Ovarian Cancer Awareness Month: Strides in Up-front and Maintenance Therapy

Gizelka A. David-West, MD

Most women who receive a diagnosis of ovarian cancer present with advanced stage disease (International Federation of Gynecology and Obstetrics stage IIIC or IV). This is due to vague symptomatology that often leads to misdiagnosis or delayed diagnosis, and lack of screening tests for the general population. Over the past several years, investigators have focused on treatment of advanced stage disease and recurrent disease, and there have been promising outcomes where women with ovarian cancer are living with longer disease-free intervals. The most compelling changes to treatment algorithms have been in the up-front treatment of this disease and in the use of maintenance therapy.

In 2016, the Society of Gynecologic Oncology (SGO) and the American Society of Clinical Oncology (ASCO) published a clinical practice guide in response to the practice-changing use of neoadjuvant chemotherapy (NACT) for newly diagnosed stage IIIC or IV epithelial ovarian cancer.¹ In this guide, 4 phase 3 randomized controlled trials (RCTs) were highlighted, and their published results demonstrated either the noninferiority of NACT to primary cytoreductive surgery (PCS) or the decreased invasiveness of NACT compared with PCS, or both.^2-5 It is important to note, however, that these RCTs have been criticized for the lower-than-expected median overall survival (OS) and rates of optimal PCS, leading to some controversy and the consensus that the treatment decision for women with advanced ovarian cancer must be a collaborative one with medical oncology, gynecologic oncology, and the patient. The algorithm for the clinical evaluation and treatment of stage IIIC or IV ovarian cancer highlights the collaborative approach to treatment and that PCS is still preferred and recommended if the treating gynecologic oncologist determines that an optimal resection (R=0 or R≤1 cm) is highly likely based on tumor characteristics.¹

Choosing Chemotherapy and Number of Cycles

Another aspect of the decision to prescribe NACT that deserves attention is the choice of cytotoxic regimen and number of cycles. Based on the prospective data from the 4 RCTs, the most commonly used regimen was carboplatin and paclitaxel, which was given every 3 weeks. Consideration for weekly paclitaxel or the use of bevacizumab (Avastin) in combination with carboplatin and paclitaxel in this setting have been made based on data from JGOG3016 (NCT00226915) and GOG-0262 (NCT01167712) trials; however, those regimens have not been prospectively studied in NACT trials. This is where the art of medicine and employing a personalized treatment plan come into play. One size does not fit all, and in the patient presenting with stage IV disease with large pleural effusions, ascites, and a high tumor burden, the addition of bevacizumab to the platinum doublet is justified based on data from GOG-0218 (NCT00262847), which demonstrated a benefit in such high-risk cases.⁶

Regarding the number of cycles to prescribe, all 4 RCTs investigated either 3 or 4 cycles of NACT followed by interval cytoreductive surgery (ICS) and 3 cycles after ICS. Prospective data have not explored administration of 6 cycles followed by ICS, therefore it is imperative that treating medical oncologists establish a relationship with gynecologic oncologists prior to the start of treatment and regularly monitor the patient’s response to NACT using cancer antigen 125, clinical examination, and imaging so that coordination of care can be streamlined, and patients can receive their ICS at the appropriate time interval.

Hyperthermic Intraperitoneal Chemotherapy

Since the SGO and ASCO guide was published, an RCT was conducted on the utilization of hyperthermic intraperitoneal chemotherapy (HIPEC) at the time of ICS in patients with stage III ovarian cancer who received NACT.⁷ Because the peritoneal cavity is the primary site of disease recurrence, the use of intraperitoneal chemotherapy was investigated in GOG-172 (NCT00003322), in which an OS advantage of 15.9 months was demonstrated when intraperitoneal chemotherapy was compared with intravenous (IV) regimens.⁸

In GOG-0262, that survival advantage was not obtained.⁹ Given the conflicting results but maintaining there is a biologic benefit to intraperitoneal therapy, HIPEC was reexplored for the NACT patients. The survival curves for surgery plus HIPEC vs surgery alone show a longer median recurrence-free survival of 3.5 months, and a longer median OS of 11.8 months was seen in the surgery plus HIPEC group. The concern most providers have with utilization of HIPEC is 2-fold: adverse events profile and a determination of whether it is advantageous for stage IV disease. Based on the data from van Driel et al, adverse events of grades 3 or 4 were similar in both groups, at a rate of 27% in the surgery plus HIPEC group and 25% in surgery alone group.⁷ This study only evaluated patients with stage III disease, and to date there are no prospective data for HIPEC in patients with stage IV disease who received NACT. Given the positive results and the biology of this disease, medical oncologists and gynecologic oncologists should consider HIPEC in the treatment armamentarium when indicated.

