The Long and Winding Road

The long and arduous road of the development of poly(ADPribose) polymerase inhibitors (PARP inhibitors) has been the epitome of potential difficulties with the drug approval process, especially for niche treatments that may affect only small populations and provide limited economic returns. After the publication of two seminal papers in 2005 that showed BRCA1and BRCA2-deficient cells were highly sensitive to PARP inhibition in preclinical models, multiple phase I and II clinical trials of different PARP inhibitors revealed promising results in patients with breast and ovarian cancer with BRCA1/2 associated malignancies. Activity was also reported in high-grade serous ovarian cancer suggesting that these tumors harbored “BRCAness.” In addition, early data led to the belief that these agents may be active in other BRCA1/2-associated malignancies such as prostate cancer. Despite the promising reports, there has been a slow development path for PARP inhibitors, but the story has recently been rejuvenated with multiple pharmaceutical companies currently running phase III trials, most notably in ovarian and BRCA1/2-related breast cancer. In the article that accompanies this editorial, Kaufman et al, report a multicenter, single-stage efficacy and safety study of the PARP inhibitor olaparib. With tumor response rate as the primary efficacy outcome, 298 patients with advanced germline BRCA1/2-associated malignancies across multiple tumor sites were enrolled (193 ovarian, 62 breast, 23 pancreatic, eight prostate, 12 other). This was a heterogeneous group of patients in terms of both tumor type and number of prior treatments. Response rates in patients with ovarian cancer were similar to those reported previously at 31.1%. The tumor response rate of 12.9% seen in patients with breast cancer in this study is lower than previously reported (Tutt et al reported an objective response rate of 41%), which may reflect prior treatment exposure. A poorer response rate was seen in those with prior platinum therapy (9.5%) compared with those without prior platinum therapy (20%) giving further evidence that similar resistance mechanisms may play a role, although this study did not quantify clinical platinum resistance. The real gem of this study, however, was the activity of olaparib in BRCA1/2-associated pancreatic cancer, with a tumor response rate of 21.7%, despite an average of two prior lines of systemic chemotherapy in this small group of patients. This study was not designed nor powered to compare response rates of olaparib to current standard treatments. These results represent the largest cohort to date in a study of BRCA1/2-associated pancreatic cancer and warrant further study. Phase I and II studies in this specific patient population are underway. A controversial feature of this study is the trial design, which has no formal hypothesis and a statistical analysis that is only descriptive in nature. Classic phase II trials are designed to evaluate the short-term therapeutic effect of a drug in a targeted group of patients using a sample size that is calculated on the expected clinical efficacy and incorporating the likelihood of type I and II errors. This trial has no formal sample size calculation and therefore could be considered an observational study, the results of which may be considered as hypothesis generating. Is this design idiosyncratic to this study, or is it a harbinger of trials to come? In the case of olaparib, multiple phase I and II studies in advanced BRCA1/2-associated malignancies have already been conducted, and there are other nuances that stand out apart from pure statistics that contribute to this trial’s credibility. Olaparib has had a long gestation, and this study afforded an opportunity for clinical researchers to gain experience across multiple tumor sites as well as to provide access to the agent for BRCA mutation carriers with advanced malignancies. This study design may also support other studies that determine eligibility with a genomic marker rather than a site of origin. With the shift of cancer drug development to molecularly targeted therapies and the increasing understanding of genomic alterations that underlie and promote malignant phenotypes, the “basket” study design is potentially an efficient tool to provide evidence of biologic activity across a wide number of malignancies to help determine further avenues of development. It is not simple, however, as common molecular events that are found across multiple tumor sites may not translate into similar responses to specific therapeutic agents. Trastuzumab, which is active in human epidermal growth factor receptor 2 (HER2) –overexpressed breast and gastric cancer, does not appear to have the same activity in HER2-overexpressed ovarian and endometrial cancer. Similarly, vemurafenib, which is active in BRAF-mutated melanoma, is not as active in BRAF-mutated colon cancer. Should these studies be limited to specific genetic alterations? By the nature of the function of BRCA1/2, it stands to reason that targeting this molecularly defined genomic alteration, as opposed to targeting the organ of origin, should work across different tumor types. PARP-1 is involved in the base excision repair (BER) pathway, and its inhibition leads to persistent single-strand DNA breaks that can deteriorate during DNA replication to form double-strand DNA breaks. Without PARP-1, mechanisms exist via homologous recombination (HR), a major role of BRCA1/2 in all human cells, to repair doublestrand breaks. However, in BRCA1/2-deficient cells, the combination of PARP inhibition and loss of HR by BRCA1/2 leads to unsustainable genetic damage and cell death or, “synthetic lethality.” Therefore, with JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 3 JANUARY 2

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.