Cancer is characterized by a breakdown of multiple biological pathways. This has led to the development of therapies to target various individual pathways alone or in combination. Currently, there are several combination therapy (CT) regimens in oncology with clinical benefits beyond monotherapy. Yet, combining multiple on-patent treatments poses varied challenges wherein manufacturers are unable to demonstrate through existing health technology assessment (HTA) processes that the value of using such CTs is commensurate with observed clinical benefits, and payers are challenged to accommodate the cost of expensive CTs. Similar to many healthcare systems (HCS) worldwide, the Canadian HCS includes HTA designed for single manufacturer submissions. The result is clinically effective CTs exceeding incremental cost-effectiveness ratios even if add-on therapies were available at zero cost. These challenges are exacerbated in the Canadian HCS due to: (i) lack of defined frameworks (i.e., through clinical trials, HTA and beyond) for attributing value to each constituent therapy, (ii) lack of mechanisms to revisit prices for existing therapies to accommodate add-on therapies, (iii) involvement in price determination by multiple agencies, including the pan-Canadian Pharmaceutical Alliance, and the Patented Medicine Prices Review Board, and (iv) legal challenges of different CT patent holders negotiating collectively with payers. Without addressing these challenges, existing frameworks have potential to disincent innovation and limit patient access to current and future innovations. All stakeholders in the healthcare ecosystem (payers, manufacturers, and health review agencies) need to acknowledge the shared problem and work towards pragmatic consensus solutions. Newly aligned models addressing both near- and long-term implementation issues, and acknowledging opportunity costs for patients and HCS, should be explored to ensure that optimal health benefits from global innovations in oncology can be accessed by Canadian patients in a timely manner.