AML, acute myeloid leukemia; ARPI, androgen receptor pathway inhibitor; MDS, myelodysplastic syndrome; PARPi, poly [adenosine diphosphate (ADP)-ribose] polymerase inhibitor; PE, pulmonary embolism; SAE, serious adverse event; TRAE, treatment-related adverse event; VTE, venous thromboembolism.
Understanding the toxicity of an ARPI + PARPi combination is critical to optimal patient selection, monitoring and ultimately clinical outcomes for patients with mCRPC. A key observation in PROpel is that most AEs occurred within 6 months of initiating treatment and peaked very early at 2 months. This is in keeping with TALAPRO-2 (3), where haemoglobin levels reached a nadir between 13–15 weeks (7). Together, this data reinforces the need for close monitoring within the first 6 months after initiating an ARPI + PARPi combination, thus enabling timely dose interruptions and reductions, which potentially reduces the risk of treatment discontinuation due to an AE. In PROpel, 14% of patients treated with olaparib plus abiraterone had treatment discontinuation due to an AE, with comparable findings in the experimental arms of TALAPRO-2 (19%) (3) and MAGNITUDE (15%) (5). Of note, treatment reduction rates were higher in TALAPRO-2 (53%) than seen in PROpel and MAGNITUDE—23% and 20% respectively.
Anaemia is the most common AE seen with PARPi, whether used as monotherapy or in combination with an ARPI. Grade 3–4 anaemia was highest with enzalutamide plus talazoparib (46%) compared to olaparib plus abiraterone (16%) and niraparib plus abiraterone (30%), although 49% of all patients enrolled on TALAPRO-2 had grade 1–2 anaemia at study entry. Nevertheless, talazoparib and enzalutamide appears to have greater haematological toxicity than olaparib with grade 3–4 neutropenia, more than double in the experimental arm of TALAPRO-2 compared to PROPel (18% vs. 8.3%). This is also reflected in greater rates of packed red blood cell transfusions required in the experimental arm of TALAPRO-2 at 39%, compared with 27% in MAGNITUDE and 18% in PROpel. Talazoparib exerts the most potent PARP1 enzyme inhibition and has the highest PARP1 trapping capacity, which may explain the increased anaemia observed in TALAPRO-2 (8). Myelosuppression, in particular anaemia, is an important consideration for patient selection, and underscores the need for close monitoring as well as understanding the practical impact of anaemia on the patient’s quality of life (QoL) and resources required from the health system.
VTE events are another important AE observed in many PARPi trials. In PROpel, 7.3% of patients treated with olaparib plus abiraterone experienced a VTE, with nearly all cases (total 7%) a pulmonary embolism. All cases of VTE in the olaparib plus abiraterone arm were asymptomatic and were detected on routine re-staging scans. Importantly, no patients in the olaparib plus abiraterone arm who developed a VTE had to discontinue treatment due to this AE and only 2% had to interrupt treatment. Awareness and monitoring for potential VTE events needs to be considered for all patients receiving an ARPI + PARPi combination.
Onset of myelodysplastic syndrome (MDS) and/or acute myeloid leukaemia (AML) is a serious sequela of PARPi monotherapy, typically associated with longer-term use. The rates of MDS/AML in advanced ovarian cancer, where PARPi are an established standard treatment, have been approximated at 1–3%, though some recent studies have noted a higher incidence (4–8%) (9). With a median duration of follow-up limited to less than 27 months in both PROpel and TALAPRO-2, two cases of AML/MDS were reported in the ARPI + PARPI arm, and no cases in the experimental arm of MAGNITUDE (1 case was reported in the control arm). With longer follow up, we are likely to expect a higher incidence. This has important implications, particularly in the setting where such combinations may be prescribed earlier in the treatment landscape, where treatment duration and prostate cancer-related survival may be longer.
The safety analysis of PROpel presented by Saad et al. suggests that olaparib plus abiraterone is generally well tolerated in first-line mCRPC in the context of relatively low rates of dose reductions and treatment discontinuation due to AEs. Further, the experimental arm in PROpel was not associated with worsening health-related QoL (HRQoL) outcomes as assessed by the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire, or time to pain progression based on the Brief Pain Inventory-Short Form (BPI-SF) (10). Similar results were seen in the MAGNITUDE study for the BRCA-mutated cohort (11), and an exploratory subgroup analysis of TALAPRO-2 found that the ARPI + PARPi combination resulted in maintained or improved outcomes for all HRQoL measures assessed (12).
While most toxicities can be reliably monitored for and safely managed with supportive care, there remains a potential for delayed and serious side effects such as MDS/AML which need to be considered when selecting patients for an ARPI + PARPi combination.
Acknowledgments
None.
Footnote
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Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-209/coif). S.W. reports payments for travel and accommodation from Astellas; and financial support for attendance to ASM from ANZUP. L.K. reports honoraria from Astellas, Bayer and AstraZeneca; and serves on the advisory board for Astellas. A.A.A. reports research funding from Astellas, Merck Serono, Astra Zeneca, Bristol Myers Squibb, Astra Zeneca, Aptevo Therapeutics, Glaxo Smith Kline, Pfizer, MedImmune, Astellas, SYNthorx, Bionomics, Sanofi Aventis, Novartis, Ipsen, Exelixis, Merck Sharpe Dohme, Janssen, Lily, Gilead Sciences, Merck Serono, and Hinova; consulting fees from Astellas, Janssen, Novartis, and Aculeus Therapeutics; honoraria from Astellas, Novartis, Sanofi, AstraZeneca, Tolmar, Pfizer, Telix, Merck Serono, Janssen, Bristol Myers Squibb, Ipsen, Bayer, Merck Sharpe Dohme, Amgen, Noxopharm, Aculeus Therapeutics, and Daiichi Sankyo; support for travel and accommodation from Astellas, Merck Serono, Amgen, Novartis, Janssen, Tolmar, Pfizer, Bayer, and Hinova; serves on the advisory boards for Astellas, Novartis, Sanofi, AstraZeneca, Tolmar, Pfizer, Telix, Merck Serono, Janssen, Bristol Myers Squibb, Ipsen, Bayer, Merck Sharpe Dohme, Amgen, Noxopharm, Daiichi Sankyo, and Arvinas; serves as Chair for Urologic Oncology Group, Clinical Oncology Society of Australia; Chair for Translational Research Subcommittee, ANZUP Cancer Trials Group; Scientific Advisory Committee, ANZUP Cancer Trials Group; and receives medical writing support from Astellas, Exelixis, Pfizer. The authors have no other conflicts of interest to declare.
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Cite this article as: Williams S, Kostos L, Azad AA. Abiraterone + olaparib in metastatic castration-resistant prostate cancer: tolerable, not toxic. AME Clin Trials Rev 2025;3:38.
