Krivak on PARP Inhibitors and Maintenance Therapy in Ovarian Cancer

Thomas C. Krivak, MD

Director, Ovarian Cancer Center of Excellence

Gynecologic Oncology Research

Cochair, Society of Gynecologic Oncology Research Institute

West Penn Hospital

Allegheny Health Network

Pittsburgh, PA

CASE SUMMARY

A 67-year-old patient with obesity presented to her gynecologist with chief complaints of abdominal bloating, early satiety, and nausea for 4 months.

Past medical, family, and social history

• Polycystic ovary syndrome
• Gravida 3, para 0
• 5 ft 4; body mass index on annual wellness examination was 35.3
• Never smoked
• Hypertension adequately controlled with lisinopril, 10 mg daily

Focused physical examination

• Vital signs: within normal limits; blood pressure: 122/78 mm Hg
• Abdominopelvic: abdominal fullness, noncompressible mass on palpation with shifting dullness on percussion, and palpable, firm adnexal masses

Diagnostic testing

• Contrast-enhanced CT chest/abdomen/pelvis: small-volume ascites, bilateral 8-cm adnexal masses, involvement of the peritoneum + retroperitoneal lymphadenopathy
• Cancer antigen (CA) 125: 285 U/mL
• Human epididymis protein 4 (HE4): 510 pg/mL

Primary treatment

• Exploratory laparotomy followed by omentectomy, bilateral salpingo-oophorectomy, and resection of retroperitoneal nodules for poorly differentiated stage IIIC high-grade serous carcinoma (HGSC)
• Optimal cytoreduction achieved with <1 cm of residual disease after surgery

Histopathology

• Poorly differentiated HGSC

Molecular assays

• Germline molecular testing: BRCA wild type
• Myriad myChoice CDx: homologous recombination deficiency (HRD) ≥42 (+)
• Immunohistochemistry: High nuclear p53 protein expression (> 6.07)

Treatment

• Intravenous carboplatin and paclitaxel every 3 weeks for 6 cycles
• NK1 and 5-HT3 receptor antagonists, and dexamethasone added for chemotherapy-induced nausea and vomiting prophylaxis
• The patient achieved a partial response to adjuvant chemotherapy.

Three-month follow-up evaluation

• CA 125 concentration: 140 U/mL
• HE-4 level: 320 pg/mL
• Contrast-enhanced CT: 40% reduction in adnexal masses to 5 cm in longest diameter
• Clinically no evidence of disease

Peers & Perspectives in Oncology: What are some of the key studies in the field of ovarian cancer maintenance therapy that you would recommend exploring?

KRIVAK: There are several important studies. [Key trials include] GOG-0218 [NCT00262847],¹ SOLO-1 [NCT01844986],² PRIMA [NCT02655016],³ and PAOLA [NCT02477644].⁴ GOG-0218 looked at bevacizumab [Avastin], SOLO-1 focused on olaparib [Lynparza], PRIMA was niraparib [Zejula], and PAOLA was different [and explored] a combination of olaparib and bevacizumab. Each study has a distinct treatment arm, with various combinations of targeted therapies and maintenance treatments for ovarian cancer.

In the GOG-0218 trial, the treatment arm involved bevacizumab, and the control arm received a placebo.¹ SOLO-1 compared olaparib with placebo.² PRIMA involved niraparib vs placebo, and PAOLA was a combination of olaparib and bevacizumab vs bevacizumab alone.^3,4 Unlike the other studies, PAOLA’s placebo arm was not a true placebo but involved active treatment (bevacizumab), which sets it apart from the rest.

How were patient populations stratified in these studies?

Most of these studies involved all-comer populations. SOLO-1 [was more focused], specifically targeting patients with BRCA mutations, both germline and somatic, and stage III/IV high-grade serous or high-grade endometrioid ovarian cancer.² Other trials, such as PRIMA and PAOLA, included patients with more advanced disease stages.

SOLO-1 had only 1.5% of patients who had no surgery, while PAOLA had 7%. This discrepancy is explained by patient factors—some are [older] or frail and may not be suitable candidates for surgery. These patients were instead placed on chemotherapy maintenance, which can be an appropriate approach when surgery is not feasible.

How long did maintenance therapy last in these trials?

In GOG-0218, bevacizumab was continued for 15 to 22 treatments after chemotherapy. SOLO-1 was 2 years or unacceptable toxicity. PRIMA with niraparib was 3 years until progressive disease or toxicity. PAOLA was 2 years of therapy, with 15 months of bevacizumab and 1 year of olaparib after bevacizumab.^1-4

Could you explain the results from the PAOLA study, especially in relation to HRD status?

PAOLA was a phase 3 trial of olaparib/bevacizumab vs bevacizumab.⁴ It was a 2:1 randomization, again stratified by BRCA status, and then it was retrospectively looked at by HRD status. It looked at a higher-risk group and a lower-risk group. The primary end point was [progression-free survival (PFS)] and key secondary end points were PFS2 and [overall survival (OS)]. We are always going to be looking at quality of life in these trials as well. Bevacizumab plus olaparib is the treatment arm. Bevacizumab is the maintenance arm.

