Holloway Discusses the Rationale for PARP Inhibition in Advanced Ovarian Cancer

Robert Holloway, MD

Medical Director, Gynecologic Oncology Program

AdventHealth Cancer Institute

Orlando, FL

CASE SUMMARY

• A 49-year-old woman presented to her primary care physician complaining of abdominal bloating and nausea.
• She had a medical history of mild hypertension.
• Her mother died of breast cancer aged 59 years, and a cousin on her mother’s side died of ovarian cancer aged 65 years.
• CT scan: small-volume ascites, bilateral 8-cm adnexal masses
• Cancer antigen 125 level: 285 U/mL.
• She underwent exploratory laparotomy followed by omentectomy, bilateral salpingo-oophorectomy, and resection of peritoneal nodules for stage IIIC high-grade serous carcinoma.
• Optimal cytoreduction with less than 1 cm of residual disease after surgery

Targeted Oncology: What phase 3 trials provide the rationale for using PARP inhibitors for patients with advanced ovarian cancer?

HOLLOWAY: GOG-0218 [NCT00262847] with maintenance bevacizumab [Avastin] has been the standard of care for many years.¹ SOLO-1 [NCT01844986] [proved the use of] olaparib [Lynparza] for patients who had a BRCA mutation [in their tumor],² and the PRIMA trial [NCT02655016] looked at the use of niraparib [Zejula] in all comers who underwent homologous recombination deficiency [HRD] testing, which included a number of nested cohort analyses.³

[Looking at combination therapies], PAOLA-1 [NCT02477644] used bevacizumab plus olaparib in all comers, and all patients on the trial underwent BRCA mutation testing.⁴ Finally, the ATHENA trial [NCT03522246] looked at rucaparib [Rubraca] monotherapy vs placebo in all comers for part 1 of [the] study.⁵

Part 2 of the study goes through a complicated randomization schema with placebo/PARP inhibitor or PARP with immunotherapy, but those results won’t be out for another year or so. All the patients in the study had stage III and IV [disease]. They varied somewhat in [the number of patients who had] frontline surgery and interval surgery, but they basically are all large prospective phase 3 randomized trials testing maintenance therapy.

What do the National Comprehensive Cancer Network (NCCN) guidelines suggest for patients like this?

It’s a complicated schema that you have to read through carefully, but it does make sense. They start with patients who have stage II to IV disease, and then they dichotomize patients by whether they received bevacizumab in frontline therapy with carboplatin/paclitaxel or not.⁶ If they did not receive bevacizumab and [the tumor is] BRCA1/2 mutated, wild type, or unknown, and they had a complete response [CR] or partial response [PR] maintenance therapy, the next step could include observation, niraparib, or rucaparib.⁶ If they have a germline or somatic BRCA mutation and they have a CR or PR, then they can also receive olaparib in addition to the previously mentioned treatments as a single agent: niraparib, rucaparib, or [you should] consider observation. If they have stable disease or disease progression, then maintenance therapy is not recommended. If patients received bevacizumab and they have a BRCA1 mutation or they’re wild type or unknown and have a CR/PR and they’re found to be homologous recombination proficient, or their homologous recombination status is unknown, then they continue maintenance with bevacizumab. If they have stable disease or progression, then no maintenance therapy would be given. If they have a germline or somatic mutation and have had a response, they can receive either combination bevacizumab and olaparib, olaparib single agent, niraparib, or rucaparib.⁶ It’s a complicated schema, and I think it’s important to understand that we have many options for maintenance therapy in patients with ovarian cancer.

They should be stratified on these schemata by use of bevacizumab, frontline therapy, and then what their homologous recombination or mutation status is going forward. I’m sure [many physicians] keep the NCCN guidelines on their phone or office computer [ for quick access], and sometimes it is a bit challenging [to treat these patients in this setting], and sometimes you have to go to these schemata to understand what your options are for your patients.

What was the makeup of the PRIMA trial?

The PRIMA trial was an international trial done with the European Network for Gynaecological Oncological Trial [ENGOT] groups looking at niraparib vs placebo in [patients with] high-risk first-line ovarian cancer.³ Patients were randomly assigned 2:1 with niraparib vs placebo and were treated once daily for 36 months or until disease progression. The primary end point was progression-free survival [PFS], and the secondary key end [points were] overall survival, PFS2, and safety.

Patients were stratified based on whether they had neoadjuvant chemotherapy vs primary surgery, their best response to frontline treatment, and their homologous recombination deficient [HRD] status. Individualized starting doses occurred during the conduct of this trial and, initially, everybody started at 300 mg daily and then further into the trial they switched to weight- and platelet-based treatment measurements. So, 200 mg for patients who weighed less than 77 kg or who had a platelet count of less than 150,000 cells/uL at entry or 300 mg if they weighed more than 77 kg and had a platelet count higher than 150,000 cells/uL.

The demographics [on this trial] were essentially the same as in the olaparib trial, with a median age of about 62 years old. Most had an ECOG performance status of 0, and there were more stage IV patients. The other trial was made up of 75% patients with stage III disease and 25% stage IV in SOLO‑1,² whereas this trial is 56% stage IV patients and 36% stage III patients. About one-third of patients had neoadjuvant chemotherapy, and the majority of patients got 6 or more platinum cycles.

What were the outcomes of this trial?