Maintenance Therapy

Although up-front treatment for advanced ovarian cancer is very effective, approximately 70% of patients will have disease recurrence within 5 years of receiving a diagnosis. Therefore, a major change in the treatment landscape has been a focus on maintenance therapy. In the past decade, there has been a rise of 2 major players in the maintenance arena: bevacizumab and PARP inhibitors (PARPi). GOG-0218 and ICON7 (NCT00483782) were phase 3 RCTs that showed a progression-free survival (PFS) advantage when bevacizumab was used in frontline treatment of advanced ovarian cancer and continued as maintenance therapy for 10 to 12 months.^6,10 When PARPi came to the forefront, it initially was approved as maintenance therapy for platinum-sensitive recurrent ovarian cancer, irrespective of biomarker status.

Three phase 3 RCTs—NOVA/ENGOT-OV16 (NCT01847274), SOLO-2/ENGOT-OV21 (NCT01874353), and ARIEL3 (NCT01968213)—demonstrated improvements in PFS and led to regulatory approval of niraparib (Zejula), olaparib (Lynparza), and rucaparib (Rubraca), respectively.¹¹ In the final analysis of SOLO-2, the effect of olaparib on OS was investigated and the study found a median OS benefit of 12.9 months in favor of olaparib.¹² The authors concluded that, although this did not reach statistical significance, this OS advantage was clinically meaningful for patients with BRCA1/2 mutations with platinum-sensitive relapsed ovarian cancer.

More recent investigations have explored the use of PARPi in the frontline setting with even more compelling results. The 4 phase 3 RCTs that have paved the way for the use of PARPi as maintenance therapy after frontline treatment are SOLO-1 (NCT01844986), PAOLA-1/ENGOT-OV25 (NCT02477644), PRIMA/ENGOT-OV26 (NCT02655016), and VELIA/GOG-3005 (NCT02470585), investigating olaparib, olaparib plus bevacizumab, niraparib, and veliparib, respectively.¹¹

The patient population in SOLO-1 was BRCA1/2 mutated, where the other 3 trials evaluated an “all comers” population of BRCA1/2 mutated, non–BRCA mutated, homologous recombination deficiency (HRD) positive, HRD positive non–BRCA mutated, and HRD negative. Each trial evaluated patients on PARPi for up to 2 or 3 years. Mirza et al showed a clear and concise display of the efficacy of PARPi as maintenance therapy after frontline treatment of advanced ovarian cancer.¹¹ The general theme is improved median PFS in favor of PARPi for all, but it was more pronounced in the BRCA1/2-mutated or HRD-positive cohorts. At the virtual SGO 2021 Annual Meeting, 5-year follow up results from SOLO-1 were presented and revealed median PFS of 56 months vs 14 months, favoring olaparib maintenance in the BRCA1/2 population.¹³ This long-term data found a 63% reduction in risk of progression or death in patients who used PARPi maintenance after achieving a complete response to frontline treatment with surgery and chemotherapy.

As remarkable as these data are and the glimmer of hope they give to prolonging life without disease for patients with advanced ovarian cancer, it is important to remember that nothing comes without risk. Data on the tolerability of olaparib from SOLO-1 long term follow-up found no new safety signals, the occurrence of adverse events early in the maintenance therapy course allowing for early management and less discontinuation, and the risk of myelodysplastic syndrome and acute myeloid leukemia remained less than 1.5%.¹⁴ PARPi should be prescribed with great care. National Comprehensive Cancer Network guidelines to perform genetic testing on all patients with a history of ovarian cancer should be followed.¹⁵ This is because, although there is a PARPi for all comers, it cannot be denied that the benefit is more pronounced in patients with BRCA1/2 mutations and with HRD-positive status, making it more acceptable to risk the known PARPi adverse events and long-term risk of myelodysplastic syndrome and acute myeloid leukemia.

With 2 drug classes as options for patients in the maintenance setting, treating oncologists are faced with the question: “Which drug do I prescribe?” Again, this is the art of medicine, and knowing the patient and their disease will allow for the best sequencing strategy and hopefully a prolonged PFS. Mirza et al offer treatment algorithms for consideration based on BRCA and HRD status. The authors state that the subgroup inferences should be considered with caution as they have not been validated in prospective trials.¹¹

Moving Forward in the Ovarian Landscape

In this past decade, there have been great strides in the advancement of ovarian cancer treatment, particularly toward a more personalized medicine approach. Treatment plans can be tailored to decrease morbidity of surgery in frail patients with NACT or to offer PARPi maintenance therapy thoughtfully to the patients who will benefit the most. These successes make the future of ovarian cancer treatment hopeful. When the world was faced with the devastating COVID-19 pandemic, and most things came to a standstill, research efforts and clinical trials prevailed, and there is much on the horizon. Investigations for early detection tests for ovarian cancer and the utility of immunotherapy in the treatment of recurrent ovarian cancer are underway. Clinical trials are always an option and are the best way to decrease disparity in care and make clinically meaningful advances in the treatment and hopeful cure of ovarian cancer.

