Following on from Part 1 of this series, which focused on two common gynecological disorders of the uterus and endometrium—uterine fibroids and endometriosis, Part 2 will profile common types of women’s cancers— breast cancer and the main gynecological malignancies, ovarian cancer, endometrial cancer and cervical cancer.

Breast cancer: Breast cancer is the second-most commonly diagnosed cancer in women in the United States, and although improvements in survival have been made over the past decades (a result of increased screening and therapeutic options), the disease remains the second-leading cause of cancer-related death among women. Current treatment of breast cancer is guided by hormone (estrogen and progesterone) receptors [HR] and HER2 status, which predict the likely benefit of hormonal therapy and HER2-targeted therapies (Roche/Genentech/Chugai’s Herceptin, Pejeta and Kadcyla, Novartis’s Tyverb/Tykerb), respectively. Chemotherapy is a frequently used treatment option for breast cancer, irrespective of HR and HER2 status, and remains a pivotal component of treatment for many breast cancer populations, especially those with a poor prognosis and patients with triple negative disease (patient that are HR and HER2-negative).

  • Treatment for breast cancer is dictated by the stage of the disease at diagnosis. In an aim to prevent disease recurrence and increase, patients with early-stage disease (stage I-III) can receive drug treatment (with chemotherapy, hormonal therapy, or a HER2-targeted agent, depending on receptor status).
  • The aim of treatment in the metastatic setting is to extend survival, delay disease progression, but also to palliate symptoms and relieve pain. Treatment of metastatic disease also employs chemotherapy, hormone therapy, and HER2-targeted agents. Pfizer’s CDK4/6 inhibitor Ibrance is the most-recent addition to the breast cancer armamentarium, approved after demonstrating a dramatic improvement in the progression free survival of HR-positive, HER2-negative metastatic breast cancer patients.
  • Despite great advances in the development of breast cancer therapies, a significant unmet need remains. In particular, developing more efficacious treatments for advanced/metastatic disease, particularly for triple negative breast cancer, and the identification of novel biomarker-driven therapies are two of the most important unmet needs for breast cancer. Despite a swelling pipeline, emerging therapies currently in the late-phase pipeline will only reach partially address such unmet needs. They will, nevertheless, provide much-needed therapeutic options, and agents such as PARP inhibitors are generating a lot of physician interest, after showing promising efficacy in BRCA1/2-mutation-positive patients (most of whom are triple-negative). Below is a snapshot of the current late-phase pipeline for breast cancer:
Compound Status (US/EU5) Marketing Company
CDK4/6 inhibitors
Kisqali Marketed/III Novartis
Abemaciclib III Eli Lilly
PARP inhibitors
Lynparza III AstraZeneca
Talazoparib III Pfizer
Veliparib III AbbVie
Niraparib III Tesaro
PI3K/AKT/mTOR pathway inhibitors
Buparlisib III Novartis
Taselisib III Roche
Alpelisib III Novartis
Immune checkpoint inhibitors
Keytruda III Merck & Co.
Tecentriq III Roche/Genentech
Bavencio III Merck KGaA/Pfizer
HER2 inhibitors
Neratinib Pre-registration Puma Biotechnology
Tucatinib II Cascadian Therapeutics
Margetuximab III MacroGenics
Cytotoxic agents
Etirinotecan pegol III/Pre-registration Nektar Therapeutics
MM-302 II/III Merrimack Pharmaceuticals
Sacituzumab govitecan III/- Immunomedics
Glembatumumab vedotin II Celldex Therapeutics
HDAC inhibitors
Entinostat III/- Syndax Pharmaceuticals
Androgen receptor modulators
Xtandi II Medivation/Astellas
RANKL-targeting agents
Denosumab III Amgen

Ovarian Cancer: Survival rates are much lower for ovarian cancer than other cancers that affect women, largely because over 70% of ovarian cancer cases are diagnosed late, often after the cancer has spread throughout the pelvis and abdomen. For the minority of cases that are diagnosed early, the outlook is very different: a five-year survival rate of more than 90%. Unfortunately, early detection is impeded by the presence of non-specific symptoms such as abdominal bloating and the absence of an effective screening program.

  • Treatment of all stages of ovarian cancer typically includes surgery, although it is not always performed with curative intent as the majority of ovarian cancer patients are diagnosed with advanced (stage III-IV) disease. The mainstay of treatment for advanced ovarian cancer remains platinum-based chemotherapy. Although treatment can be curative for early-stage disease, for the majority of ovarian cancer patients (who are diagnosed in later-stages) their disease will recur. Recurrence is associated with a poor prognosis because of the eventual development of chemotherapy-resistant disease.
  • Recent approvals and significant pipeline developments are signaling considerable change in the management of ovarian cancer. Treatment is increasingly shifting to a targeted approach with the continued uptake of Roche/Genentech’s anti-angiogenic agent Avastin in several disease settings, as well as the approval of three poly ADP ribose (PARP) inhibitors, AstraZeneca’s Lynparza, Clovis Oncology’s Rubraca, and Tesaro’s Zejula, in an array of disease settings and patient populations.
  • The PARP inhibitors are raising the efficacy bar for developers, and have emerged as one of the most exciting drug classes for the treatment of ovarian cancer. Whilst initial PARP inhibitor approvals were confined to patients with germline or somatic BRCA1/BRCA2 mutations (found in 10-15% of ovarian cancer cases), recent data from the ENGOT-OV16/NOVA trial evaluating maintenance Zejula in recurrent platinum-sensitive ovarian cancer signaled that all ovarian cancer patients, irrespective of their BRCA status, may experience some degree of benefit from PARP inhibition. Based on these data Zejula was granted a broad, rather than biomarker-limited FDA label, expanding the eligible population for this drug beyond that of other PARP inhibitors.
  • Multiple immune checkpoint inhibitors, targeting programmed cell death ligand 1 (PD-L1) are also expected to launch over the next ten years and become another driver for the significant expansion of the ovarian cancer therapeutic market. Below is a summary of some of the key targeted drug classes approved or in late-phase development for ovarian cancer:
Compound (Brand) Status (US/EU5) Marketing Company
PARP inhibitors
Lynparza Marketed AstraZeneca
Rubraca Marketed/III Clovis Oncology
Zejula Marketed/III Tesaro
Veliparib III AbbVie
Immune checkpoint inhibitors
Bavencio III Pfizer/Merck KGaA
Tecentriq III Roche
Angiogenesis inhibitors
Avastin Marketed Roche/Genentech/Chugai
Cediranib III AstraZeneca
Fosbretabulin II/III Mateon Therapeutics
MAPK/ERK kinase (MEK) inhibitors
Mekinist II/III Novartis
Folate receptor targeting agents
Mirvetuximab soravtansine III ImmunoGen
Tumor cell vaccine
Gemogenovatucel-T III Gradalis