The rate of primary PFS in the intent-to-treat population at 2 years was 36% on niraparib vs 22% in the placebo group, then at 4 years that trend continued at 24% vs 14%, respectively.⁷ The median PFS in the niraparib arm was 13.8 months compared with 8.2 months on the placebo arm [HR, 0.66; 95% CI, 0.56-0.79], so it had a decent HR for the intent-to-treat population. They also broke [these results] down by patients [whose tumors] were HRD positive, BRCA mutated, and BRCA wild type mutated and homologous recombination proficient [HRP].⁷

How did treatment with niraparib hold up in these subgroups of patients?

[The most benefit was seen] for patients who were homologous repair deficient and those patients with BRCA wild-type and BRCA mutated disease who were also HRD.⁷ Usually, when you look at these subgroups, the best benefit is going to be in a patient with a BRCA mutation, like in SOLO1,² and next would be those who are HRD, which will include BRCA mutation plus BRCA wild-type HRD patients.⁷

In the HRD BRCA wild-type group alone, the patient had a treatment benefit from being HRD even if they didn’t carry the BRCA mutation, but not to the same degree.⁷ For patients who were HRP, it’s hard to see a difference, and it’s really a median increase in PFS of about 3.5 months for a short period of time. So they don’t have a long-lasting benefit to PARP inhibition, which if you have no other options then clearly doubling [the patients’] PFS for that short period of time could be clinically meaningful, but my concern is what happens on retreatment and whether we are inducing platinum resistance for a group of patients that didn’t get a big benefit from the drug [in the first place].

To recap, in the HRD group the median PFS was 24.5 months with niraparib vs 10.4 months for those on placebo [HR, 0.52; 95% CI, 0.40-0.68; P < .001]…. The HRs in the overall intent-to-treat and HRD populations are very good in the HRD group with 57% reduction in disease progression.⁷ Clearly, [this is] a viable maintenance strategy with a single agent once a day PARP inhibitor. In the subgroups analysis, all patients benefited on niraparib, however, patients with stage IV disease crossed the unity line slightly and the homologous recombination unknown group crossed unity so probably had a preponderance of HRP in that group. All other subgroups by stage, age, neoadjuvant, chemotherapy, debulking status, response, and geographic region received a treatment benefit.

Were there any factors that could predict a patient’s PFS with niraparib?

Predictors of long-term PFS in niraparib-treated patients are their BRCA mutation and HRD status, primarily for those patients with stage III disease over stage IV.⁸ Looking at the primary tumor sites, primary peritoneal and the fallopian tube are rather equal predictors as opposed to ovarian, with an OR of 0.53 (95% CI, 0.21-1.33) vs 0.54 (95% CI, 0.28-1.05) vs 1.0, respectively. So about half of the OR in ovarian as the primary tumor site, which is probably reflecting BRCA mutation status, because those patients have a preponderance of fallopian tube primary, and we think that’s where the majority of these genetic tumors arise in the distal fallopian tube.

What was the toxicity profile of this therapy?

The majority of patients had grade 1 and 2 toxicities.⁷ Eighty-percent of patients got a dose interruption, and 71% got a dose reduction in this trial. Again, it’s a long-term strategy where you’re interested in keeping patients on maintenance therapy. If patients cannot tolerate the therapy and don’t stay on therapy, of course they won’t benefit and won’t achieve the results shown in the PRIMA trial. Though it’s important to understand that you can get benefits from these drugs, it does require some management, especially in the first few months when most of the dose interruptions and dose reductions occur.

It’s important that your staff stays in touch with patients on niraparib, or any PARP inhibitor, during those first few months to keep them from having adverse events that lead the patient to want to stop therapy. Thrombocytopenia is the No. 1 hematologic adverse event for niraparib as opposed to anemia for olaparib. Again, most of these occur in the first 2 or 3 months and require delay or dose reduction but you can successfully keep most patients on treatment…. It really makes it much more palatable of a treatment to avoid the severe thrombocytopenia, which can occur rather rapidly.

_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. Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018;379(26):2495- 2505. doi:10.1056/NEJMoa1810858}

_{3. González-Martín A, Pothuri B, Vergote I, et al; PRIMA/ENGOT-OV26/GOG-3012 investigators. Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2019;381(25):2391-2402. doi:10.1056/NEJMoa1910962}

_{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}

_{5. Monk BJ, Parkinson C, Lim MC, et al. A randomized, phase III trial to evaluate rucaparib monotherapy as maintenance treatment in patients with newly diagnosed ovarian cancer (ATHENA-MONO/GOG-3020/ENGOT-ov45). J Clin Oncol. 2022;40(34):3952-3964. doi:10.1200/JCO.22.01003}

_{6. NCCN. Clinical Practice Guidelines in Oncology. Epithelial ovarian cancer/fallopian tube cancer/primary peritoneal cancer, version 2.2023. Accessed October 23, 2023. https://bit.ly/3SqmagL}

_{7. González-Martin AJ, Pothuri B, Vergote IB, et al. PRIMA/ENGOT-OV26/GOG-3012 study: updated long-term PFS and safety. Ann Oncol. 2022;33(suppl 7):S789. doi:10.1016/j.annonc.2022.07.658}

_{8. Graybill W, Pardo B, O’Malley DM, et al. Predictors of long-term progression-free survival (PFS) in niraparib-treated patients (pts) from the PRIMA/ENGOT-OV26/ GOG-3012 study. J Clin Oncol. 2023;41(suppl 16):5589. doi:10.1200/ JCO.2023.41.16_suppl.5589}