[The PAOLA study] found that adding olaparib to bevacizumab significantly improved overall survival in BRCA-mutated and HRD-positive patients, with a 10% improvement in 5-year survival rates. For patients who tested negative for HRD, there was no observed benefit from the combination therapy, highlighting the importance of HRD status in treatment decisions.

What were the key findings from the SOLO-1 study?

SOLO-1 was a pivotal trial that focused on patients with BRCA-mutated [disease], demonstrating that maintenance therapy with olaparib resulted in a 45% decrease in the risk of death.² The study showed long-term benefits with 67% to 70% of patients alive after 7 years, a remarkable achievement compared with past outcomes. Moreover, patients who received olaparib maintenance had better PFS and quality of life compared with those who received placebo.

What about the results from the PRIMA study using niraparib?

PRIMA utilized niraparib in advanced-stage ovarian cancer.³ [It enrolled] 733 patients with stage III/stage IV disease, high-grade serous, high-grade endometroid, using a 2:1 randomization. PFS and PFS2 were the key end points. The key secondary end point was overall survival and additional secondary end points were PFS2, time to subsequent therapy, as well as patient-reported outcomes.

In the overall population—this includes germline, somatic, and wild-type patients—the PFS hazard ratio was 0.62. In the HRD-positive tested population, the hazard ratio was 0.43. You can see the duration of exposure in this trial. Patients were allowed to remain on maintenance therapy for up to 3 years. The median duration of exposure was 11 months, and the majority of patients received around 12 months of maintenance niraparib.

Looking at overall survival at 3, 4, and 5 years, the outcomes were very similar. There was no OS benefit with niraparib in this group. While there was an improvement in PFS, the hazard ratio hovered around 1.0, meaning there was no significant difference in outcomes. Unlike PAOLA and SOLO-1, we did not see an OS benefit.

When looking at the prespecified groups, all the confidence intervals crossed unity with respect to PRIMA. This makes me wonder: Are patients coming off treatment due to progression, or due to toxicity? It is a question we need to examine further in the data. If patients are going to be on maintenance therapy, it needs to be prolonged, with low [adverse events] and good tolerability, so they can complete the intended 2 to 3 years of treatment.

What can you discuss regarding safety throughout the trials?

Adverse events varied across the studies. Common [adverse events] included fatigue, gastrointestinal issues, and renal concerns, especially with niraparib. Bevacizumab and olaparib had adverse events such as dyspnea and cough, with rare cases of pneumonitis. Niraparib, in particular, was associated with significant thrombocytopenia, leading to some dose reductions. Overall, it’s essential to manage adverse events effectively to allow patients to continue maintenance therapy for optimal results.

How do you interpret the differences in survival among these trials?

Looking at PFS and median follow-ups for these patients, it is encouraging to see a long median follow-up—62 months, 64 months, even up to 90 months. Patients are living longer, allowing for robust follow-up data. You can see the percentage of HRD-positive and HRD-negative patients in each trial. In SOLO-1, almost all patients were HRD-positive.

Examining the hazard ratios for PFS and OS across PAOLA, PRIMA, and SOLO-1, we see a significance in PAOLA and SOLO-1, but PRIMA shows PFS benefit without an OS benefit. This is quite different compared with olaparib. The PRIMA data was just presented at [the European Society of Medical Oncology Congress] in September, and many of us are still processing how we will use PARP inhibitors—determining which PARP to use, when to use it, and how to [treat patients with] HRD-negative, HRP, and BRCA-mutated disease, along with potential adverse events. There are a lot of data and different end points to consider, including crossover effects.

What is the takeaway from these trials?

The key question is: Which outcomes matter most? Are the studies designed primarily for PFS? Is PFS the better end point because OS is complicated by post-progression treatments? How many patients crossed over or received additional treatments? Or is OS the critical measure, given that 2 upfront ovarian cancer trials have shown OS improvement?

There was consistency in PFS, PFS2, and response rates across PAOLA, SOLO-1, and PRIMA. However, when looking at OS, we see stark differences in patients with BRCA-mutated and HRD-positive disease.

_REFERENCES

_{1. Tewari KS, Burger RA, Enserro D, et al. Final overall survival of a randomized trial of bevacizumab for primary treatment of ovarian cancer. J Clin Oncol. 2019;37(26):2317-2328. doi:10.1200/JCO.19.01009}

_{2. DiSilvestro P, Banerjee S, Colombo N, et al; SOLO1 Investigators. Overall survival with maintenance olaparib at a 7-year follow-up in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation: the SOLO1/GOG 3004 trial. J Clin Oncol. 2023;41(3):609-617. doi:10.1200/JCO.22.01549}

_{3. Monk BJ, Barretina-Ginesta MP, Pothuri B, et al. Niraparib first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer: final overall survival results from the PRIMA/ENGOT-OV26/GOG-3012 trial. Ann Oncol. 2024;35(11):981-992. doi:10.1016/j.annonc.2024.08.2241}

_{4. Ray-Coquard I, Leary A, Pignata S, et al; PAOLA-1/ENGOT-ov25 investigators. Olaparib plus bevacizumab first-line maintenance in ovarian cancer: final overall survival results from the PAOLA-1/ENGOT-ov25 trial. Ann Oncol. 2023;34(8):681-692. doi:10.1016/j.annonc.2023.05.005}