Olaparib in combination with pegylated liposomal doxorubicin for platinum-resistant ovarian cancer regardless of BRCA status: a GEICO phase II trial (ROLANDO study)

Poly-adenosine diphosphate ribose polymerase (PARP) inhibitors (PARPi) are approved for BRCA1/2 carriers with HER2-negative breast cancer in the adjuvant setting with a high risk of recurrence as well as the metastatic setting. However, the indications for PARPi are broader for patients with other cancer types (e.g., prostate and ovarian cancer), involving additional biomarkers (e.g., ATM, PALB2, and CHEK) and genomic instability scores. Herein, we summarize the data on PARPi and breast cancer and discuss their use beyond BRCA carriers.

Section: Discussionmentioning

confidence: 99%

PARP Inhibitors for Breast Cancer: Germline BRCA1/2 and Beyond

Menezes

Raheem

Mina

et al. 2022

“…Regarding PARPi, olaparib monotherapy was approved by the FDA for patients treated with three or more lines based on the results (ORR of 34% and median PFS of 7.9 months) of a series of patients with BRCA mutations and platinum-resistant disease [ 30 ]. In the ROLANDO trial [ 31 ], olaparib combined with pegylated liposomal doxorubicin was assessed in platinum-resistant ovarian cancer and showed an ORR of 29%. However, the number of prior therapy lines was limited to a maximum of four, with at least one previous platinum-sensitive relapse, and BRCA mutations were present in 16% of patients compared with 7% of patients in the present study.…”

Section: Discussionmentioning

confidence: 99%

“…The lack of predictive power of HRR gene mutations could be explained by differences regarding the characteristics of the population, given that the population is composed principally of patients with HGS ovarian cancer who have been heavily pretreated and a lower frequency of BRCA mutations compared with other series. Recent reports have evidenced that mainly cases harboring BRCA mutations and, marginally, other HRR genes, such as RAD51C conferred sensitivity to PARPi [ 31 , 32 ]. Clinical and methodological issues might also have an impact on the results.…”

Section: Discussionmentioning

confidence: 99%

“…However, only two of them have been commercially approved: Myriad MyChoice ® and the one from Foundation Medicine ® . Even if both approaches have been extensively validated [ 6 , 31 ], developing an in-house tool adapted to our requirements and being able to establish the GI based on different parameters were advantages. Additionally, for the mutational analysis, we assessed the whole-genome CNV phenotype and adjusted an in-house pipeline to interrogate and define the GI patterns with regard to the combined treatment response.…”

Section: Discussionmentioning

confidence: 99%

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Phase 2 Trial (POLA Study) of Lurbinectedin plus Olaparib in Patients with Advanced Solid Tumors: Results of Efficacy, Tolerability, and the Translational Study

Poveda

López-Reig

Oaknin

et al. 2022

We hypothesized that the combination of olaparib and lurbinectedin maximizes DNA damage, thus increasing its efficacy. The POLA phase 1 trial established the recommended phase 2 dose of lurbinectedin as being 1.5 mg (day 1) and that of olaparib as being 250 mg/12 h (days 1–5) for a 21-day cycle. In phase 2, we explore the efficacy of the combination in terms of clinical response and its correlation with mutations in the HRR genes and the genomic instability (GI) parameters. Results: A total of 73 patients with high-grade ovarian (n = 46), endometrial (n = 26), and triple-negative breast cancer (n = 1) were treated with lurbinectedin and olaparib. Most patients (62%) received ≥3 lines of prior therapy. The overall response rate (ORR) and disease control rate (DCR) were 9.6% and 72.6%, respectively. The median progression-free survival (PFS) was 4.54 months (95% CI 3.0–5.2). Twelve (16.4%) patients were considered long-term responders (LTR), with a median PFS of 13.3 months. No clinical benefit was observed for cases with HRR gene mutation. In ovarian LTRs, although a direct association with GI and a total loss of heterozygosity (LOH) events was observed, the association did not reach statistical significance (p = 0.055). Globally, the total number of LOHs might be associated with the ORR (p =0.074). The most common grade 3–4 toxicities were anemia and thrombocytopenia, in 6 (8.2%) and 3 (4.1%) patients, respectively. Conclusion: The POLA study provides evidence that the administration of lurbinectedin and olaparib is feasible and tolerable, with a DCR of 72.6%. Different GI parameters showed associations with better responses.

“…Among PARP inhibitors, olaparib and veliparib in combination with chemotherapy, have been the most investigated. Hematological AEs represented the main toxicities in early phase non-randomized trials, with different incidence and severity according to the safety profile of the chemotherapeutic partner [ 90 , 91 , 92 , 93 , 94 , 95 ]. However, the addition of a PARP inhibitor to chemotherapy inconsistently increased the rate and grade of hematological and non-hematological AEs in randomized studies.…”

Section: Combination Regimensmentioning

confidence: 99%

Everything Comes with a Price: The Toxicity Profile of DNA-Damage Response Targeting Agents

Martorana

Silva

Sessa

et al. 2022

Targeting the inherent vulnerability of cancer cells with an impaired DNA Damage Repair (DDR) machinery, Poly-ADP-Ribose-Polymerase (PARP) inhibitors have yielded significant results in several tumor types, eventually entering clinical practice for the treatment of ovarian, breast, pancreatic and prostate cancer. More recently, inhibitors of other key components of DNA repair, such as ATR, CHK1 and WEE1, have been developed and are currently under investigation in clinical trials. The inhibition of DDR inevitably induces on-target and off-target adverse events. Hematological and gastrointestinal toxicities as well as fatigue are common with all DDR-targeting agents, while other adverse events are drug specific, such as hypertension with niraparib and transaminase elevation with rucaparib. Cases of pneumonitis and secondary hematological malignancies have been reported with PARP inhibitors and, despite being overly rare, they deserve particular attention due to their severity. Safety also represents a crucial issue for the development of combination regimens incorporating DDR-targeting agents with other treatments, such as chemotherapy, anti-angiogenics or immunotherapy. As such, overlapping and cumulative toxicities should be considered, especially when more than two classes of drugs are combined. Here, we review the safety profile of DDR-targeting agents when used as single agents or in combination and we provide principles of toxicity management.