Endometrial Cancer: In contrast to ovarian cancer, most cases (~70%) of endometrial cancer are diagnosed at an early-stage - due to irregular vaginal bleeding - and are characterized by a favorable prognosis, often cured with hysterectomy alone. However, similarly to ovarian cancer advanced stage endometrial cancer (Stage III-IV) carries a poor prognosis and patients face the prospect of cytotoxic chemotherapy with often a limited response.

  • Treatment of endometrial cancer relies heavily on surgical procedures, hormone therapy, radiation (including brachytherapy) and chemotherapy—which can be given in combination with radiotherapy. Chemotherapy used in endometrial cancer, as in ovarian cancer, is often platinum-based. The anti-angiogenesis inhibitor, Avastin is listed as a category 2B recommendation in the NCCN guidelines for persistent or recurrent endometrial cancer. Thus even though the agent has not received regulatory approval, it may be prescribed off-label to these patients in the United States, although this practice is not common.
  • Whilst there have not been any drug approvals for endometrial cancer in over a decade, a number of potential genomic targets have been identified. One such example is the PI3K/AKT/mTOR pathway, which has been shown to be commonly mutated in endometrial tumors. Recent years have also seen many advances in immunotherapeutic approaches to treat solid tumors, and these are also being evaluated for endometrial cancer. Early phase clinical trials are ongoing and if successful they have the potential to address some of the high unmet need in this indication.
  • Unfortunately, the only agent in late-phase development for endometrial cancer- AEterna Zentaris’ Zoptarelin doxorubicin- recently failed to extend survival in advanced disease, emphasizing yet again the need for new therapies for this indication. Below is a snapshot of select therapies in clinical development for endometrial cancer:
Compound (Brand) Status (US/EU5) Marketing Company
Cytotoxic agents
Zoptarelin doxorubicin III AEterna Zentaris Inc
Folate receptor-targeting agents
Mirvetuximab soravtansine I/II ImmunoGen
Immune checkpoint inhibitors
Keytruda II Merck & Co.
Imfinzi +/-  tremelimumab II AstraZeneca
Monalizumab I/II Innate Pharma
Angiogenesis inhibitors
Lenvima/Kisplyx II Novartis/Eisai
Selective inhibitors of nuclear export (SINEs)
Selinexor II Karyopharm Therapeutics

Cervical cancer: In most developed countries, vaccination programs against the virus known to cause cervical cancer (human papillomavirus, HPV) have been introduced. Two vaccines against HPV to protect against the development of cervical cancer have been approved in the major markets covered: Merck & Co.’s Gardasil and GlaxoSmithKline’s Cervarix. Screening programs have had a significant impact on the cure rate of cervical cancer, by detecting the cancer in its early, most treatable, stage.

  • Surgery and chemoradiotherapy remain the backbone of cervical cancer management. Patients who have metastatic, recurrent, or persistent disease are typically are treated with cisplatin-based chemotherapy, which is increasingly being combined with Avastin in the first-line setting, following Avastin’s approval in August 2014 in the United States, and April 2015 in Europe. Avastin is the only branded agent in the major markets approved for treatment of cervical cancer.
  • The most critical need in the treatment of cervical cancer are for therapies for advanced, persistent, or recurrent disease. However, the low and decreasing incidence of cervical cancer in the major markets means that there is relatively little drug development specifically focusing on this indication. New systemic therapies, which offer an improved safety and tolerability profile, would also be well received; cervical cancer patients are typically younger than other cancer patients and the long-term effects of chemotherapy can be particularly debilitating.
  • Drug development in cervical cancer has historically focused on two areas: (1) small-molecule inhibitors targeting cell growth, cell survival, or angiogenesis and (2) HPV-targeting immunotherapies. Below is a snapshot of select therapies in clinical development for cervical cancer:
Compound (Brand) Status (US/EU5) Marketing Company
Therapeutic vaccine targeting HPV
Axalimogene Filolisbac (ADXS-HPV) III Advaxis Immunotherapies
Selective inhibitors of nuclear export (SINEs)
Selinexor II Karyopharm Therapeutics
Immune checkpoint inhibitors
Opdivo II Bristol-Myers Squibb

For a more in-depth analysis of breast and ovarian cancer therapies, please see Decision Resources Group’s “Breast Cancer Disease Landscape & Forecast” and “Ovarian Cancer Disease Landscape & Forecast” content.

Part 1 of DRG Perspective: A Snapshot into Current Trends and Development of New Therapeutics for Women’s Health (Part 1) – A Profile of Uterine Fibroids and Endometriosis

 

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