_References:

_{1. Wright AA, Bohlke K, Armstrong DK, et al. Neoadjuvant chemotherapy for newly diagnosed, advanced ovarian cancer: Society of Gynecologic Oncology and American Society of Clinical Oncology Clinical practice guideline. J Clin Oncol. 2016;34(28):3460-3473. doi:10.1200/JCO.2016.68.6907}

_{2. Vergote I, Tropé CG, Amant F, et al. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med. 2010;363(10):943-953. doi:10.1056/NEJMoa0908806}

_{3. Kehoe S, Hook J, Nankivell M, et al: Primary chemotherapy versus primary surgery for newly diagnosed advanced ovarian cancer (CHORUS): an open-label, randomised, controlled, non-inferiority trial. Lancet. 2015;386(9990):249-257. doi:10.1016/S0140-6736(14)62223-6}

_{4. Fagotti A, Ferrandina MG, Vizzielli G, et al. Randomized trial of primary debulking surgery versus neoadjuvant chemotherapy for advanced epithelial ovarian cancer (SCORPION-NCT01461850). Int J Gynecol Cancer. 2020;30(11):1657-1664. doi:10.1136/ijgc-2020-001640}

_{5. Onda T, Satoh T, Saito T, et al; Japan Clinical Oncology Group. Comparison of treatment invasiveness between upfront debulking surgery versus interval debulking surgery following neoadjuvant chemotherapy for stage III/IV ovarian, tubal, and peritoneal cancers in a phase III randomised trial: Japan Clinical Oncology Group Study JCOG0602. Eur J Cancer. 2016;64:22-31. doi:10.1016/j.ejca.2016.05.017}

_{6. Burger RA, Brady MF, Bookman MA, et al; Gynecologic Oncology Group. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 2011;365(26):2473-2483. doi:10.1056/NEJMoa1104390}

_{7. Van Driel WJ, Koole SN, Sikorska K, et al. Hyperthermic intraperitoneal chemotherapy in ovarian cancer. N Engl J Med. 2018;378(3):230-240. doi:10.1056/NEJMoa1708618}

_{8. Armstrong DK, Bundy B, Wenzel L, et al; Gynecologic Oncology Group. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006;354(1):34-43. doi:10.1056/NEJMoa052985}

_{9. Chan JK, Brady MF, Penson RT, et al. Weekly vs. every-3-week paclitaxel and carboplatin for ovarian cancer. N Engl J Med. 2016;374(8):738-748. doi:10.1056/NEJMoa1505067}

_{10. Oza AM, Cook AD, Pfisterer J, et al; ICON7 trial investigators. Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomised trial. Lancet Oncol. 2015;16(8):928-936. doi:10.1016/S1470-2045(15)00086-8}

_{11. Mirza MR, Coleman RL, González-Martín A, et al. The forefront of ovarian cancer therapy: update on PARP inhibitors. Ann Oncol. 2020;31(9):1148-1159. doi:10.1016/j.annonc.2020.06.004}

_{12. Pujade-Lauraine E, Ledermann JA, Selle F, et.al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18(9):1274-1284. doi:10.1016/S1470-2045(17)30469-2}

_{13. Bradley W, Moore K, Colombo N, et al. Maintenance olaparib for patients with newly diagnosed advanced ovarian cancer and a BRCA mutation: 5-year follow-up from SOLO1. Presented at: Society of Gynecologic Oncology 2021 Virtual Annual Meeting on Women’s Cancer; March 19-25, 2021; virtual.}

_{14. Colombo N, Moore K, Scambia G, et.al. Tolerability of maintenance olaparib in newly diagnosed patients with advanced ovarian cancer and a BRCA mutation in the randomized phase III SOLO1 trial. Gynecol Oncol. August 2, 2021. Online ahead of print. doi:10.1016/j.ygyno.2021.07.016}

_{15. NCCN. Clinical Practice Guidelines in Oncology. Ovarian cancer including fallopian tube cancer and primary peritoneal cancer, version 2.2021. Accessed August 20, 2021. https://bit.ly/2WghTSc}